Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[N+](=[CH2:20])=[N-]>>[CH3:20][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C=[N+]=[N-]
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Yield: 58 %

Procedure:
Robins et al., 1974 J. Org. Chem. 39, 1891, describe the treatment of a methanolic solution of uridine with diazomethane (in glyme) in the presence of stannous chloride dihydrate (in methanol) to synthesize 2′-O-methyluridine (58% yield). This reaction also yielded a significant fraction (28%) of 3′-O-methyluridine which is purified away from the 2′-O-methyl form by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[F:10].CON(C)[C:14]([C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]([C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc([Mg]Br)ccc1Cl
Reactant: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
0.5M (4-Chloro-3-fluorophenyl)magnesium bromide (22.5 mL, 11.2 mmol) as a solution in THF was added dropwise to a cold (0° C.) solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.45 g, 5.61 mmol) in THF (25 mL) under N2, and the reaction was allowed to warm up to room temperature overnight. The next morning, the mixture was placed in an ice bath and carefully quenched with ice. The reaction mixture was concentrated. The residue was treated for 1 hour with a solution of 30% sodium potassium and then extracted with ethyl acetate (2×). The organic layer was dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (5:1) to give (R)-tert-butyl 2-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (1.12 g, 61%). m/z (APCI-pos) (M+1)-Boc=228.1, 230.1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:9]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(#N)C.[CH:53]([C@H:55]1[CH2:60][CH2:59][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:57][CH2:56]1)=O>C1COCC1>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:53][C@H:55]2[CH2:56][CH2:57][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:59][CH2:60]2)[C:10]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Charge a flask equipped with an overhead stirrer, temperature probe, nitrogen inlet with (S)—N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-amine (5 g, 10.03 mmoles) and sodium triacetoxyborohydride (3.19 g, 15.05 mmoles) and acetonitrile (40 mL) Immerse the flask in an ice bath to cool the slurry to below about 5° C., then add (trans)-methyl 4-formylcyclohexanecarboxylate (2.99 g, 17.57 mmoles, prepared essentially according to the procedures in Houpis, I. N. et al, Tetrahedron Let. 1993, 34(16), 2593-2596 and JP490-48639) dissolved in THF (10 mL) via a syringe while maintaining the reaction mixture at or below about 5° C. Allow the reaction to warm to RT and stir overnight. Add NH4Cl (25 mL, 50% saturated aqueous solution) and separate the aqueous layer from the organic layer. The pH of the organic layer should be about 5.5. Warm the organic layer to about 45° C. and add water (16 mL). Add a seed crystal of the titled compound and cool to about 35° C. Collect the resulting solid by filtration and rinse with ACN. Dry to provide 5.80 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1ccc(-c2ccc(F)cc2)cc1
Yield: 88.8 %

Procedure:
Using 2.8 g (14.9 mmol) of 4-fluoro-4'-hydroxybiphenyl, 50 ml of acetonitrile, 2.17 g (15.6 mmol) of 3-bromopropanol and 4.11 g (30 mmol) of anhydrous potassium carbonate, synthetic treatment was carried out in the same manner as in Example 2. The obtained colorless powder was recrystallized from benzene/n-hexane to obtain 3.26 g (yield: 89%) of 4-fluoro-4'-(3-hydroxypropoxy)biphenyl (18) as a colorless powder.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.C([O-])(=O)C.[Cs+].BrC1[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][N:32]=1>[Cu]>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:11][C@H:8]([NH:7][C:6]3[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][N:32]=3)[CH2:9]2)[C:13]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Reactant: CNC(=O)c1ccc(Br)nc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Product: CNC(=O)c1ccc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Temperature: 100 °C

Procedure:
Intermediate 26 (100 mg, 0.373 mmol), cesium acetate (516 mg, 2.69 mmol), 6-bromo-n-methylnicotinamide (120 mg, 0.560 mmol), and copper (1.899 mg, 0.030 mmol) were weighed into a microwave vial. The vial was evacuated and flushed with nitrogen. DMSO (467 μl) was then added and the mixture was heated at 100° C. for 20 h. The mixture was diluted with ethyl acetate and washed with aqueous ammonium hydroxide. The aqueous layer was back extracted with ethyl acetate and the combined organics dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by silica chromatography, eluting with a gradient of hexane/ethyl acetate (50-100%) to provide 6-((trans-3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)amino)-N-methylnicotinamide (50 mg, 0.137 mmol, 36.6% yield) as off-white solid. M+1: 366. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 2.28-2.40 (m, 2 H) 3.00 (d, J=4.82 Hz, 3 H) 3.39-3.54 (m, 2 H) 4.50 (br. s., 1 H) 5.28 (quin, J=8.59 Hz, 1 H) 5.38 (br. d, J=4.80 Hz, 1 H) 5.98 (br. s., 1 H) 6.34 (d, J=8.77 Hz, 1 H) 6.96 (dd, J=7.31, 5.26 Hz, 1 H) 7.43 (dd, J=7.16, 1.61 Hz, 1 H) 7.91 (dd, J=8.70, 2.41 Hz, 1 H) 8.18 (dd, J=5.26, 1.61 Hz, 1 H) 8.51 (d, J=2.05 Hz, 1 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:21].[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[CH2:32]Cl.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:32][C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[Cl:24])=[O:19])[C:3]=1[Cl:21]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)OCc3ccc(Cl)cc3Cl)n2)c1F
Reaction time: 24 h
Yield: 35 %

Procedure:
4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared by the methods described in U.S. Pat. No. 7,314,849 B2; 828 mg, 2 5 mmol) was dissolved in DMF (4 mL). Sodium hydride (NaH, 60% disperson in mineral oil; 154 mg, 3.85 mmol) was added portion wise. To the mixture was added 2,4-dichloro-1-(chloromethyl)benzene (586 mg, 3.0 mmol). The reaction mixture was allowed to stir for 24 hours (h). Water was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated. Purification by normal phase chromatography gave a white solid (440 mg, 35%): mp 165-168° C., 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J=8.6, 7.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 5.50 (s, 2H), 4.83 (s, 2H), 3.97 (d, J=0.8 Hz, 3H); ESIMS m/z 489 ([M−H]).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([S:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)=[O:4]>CCO>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:11][CH2:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)(=[O:27])=[O:28])[CH:30]=1
Reactant: COC(=O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1
Solvent: CCO
Product: O=C(O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1

Procedure:
The title compound was prepared following the method described in Example 1, Step C, from 5-{3-[(pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino]-propyl}-thiophene-2-carboxylic acid methyl ester of Step B using EtOH in place of MeOH as solvent. 1H NMR (400 MHz, CDCl3) δ 9.12 (d, 1H, J=Hz), 8.81 (d, 1H, J=5 Hz), 8.17-7.21 (m, 9H), 6.61 (d, 1H, J=4 Hz), 4.41 (s, 2H), 3.25 (t, 2H, J=6.5 Hz), 2.72 (t, 2H, J=6.5 Hz), 1.73 (m, 2H); MS 498 (M−1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:3].[C:21]([CH2:24][C:25](=[O:27])[CH3:26])(=[O:23])[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH2:5]([O:4][C:2]([O:27][C:25]([CH3:26])=[CH:24][C:21](=[O:23])[CH3:22])=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOC(=O)OC(C)=CC(C)=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
30.4 g (0.1 mole) of n-hexadecyl chloroformate, 15 g (0.15 mole) of acetylacetone and 80 ml of diethyl ether are charged to a 250 ml flask. Then a solution of 11 g (0.11 mole) of triethylamine in 20 ml of diethyl ether is added, with stirring, at a temperature below 10° C. over 25 minutes. The mixture is warmed to room temperature and allowed to stand for 2 days. The precipitate is isolated by filtration and washed with diethyl ether. The residue is triethylamine hydrochloride (13.8 g; theory: 13.8 g). The filtrate is washed twice with water and then dried over Na2SO4. First the solution is concentrated by rotary evaporation and then the residual acetylacetone and the dietyl ether are distilled off with an oil pump, to give colourless crystals with a melting point of 33°-35° C.
Reaction SMILES: [F:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32]C(=O)OCC5C=CC=CC=5)(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:44])(=[O:43])[N:19]=3)=[C:14]([OH:45])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:46][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH2:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:43])(=[O:44])[N:19]=3)=[C:14]([OH:45])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:46][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2)OCc1ccccc1
Solvent: CO
Product: NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.7 %

Procedure:
The crude benzyl [N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-sulfamoyl]carbamate was dissolved in methanol (5 mL) and the mixture was degassed and backfilled with nitrogen (3×). Palladium on carbon (10% dry, 180 mg) was added and the mixture was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford the crude product, which was further purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)—N-{3-[3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-sulfamide (55.7 mg, 0.099 mmol, 58.7% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19-1.24 (2H, m), 1.40-1.60 (4H, m), 2.51-2.54 (1H, m), 2.64-2.65 (1H, m), 3.04 (1H, d, J=9.3 Hz), 3.53 (1H, d, J=9.3 Hz), 4.42 (1H, d, J=15.7 Hz), 4.96 (1H, d, J=15.6 Hz), 7.15 (2H, m), 7.31-7.34 (H, m), 7.43 (1H, dd, J1=9.4 Hz, J2=2.3 Hz), 7.51-7.55 (2H, m), 9.96 (1H, s). LC-MS (ESI) calcd for C24H24FN5O6S 561.12, found 562.5 [M+H+]. Anal. calcd for C24H24FN5O6S.0.5 H2O: C, 50.51; H, 4.42; N, 12.27; found: C, 50.42, H, 4.35, N, 11.90.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=[C:25]([C:33]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=C(O)c1nc(-c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)n2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.74 mmol) and 4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.6) (0.17 g, 0.50 mmol) according to the general procedure V. Obtained as a light yellow solid (0.042 g, 16%). MS (ISP) 516.1 [(M+H)+]; mp 302.5° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:5][N:6]2[C:11]=1[C:10]([CH2:12][OH:13])=[CH:9][CH:8]=[CH:7]2)[CH3:2].C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>ClCCl>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[C:3]([CH2:1][CH3:2])=[C:11]3[N:6]([CH:5]=2)[CH:7]=[CH:8][CH:9]=[C:10]3[CH2:12][O:13][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO[Si](C)(C)C(C)(C)C)c12
Reaction time: 48 h
Yield: 90.1 %

Procedure:
1-Ethyl-2-(4-benzyloxyphenyl)-8-hydroxymethylindolizine (21.3 g, 60 mmol), triethylamine (7.88 g, 78 mmol) and tert-butyldimethylsilylchloride (17.8 g, 118 mmol) was dissolved in 200 ml of dry dichloromethane, and the mixture was stirred for 2 days. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using diethyl ether as the eluent. Fractions containing the product were combined and the solvent was evaporated. The product was crystallised from diethyl ether and petroleum ether to afford 25.5 g (90%) of 2-(4-benzyloxyphenyl)-8-(tert-butyldimethylsilanyloxymethyl)-1-ethylindolizine as yellow crystals. M.p. 79-81° C. 1H--NMR (CDCl3, 200 MHz) δ: 0.01 (s, 6 H); 0.83 (s, 9 H); 1.02 (t, 3 H); 2.74 (q, 2 H); 4.92 (s, 2 H); 4.96 (s, 2 H); 6.25 (dd, 1 H); 6.61 (d, 1 H); 6.89 (d, 2 H); 7.11 (s, 1 H); 7.17-7.37 (m, 7 H); 7.59 (d, 1 H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]([CH:21]([CH3:23])[CH3:22])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[Li]CCCC>C1COCC1.CCCCCC>[C:3]([C:4]1[C:5]([CH:21]([CH3:23])[CH3:22])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)#[CH:2]
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline (25.2 mmol) in dry THF (140 ml) was cooled to -78° C. and treated with n-BuLi (1.6M in hexane, 33 ml, 52.8 mmol) over a 1 minute period. After stirring at -78° C. for one hour, the dark brown solution was quenched with saturated NH4Cl, warmed to room temperature, diluted with H2O, and extracted with Et2O. The Et2O extract was washed with brine, dried (Na2SO4), filtered and stripped to give a yellow oil. The oil was boiled in hot hexane and cooled (-15° C.) to afford 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-quinoline (5.198 gm) as yellow crystals. The mother liquor was stripped and chromatographed (flash, Merck SiO2, 4% EtOAc in hexane) to afford additional product which was recrystallized from hot hexane. A total of 6.793 gm (93%) of 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline was obtained.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH:46]1(N)[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH:46]1([NH:8][C:9](=[O:38])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:13]=[CH:12][C:11]=2[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: NC1CCCC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)NC3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (187 mg) described in Example 769 and cyclopentylamine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (87 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1.C[O-].[Na+:38]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:24]([O-:26])=[O:25])=[CH:18][CH:17]=1.[Na+:38]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](NCc2ccc(F)cc2)C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](NCc2ccc(F)cc2)C(=O)[O-])cc1

Procedure:
Compound 18 (1.57 g) was suspended in methanol (30 mL), and sodium methoxide was added to the resultant mixture until an substantially homogeneous solution was obtained. The solution was filtered, and the filtrate was concentrated. Diethyl ether was added thereto, and the resultant colorless crystals were collected through filtration and dried under reduced pressure, to thereby yield 1.57 g of the title compound.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.[CH3:30][NH:31][CH3:32]>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:31]([CH3:32])[CH3:30])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(C4CCC(=O)C4)ccc23)C1
Reactant: CNC
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(C4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (1-hydroxy-3-methylcyclohexyl methyl)-amide, and dimethylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm (VTNMR: 80° C.): 8.26-8.24 (m, 1H), 8.11-8.09 (m, 1H), 7.97-7.94 (m, 1H), 7.73-7.70 (m, 1H), 7.56-7.54 (m, 1H), 3.87-3.85 (m, 1H), 3.46-3.33 (m, 3H), 2.77-2.49 (m, 1H), 2.25-1.34 (m, 20H), 0.87-0.77 (m, 1H). m/z: 444.0 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:26]3[CH:27]=[CH:28][C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:30])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 70.0 (73%) of the title compound.