Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:24][S:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CSc1ccccc1C1CCNCC1
Temperature: 60 °C
Yield: 63 %

Procedure:
A mixture of 1-benzyloxycarbonyl-4-(2-methylthiophenyl)piperidine (0.34 g) and thioanisole (0.58 mL) was treated with trifluoroacetic acid (5 mL) and the mixture was heated to 60° C. for 30 minutes. At the end of this period, the reaction mixture was evaporated and diluted with ether. Extraction with water, neutralization of the aqueous layer with sodium bicarbonate and extraction with ethyl acetate afforded the crude product. This material was purified by column chromatography; elution with 19:1 dichloromethane:methanol containing 5% triethylamine afforded the named product (0.13 g); MS: 208 (M+1): NMR: 1.4-1.8 (q, d, J1 =25, J2 =12, 2), 1.8-1.9 (m, 2), 2.46 (s, 3), 2.8-2.9 (d, t, J1 =12, J2 =2.7, 2), 3.1-3.2 (m, 1), 3.3 (br, 2), 4.0 (br, 1), 7.1-7.3 (m, 4).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:22](Cl)([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[C:1]1([NH:7][C:8](=[N:9][P:22](=[O:23])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(Nc1ccccc1)Nc1nc(-c2ccccc2)cs1
Reactant: CCOP(=O)(Cl)OCC
Solvent: ClCCl
Product: CCOP(=O)(N=C(Nc1ccccc1)Nc1nc(-c2ccccc2)cs1)OCC

Procedure:
A stirred suspension of 2.94 g (10 mmol) of 1-phenyl-3-(4-phenyl-2-thiazolyl) guanidine (dried at 110° C./0.1 mm) in 150 ml of methylene chloride was allowed to react with 2.03 g (10 mmol) of N,O-bis-(trimethylsilyl) acetamide and 1.73 g (10 mmol) of diethyl chlorophosphate for 3 months by the procedure of Example 4. The reaction mixture was evaporated to dryness then was subjected to "dry column" chromatography (method of B. Loev and M. M. Goodman, Chem. and Industry, 2026 (1967) on 500 g of silica gel, and developed with 700 ml of methylene chloride-ethyl acetate, 9/1 (v/v). A band in the Nylon® column at Rf 0.25-0.4, visualized as a dark band under ultraviolet light at 254 nm, was cut out, and extracted with chloroform-methanol, 3/1 (v/v). Evaporation of the extracts left 1.35 g of product as a pale yellow, thick syrup; NMR (CDCl3, 80 MHz) δ 1.37 (t, 6H, CH3), δ 4.11(5 peaks, 4H, OCH2), 6.98 (s, 1H, =CH--S), 7.35(m, 10H, aromatic); IR (neat) 1653 (C=N) and 1032 cm-1 (P=O); TLC (SiO2, CHCl3 --MEOH, 19/1 (v/v)) showed only one spot under UV light.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:18](=[O:19])[CH:17]2[CH:12]([CH:13]3[CH2:21][CH2:20][CH:16]2[CH2:15][CH2:14]3)[C:11]1=[O:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([Cl:40])[CH:36]=2)[N:31]=1.Cl>CN(C)C=O.ClCCl>[Cl:40][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH:10]3[C:18](=[O:19])[CH:17]4[CH:12]([CH:13]5[CH2:21][CH2:20][CH:16]4[CH2:15][CH2:14]5)[C:11]3=[O:22])[CH:5]=1)[CH:39]=[N:38]2
Reactant: CCc1ccc(O)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Temperature: 140 °C

Procedure:
To a mixture of 2-(2-ethyl-5-hydroxyphenyl)hexahydro-4,7-ethanoindene-1,3-dione (83 mg, 0.28 mmol) and anhydrous potassium carbonate (90 mg, 0.56 mmol) is added a solution of 2,6-dichloroquinoxaline (67 mg, 0.34 mmol) in anhydrous dimethylformamide (2.0 ml), and the mixture is heated at 140° C. for 40 minutes under microwave irradiation. The mixture is acidified with 2M aqueous hydrochloric acid and diluted with dichloromethane then filtered. The organic phase is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to afford 2-[5-(6-chloroquinoxalin-2-yloxy)-2-ethylphenyl]hexahydro-4,7-ethanoindene-1,3-dione.
Reaction SMILES: C(O[C@H](CCCCCCCCCC(C)C)CC(O)=O)C1C=CC=CC=1.[CH2:26]([O:33][C@H:34]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:35][C:36]([O:38]CC(C1C=CC(Br)=CC=1)=O)=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Zn]>[CH2:26]([O:33][C@H:34]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:35][C:36]([OH:38])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)CCCCCCCCCCC[C@H](CC(=O)OCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Agent: CC(C)CCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Agent: [Zn]
Product: CC(C)CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Yield: 90 %

Procedure:
In a manner similar to the synthesis of 107, compound 119 (350 mg, 0.611 mmol) was treated with zinc (<10 micron, 397 mg, 6.11 mmol) to afford 108 as an amorphous solid (207 mg, 97%). Rf=0.45 (toluene/ethyl acetate, 3/1, v/v); [α]25D=−2.5° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.34-7.26 (m, 5H, aromatic), 4.57 (s, 2H, CH2Ph), 3.87 (m, 1H, H-3), 2.64 (dd, 1H, J2a,2b=15.6 Hz, J2a,3=6.9 Hz, H-2a), 2.55 (dd, 1H, J2a,2b=15.6 Hz, J2b,3=5.1 Hz, H-2b), 1.68-1.38 (m, 3H, H-4, H-15), 1.26-1.14 [m, 20H, H-(5-14)], 0.86 (d, 6H, J15,16=6.9 Hz, H-16); 13C NMR (75 MHz, CDCl3): δ 176.95 (C═O), 138.08-127.71 (aromatic), 75.71 (C-3), 71.53 (CH2Ph), 39.47 (C-2), 39.05 (C-12), 34.12 (C-4), 22.65 (C-14). HR MS (m/z) calculated for C24H40O3 [M+Na]+, 399.2870. found, 399.2552.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:12])=CC=1)([O-])=O.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>O1CCCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:11](=[O:12])[N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])[CH2:18][CH2:17]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CNCCOC
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Product: COCCN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70.9 %

Procedure:
To piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (500 mg) in tetrahydrofuran (5 ml) was added N-(2-methoxyethyl)methylamine (254 mg) and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was reduced in vacuo and purified using flash chromatography to yield 4-[(2-methoxy-ethyl)-methyl-carbamoyl]-piperazine-1-carboxylic acid tert-butyl ester (304 mg). Treatment of this compound with HCl in dichloromethane/methanol yielded piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:8]([CH2:9][O:10][CH2:11]2)[CH:7]1[OH:22])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH:8]([CH2:9][O:10][CH2:11]2)[C:7]1=[O:22])[CH3:2]
Reactant: CCOC(=O)CC1CC2COCC(C1O)N2C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CC1CC2COCC(C1=O)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of compound 123d (960 mg, 3.0 mmol) in dichloromethane (30 mL) was added Dess-Martin reagent (2.54 g, 6.0 mmol) at 40° C. The reaction mixture was stirred for three hours, then another batch of Dess-Martin reagent (1.27 g, 3.0 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was poured into ice-water, and filtrated. The filtrate was washed with sodium bicarbonate solution and sodium sulphite solution, extracted with dichloromethane (50 mL) three times. The organic phase was dried over Na2SO4, and concentrated. The residue was purified by silica gel column to give tert-butyl 7-(2-ethoxy-2-oxo-ethyl)-6-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 125b (780 mg, yield: 80%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)(=[O:11])=[O:10].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([S:30][CH3:31])[N:21]=1.[F-].[K+]>C(#N)C>[CH3:31][S:30][C:22]1[N:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([N:14]2[CH2:15][CH2:16][C@H:12]([S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:17])([F:1])[F:18])(=[O:11])=[O:10])[CH2:13]2)[N:21]=1
Reactant: O=S(=O)(c1ccccc1C(F)(F)F)[C@H]1CCNC1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CSc1nc(N2CC[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C2)cc(C(F)(F)F)n1

Procedure:
(S)-3-(2-Trifluoromethyl-benzenesulfonyl)-pyrrolidine (500 mg) was dissolved in acetonitrile (3.5 mL) in a microwave tube. 4-Chloro-2-(methylsulfanyl)-6-(trifluoromethyl)pyrimidine (450 mg), TEA (0.75 mL) and KF (10 mg) were added. The reaction mixture was irradiated in the microwave oven at 150° C. for 1.5 h. The reaction mixture was evaporated to dryness and purified by flash chromatography (50 g silica gel, ethyl acetate/n-heptane:0:1→1:0) to yield a light yellow oil (790 mg; 94%) MS: m/z=472.2 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH2:2]([S:1][CH2:12][C:13]#[N:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: N#CCCl
Reactant: O=C(CS)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCSCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Part A. A mixture of 2-mercaptoacetophenone (6.96 g, 45.7 mmol), chloroacetonitrile (3.00 mL, 47.4 mmol), and potassium carbonate (7.21 g, 52.2 mmol) in tetrahydrofuran (100 mL) was stirred at ambient temperature for 12 hours. The mixture was poured into water (400 mL), and this was extracted with ethyl acetate (400 mL), then methylene chloride (400 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane) to afford the product, phenacylthio-acetonitrile, as a pale pink oil (7.51 g, 39.3 mmol, 86%). 1H NMR (CDCl3): δ 7.96 (2H, dd, J=8.0, 1.1 Hz); 7.65-7.56(1H, m); 7.50 (2H, t, J=7.7 Hz); 4.13 (2H, s); 3.45 (2H, s). Mass spectrum (NH3 -CI/DDIP): m/z 210 (21%); 209 (100%); 192 (2%); 170 (1%); 139 (1%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([C:19]4([F:26])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])[C:14]([CH3:28])([CH3:27])[C:11]=3[NH:12][N:13]=2)[C:5]([F:29])=[CH:4][N:3]=1.[CH3:30][C:31]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[F:26][C:19]1([C:17]([N:15]2[CH2:16][C:10]3[C:9]([NH:8][C:6]4[C:5]([F:29])=[CH:4][N:3]=[C:2]([CH:30]=[CH2:31])[N:7]=4)=[N:13][NH:12][C:11]=3[C:14]2([CH3:28])[CH3:27])=[O:18])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1
Reactant: CN1CCC(F)(C(=O)N2Cc3c(Nc4nc(Cl)ncc4F)n[nH]c3C2(C)C)CC1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: C=Cc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)C2(F)CCN(C)CC2)C3(C)C)n1
Temperature: 100 °C

Procedure:
To a pressure vessel was added starting material [3-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl]-(4-fluoro-1-methyl-piperidin-4-yl)-methanone (0.375 g, 0.881 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2 dioxaborolane (0.407 g, 2.64 mmol), Na2CO3 (0.280 g, 2.64 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.144 g, 0.176 mmol) followed by DME (10 mL) and water (2 mL). The reaction mixture was purged with argon for 2 min, then heat to 100° C. for 15 h. The volatiles were concentrated in vacuo and the residue redissolved in EtOAc (15 mL). The organic layer was washed with water (10 mL), dried over MgSO4, filtered, and concentrated to give the desired product G1(i) as a brown foam (0.35 g, 95%). Mass Spectrum: Calcd for C20H26N7OF2 (M+H): 418. Found: 418.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[C:21]([N+:26]([O-])=O)[CH:22]=[N:23]2)=[CH:18][CH:17]=1>O.ClCCl.[Br-].[Br-].C([N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1)C>[NH2:26][C:21]1[CH:22]=[N:23][C:24]2[C:19]([C:20]=1[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:18][CH:17]=[C:16]([Br:15])[CH:25]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of sodium hydrosulfite (43.35 g, 249 mmol) and potassium carbonate (38.28 g, 277 mmol) in water (300 mL) was added to a mixture of tert-butyl [4-(7-bromo-3-nitroquinolin-4-ylamino)butyl]carbamate (24.3 g, 55.3 mmol) and 1,1′-diethyl-4,4′-bipyridinium dibromide (1.03 g, 2.76 mmol) in dichloromethane (368 mL) and water (40 mL), and the reaction was stirred overnight at ambient temperature. The reaction mixture was filtered through a layer of CELITE filter aid. The aqueous filtrate was extracted with dichloromethane, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 22.4 g of tert-butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate as a brown powder.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:25][N:18]([C@H:19]([C:21]([O:23]C)=[O:22])[CH2:20]2)[C:17](=[O:26])[C@@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:25][N:18]([C@H:19]([C:21]([OH:23])=[O:22])[CH2:20]2)[C:17](=[O:26])[C@@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCC=CCS2
Agent: CC(C)(C)OC(=O)N[C@H]1CCCC/C=C/CS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Agent: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCC/C=C/CS2
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCCC=CCS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Reaction time: 15 h

Procedure:
To a solution of (3S,12R,14S,E)-methyl 12-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-11-thia-1-azabicyclo[10.2.1]pentadec-8-ene-14-carboxylate (90 mg, 0.159 mmol) in THF (1 mL) and MeOH (1.000 mL) was added pre-made solution of lithium hydroxide hydrate (20.06 mg, 0.478 mmol) in Water (1 mL). The resulting cloudy solution was stirred at room for 15 h. LS/MS showed the reaction was only half way done. Another portion of lithium hydroxide hydrate (20.06 mg, 0.478 mmol) was added, and stirred for additional 20 h. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (3S,12R,14S,E)-12-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-11-thia-1-azabicyclo[10.2.1]pentadec-8-ene-14-carboxylic acid (72 mg, 0.118 mmol, 73.8% yield) as a white foam. LC-MS (retention time: 3.10 min, method C), MS m/z 551 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.P(Br)(Br)([Br:22])=O>ClCCCl>[Br:22][C:13]1[C:12]2=[CH:19][N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=[C:11]2[C:16]([F:17])=[CH:15][N:14]=1
Reactant: O=P(Br)(Br)Br
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Solvent: ClCCCl
Product: Fc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5-oxide (2.5 g, 8.4 mmol) in DCE (55 mL) under nitrogen was added phosphorous oxybromide (7.2 g, 25.2 mmol). The reaction mixture was stirred for 30 minutes, warmed to room temperature, and stirred for a further 4 hours. The reaction was quenched with sodium carbonate (sat. aq.) and the layers were partitioned. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (927 mg, 31% yield). LCMS (Method D): RT=3.74 min, m/z: 360 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:28](=[O:29])[C:11]2=[N:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C([Sn](CCCC)(CCCC)[C:35]1[N:36]=[CH:37][S:38][CH:39]=1)CCC.[F-].[Cs+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:28](=[O:29])[C:11]2=[N:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:35]4[N:36]=[CH:37][S:38][CH:39]=4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=c1c2nn(Cc3ccc(I)cc3)c3ccccc3c-2nn1-c1ccccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2nn(Cc3ccc(-c4cscn4)cc3)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Fluorophenyl)-5-[(4-iodophenyl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 19) 25 mg, 0.050 mmol] and 4-(tributylstannyl)thiazole (28 mg, 0.076 mmole, 1.5 equiv) were dissolved in degassed N,N-dimethylformamide (1 mL) and treated with cesium fluoride (15 mg, 0.101 mmol, 2 equiv), copper(I)iodide (4 mg, 0.020 mmol, 0.4 equiv), and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol, 0.2 equiv). The mixture was stirred at ambient temperature for one hour, diluted with ethyl acetate (15 mL) and filtered. The solids were discarded, the filtrate was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (20:80 to 80:20; acetonitrile containing 0.1% trifluoroacetic acid:water containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.99 (1H, s), 8.34 (1H, d, J=8.3 Hz), 7.89 (2H, d, J=8.2 Hz), 7.69-7.55 (6H, m), 7.41 (2H, d, J=8.2 Hz), 7.32-7.24 (2H, m), 5.90 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 453.9 [(M+H)+; calculated for C25H16FN5OS: 453.4]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=2.[CH3:17][O:18][C:19]1[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=1[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C1(O)CCCCC1>[CH3:17][O:18][C:19]1[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=1[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:3]2[C:2]([Br:1])=[CH:11][C:10]3[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=3)[N:4]=2)=[CH:24][CH:23]=1
Reactant: COc1cc2ncc(Br)c(Cl)c2cc1OC
Reactant: COc1ccccc1Oc1ccc(N)cc1
Solvent: OC1CCCCC1
Product: COc1cc2cc(Br)c(Nc3ccc(Oc4ccccc4OC)cc3)nc2cc1OC
Temperature: 130 °C
Yield: 37.5 %

Procedure:
A mixture of 3-bromo-4-chloro-6,7-dimethoxyquinoline (302 mg) and 4-(2-methoxyphenoxy)-aniline (236 mg) in cyclohexanol (5 ml) was stirred and heated at 130° C. for 24 hours. The mixture was cooled to ambient temperature and then filtered. The crystals were washed first with methanol and then with diethyl ether and then dried to give 4-(2-methoxyphenoxy)-anilino-3-bromo-6,7-dimethoxyquinoline (Compound 2) (180 mg, 37%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[CH2:7][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1
Reactant: OC(c1cccc(Cl)c1)c1cc(Cl)sc1Br
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(Cc2cc(Cl)sc2Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-bromo-5-chloro-3-thienyl)(3-chlorophenyl)methanol from Example 1, Step 4 (2.50 g, 7.40 mmol) in dichloromethane at r.t. was added trifluoroacetic acid (5.70 mL, 74.0 mmol) (a red solution formed) followed by triethylsilane (5.91 mL, 37.0 mmol) (red solution turned into yellow) and the mixture was stirred at r.t. for 30 min. and concentrated. The residue was co-evaporated with toluene and then pumped under high vacuum. The crude was purified by flash chromatography (100% hexanes) to give the desired product as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH:24]=[O:25])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)(=O)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:12])[C:24]=2[OH:25])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CNN=CC(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Solvent: CC(=O)O
Product: Cn1nc(C(=O)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Oxo(phenyl)acetaldehyde methylhydrazone (5.46 mmol, 886 mg) synthesized in Reference Synthetic Example 36 and (4-t-butylphenyl)(oxo)acetaldehyde (5 mmol, 951 mg) were dissolved in acetic acid (26 mL) and stirred at 100° C. for about 2 hours. Then, the solvent was evaporated, and the residue was recrystallized from chloroform/n-hexane to give the desired product as a yellow solid (993 mg, yield 59%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[I-:14].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCCCBr)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CCCCI)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture consisting of 30.2 g (124 mmol) 1-(4-bromo-butyl)-4-methoxy-benzene, 19.2 g (128 mmol) sodium iodide and 508 ml acetone was heated to reflux temperature for 1 h. The resulting suspension was cooled to r.t. and the precipitated sodium bromide removed by filtration. The filtrate was stripped off the solvents by vacuum distillation and the residue distributed between water and diethyl ether. After drying of the organic phase over sodium sulphate, vacuum distillation gave 34.9 g (97%) of the title compound as slightly yellow coloured liquid.