Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-4-yl)ethanone (55 mg, 0.13 mmol) was dissolved in ethanol (5 mL). Sodium borohydride (24 mg, 0.63 mmol) was added and the mixture was stirred at rt for 10 min. Acetone (2 mL) was added and the mixture was stirred for 20 min. The solvent were evaporated. The residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM to give the title compound as a solid, 40 mg (72%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2ccnn2)nc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-n2ccnn2)nc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
57.2 mg (corresponding to 0.304 mmol) of 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine was dissolved in 2.0 mL of dichloromethane and 127 μL of triethylamine, and then 78.9 μL (corresponding to 0.608 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then the reaction solution was supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 2.0 mL of tetrahydrofuran, and 54.1 mg (corresponding to 0.304 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 66.4 mg (corresponding to 0.249 mmol) of 5-(2-bromoacetyl)-2-(1H-1,2,3-triazole-1-yl)pyridine (FIG. 1, step 2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[C:16]([C:39]4[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=4)=[N:17][N:18]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:46]1[C:44]([C:42]2[S:43][C:39]([C:16]3[C:15]([C:12]4[CH:13]=[CH:14][C:9]5[N:10]([C:6]([C:2]6[S:1][CH:5]=[CH:4][N:3]=6)=[CH:7][N:8]=5)[CH:11]=4)=[CH:19][N:18]([C:20]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:17]=3)=[CH:40][CH:41]=2)=[N:45][N:48]=[N:47]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5nccs5)n4c3)c(-c3ccc(-c4nnn[nH]4)s3)n2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
100 mg 5-[4-(3-thiazol-2-yl-imidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]-thiophen-2-carbonitrile (compound in Example 440) was dissolved in 3 mL N,N-dimethylformamide, and 12 mg sodium azide and 9.5 mg ammonium chloride were added thereto and stirred at 100° C. for 18 hours in a stream of nitrogen. 24 mg sodium azide and 19 mg ammonium chloride were further added thereto and stirred for additional 24 hours. Water was added to the reaction solution which was then extracted with ethyl acetate and purified by silica gel column chromatography (ethyl acetate/hexane), to give 60 mg of the title compound (pale pink solid).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[NH:12][CH:11]=1>O1CCOCC1>[F:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Solvent: C1COCCO1
Product: Fc1ccc2[nH]cc(CCN3CCCCC3)c2c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Piperidine (3.52 g, 4.08 ml, 41.3 mmol) was dissolved in abs dioxane (100 ml), 3-(2-bromo-ethyl)-5-fluoro-1H-indole (5.00 g, 20.7 mmol) was added at RT and the mixture was stirred at 70° C. for 16 h. The solution was concentrated, the residue was taken up in CHCl3 (150 ml) and the mixture was washed with water (2×50 ml). The organic phase was dried over Na2SO4, filtered and concentrated i. vac. The residue obtained was purified by flash chromatography with 200 g of silica gel and ethyl acetate/ethanol (9:1→1:2).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:18]2[CH2:20][CH2:19]2)[C:9]=1[CH3:21])=[O:7])[CH3:4]>C(O)(=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:1])=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:18]2[CH2:19][CH2:20]2)[C:9]=1[CH3:21])=[O:7])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2ccc(O)cc12
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Bromine (277 μL, 5.40 mmol) is added to a suspension of 1-cyclopropyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (1.40 g, 5.40 mmol) in acetic acid (50 mL). The mixture is stirred for one hour at room temperature. The mixture is diluted with water and the resultant solids are filtered and washed with water. The solids are adsorbed onto silica gel and purified via flash chromatography eluting with 30% THF-heptane. The fractions are combined to yield the title compound (763 mg, 42%). ES/MS m/e 339.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1C=C([O:31]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@@H:17]([CH2:19][NH+:20]([O-:31])[C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (III-A, R1=COCH8, X1=F, X2=H) (12.5 g) is suspended in 200 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 11.5 g) is added and the resulting suspension is stirred at 25° C. for two hours. The reaction mixture is filtered and the filtrate is concentrated to afford a light-yellow solid. This material is chromatographed on silica gel using 10% methanol (saturated with ammonia) in chloroform as eluent to afford 8.75 g of the N-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:15][CH3:16])[CH:12]([OH:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:15]([CH:11]1[C:5]2[C:6](=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:23]([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[C:20]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[O:14][CH:12]1[CH3:13])[CH3:16]
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: CCC(c1ccc(OC)c(OC)c1)C(C)O
Product: CCC1c2cc(OC)c(OC)cc2C(c2ccc(OC)c(OCc3ccccc3)c2)OC1C

Procedure:
Reaction of 3-(3,4-dimethoxyphenyl)pentan-2-ol with 4-methoxy-3-(phenyl-methoxy)benzaldehyde to yield 4-(4-ethyl-6,7-dimethoxy-3-methyliso-chromanyl)-1-methoxy-2-(phenylmethoxy)benzene.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)C.[C:21]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][C:24]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(CCCCO)cc1)OC
Product: CO[C@@H](Cc1ccc(CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(4-Hydroxy-butyl)-phenyl]-2-methoxy-propionic acid ethyl ester and 4-phenylphenol following the Standard Procedure of coupling-hydrolysis A. 1H-NMR (CDCl3, 200.15 MHz): δ 7.55–7.23 (m, 7H); 7.14 (d, 4H, J=1.1); 6.93 (d, 2H, J=8.4); 4.02–3.96 (m, 3H); 3.37 (s, 3H); 3.11 (dd, 1H, J=14.3, 4.4); 2.97 (dd, 1H, J=14.3, 7.3); 2.66 (t, 2H, J=7.0); 1.83–1.80 (m, 4H). MS (ES) for C26H28O4 [M+NH4]+: 422.2, [M+Na]+: 427.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Cl.[C:15]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[C:22](Cl)=[O:23])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([CH3:13])[C:11]([O:12][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([CH3:30])([CH3:31])[CH3:32])[C:27]([OH:28])=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:20]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.4 grams of methyl 3,5-dimethyl-4-hydroxybenzoate (0.03 moles) is dissolved in 30.8 ml of a 0.99 molar toluene solution of 3,5-di-tert.butyl-4-hydroxybenzoyl chloride and heated at reflux (119° C) for 2 and 1/2 hours the evolved hydrogen chloride being swept out of the reaction by a stream of nitrogen. After this period, sufficient toluene (ca 5 to 10 ml) is removed so as to raise the reaction temperature to 128° to 132° C and heating continued under a nitrogen atmosphere for an additional 2 hours. After cooling to room temperature, the reaction mixture is dissolved in 100 ml of toluene and successively and washed with 2N aqueous sodium hydroxide and then with water until the wash waters were neutral. The washed toluene solution was dried over anhydrous sodium sulfate, filtered and the solvent removed by distillation under vacuum at 50°-60° C initially at about 20 mm Hg. and finally at 0.3 mm Hg. The resulting residue is ground to a powder and triturated with boiling hexane. The ice-cold slurry is then filtered to yield light yellow crystals, which are then recrystallized from a solvent mixture of 50 ml of toluene and 40 ml of n-hexane. The crystals were filtered, washed with same solvent mixture and dried in vacuum. Methyl-4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy)-3,5-dimethylbenzoate is then obtained as white crystals melting at 180°-182° C.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][C:9]=2N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[I-:25].[K+].S(S([O-])=O)(O)=O.[Na+]>C(Cl)Cl>[C:2]1([C:8]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][C:9]=2[I:25])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2ccccc2)ccc1-c1ccccc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])S(=O)O
Solvent: ClCCl
Product: Ic1cc(-c2ccccc2)ccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 67 %

Procedure:
3N hydrochloric acid (300 milliliters) was added to 2,5-diphenylanilin obtained in the foregoing (25 g, 101.91 mmol, 1.0 equivalent), and the mixture was stirred at 80° C. for 2.5 hours. After that, the mixture was cooled to room temperature. After that, the mixture was further cooled to 5° C. While the temperature of the mixture was kept at 10° C. or lower (5 to 8° C.), an aqueous solution of sodium nitrite (NaNO2: 8.43 g, 122.29 mmol, 1.2 equivalents, H2O: 60 milliliters) was slowly added to the mixture, and the whole was stirred for 0.5 hour. The reaction liquid was dropped into an aqueous solution of potassium iodide (KI: 60.9 g, 366.87 mmol, 3.6 equivalents, H2O: 180 milliliters). An appropriate amount of methylene chloride was further added to the mixture so that a reaction was completed, and the whole was stirred for 0.75 hour at room temperature. Sodium hydrogen dithionite was added to the reaction liquid until the color of the reaction liquid was turned into a yellow color. After that, the mixture was stirred for 0.5 hour, and the organic layer of the resultant reaction liquid was extracted. The extracted organic layer was washed with a saturated salt solution, dried with anhydrous sodium sulfate, and concentrated. The resultant residue was purified by short column chromatography (methylene chloride) and silica gel chromatography (methylene chloride:hexane=1:1→2:1), and the purified residue was dried, whereby a pale pink solid was obtained (24.35 g, yield: 67%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:21][NH:20][CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2)=[O:11].[C:22]([O:30][C:31](Cl)=[O:32])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([CH:12]1[CH2:21][N:20]([C:31]([O:30][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])[CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2)=[O:11]
Reactant: COC(=O)C1CNCCC12OCCO2
Reactant: O=C(Cl)OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC12OCCO2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
Triethylamine (29.0 mL, 208 mmol) was added to a solution of 1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (91) (16.6, 82.5 mmol) in CH2Cl2 (159 mL, 0.5 M). The solution was cooled to 0° C. in an ice bath, then benzoylchloroformate (12.8 mL, 89.9 mmol) was added dropwise, with stirring, over 40 minutes. When the reaction was judged complete by TLC (0.75 h), the solution was concentrated in vacuo and purified by silica gel chromatography (10:3 Hexanes:EtOAc) to provide pure 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (92) (23.43 g, 85%). 1H NMR (CDCl3): 7.41-7.25 (5H, m), 5.10 (2H, broad s), 4.02-3.50 (11H, m), 2.80-2.62 (1H, broad s), 2.20-2.00 (1H, broad s), 1.70-1.50 (1H, broad s) ppm. 13C NMR (CDCl3): 170.26, 154.88, 136.47, 128.32, 127.86, 127.74, 106.78, 67.09, 64.90, 64.59, 51.71, 48.63, 43.94, 41.76, 33.15 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:17]([CH3:25])[CH2:18][CH2:19][NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:34]([F:46])=[CH:33][C:32]=1[N:47]1[C:59](=[O:60])[C:58]2[S:57][C:56]3[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=3[C:50]=2[CH:49]=[N:48]1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.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]>[F:46][C:34]1[CH:33]=[C:32]([N:47]2[C:59](=[O:60])[C:58]3[S:57][C:56]4[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=4[C:50]=3[CH:49]=[N:48]2)[C:31]([CH2:30][O:29][C:26](=[O:28])[CH3:27])=[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[N:16]=[C:15]([N:17]([CH3:25])[CH2:18][CH2:19][NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:14]=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:35]=1
Reactant: C=CC(=O)NCCN(C)c1cccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C=CC(=O)NCCN(C)c1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 90 °C
Reaction time: 7 h
Yield: 71.7 %

Procedure:
A mixture of N-(2-((6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yl)(methyl)amino)ethyl)acrylamide 110f (120 mg, 0.3 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 108c (179 mg, 0.36 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol) and K3PO4 (159 mg, 0.75 mmol) in acetonitrile (5 mL) and water (1.0 mL) was stirred at 90° C. under N2 for 7 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-TLC (EA/MeOH=25/1) to give N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]-methyl-amino]ethyl]prop-2-enamide 111a (150 mg, 60%) as a light yellow solid. ESI-LCMS: m/z=698.2
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([O-:3])=[O:2].[OH-].[CH2:19]([N+:26](C)(C)C)[C:20]1C=CC=C[CH:21]=1>C(#N)C=C.CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:21][CH2:20][C:19]#[N:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([O-:3])=[O:2]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1F
Agent: [OH-]
Solvent: CO
Solvent: C=CC#N
Product: N#CCCN(c1ccccc1F)c1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 3 h

Procedure:
N-(2-Nitrophenyl)-2-fluoroaniline (17.8 g) was dissolved in acrylonitrile (100 ml), triton B (40% benzyltrimethylammonium hydroxide in methanol) (1.0 ml) was added, the mixture was stirred at 50-60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby obtain 6.37 g of the titled compound as a orange color crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45](O)=[O:46])[CH2:44][C@H:17]2[CH2:16][C:15]([F:49])([F:48])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.N1CCCN2CCCCCC=12>ClC(Cl)C>[CH:50]1([S:53]([NH:56][C:45]([C@@:18]23[CH2:44][C@H:17]2[CH2:16][C:15]([F:49])([F:48])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]4[N:30]=[C:31]5[C:36](=[C:37]6[C:42]=4[CH:41]=[CH:40][CH:39]=[CH:38]6)[CH:35]=[CH:34][CH:33]=[CH:32]5)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19]3)=[O:46])(=[O:55])=[O:54])[CH2:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Reactant: NS(=O)(=O)C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A solution of (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (215 mg, 0.316 mmol) and di(1H-imidazol-1-yl)methanone (Example 19d, 114 mg, 0.701 mmol) in dichloroethane (2 mL) was stirred for 2 h at room temperature. To this mixture was added cyclopropanesulfonamide (115 mg, 0.948 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.143 mL, 0.948 mmol, dried with 4 A sieves powder at 42° C. for 2 h prior to usage), and the solution was stirred for 2 h. The reaction mixture was diluted with ethyl acetate (7 mL) and washed with 10 mL of 0.1 N HCl followed by saturated aqueous sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure leaving 0.23 g crude solid which was purified via flash chromatography on silica gel (3% methanol/dichloromethane) to provide the title compound tert-butyl (2R,6S ,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (195 mg, 0.249 mmol, 79% yield). MS (ESI): m/z=784.1 [M+H]. Example 19 provided an IC50 of <0.1 nM in a 1a enzyme assay; an IC50 of <0.1 0 nM in a 1b enzyme assay; a HLM stability value of >100 μl/min/mg; an EC50 of <1.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of <1.0 nM in a replicon cell line assay in a 1-con1 background.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl.[Cl:5][C:6]1[C:11](N)=[C:10]([CH3:13])[CH:9]=[CH:8][CH:7]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:13])[C:11]=1[C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1cccc(Cl)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1C#N
Temperature: 0 °C
Reaction time: 3 h
Yield: 4.6 %

Procedure:
Sodium cyanide (65 g, 1.33 mol) in 100 ml of water is added to cuprous chloride (49.5 g, 0.5 mol) in 200 ml of water while stirring mechanically in a 5 l. 3-necked flask. Evolution of heat resulted and the cuprous chloride dissolves. This is then cooled in an ice bath to 0° C. A milky suspension of cuprous cyanide results. To this is added 100 ml of toluene. 6 N Hydrochloric acid (140 ml) is added slowly to 6-chloro-2-methylbenzenamine (56 g, 0.4 mol) while swirling in a 2 l. erlenmeyer flask and keeping the temperature at 0° C. A solution of sodium nitrite (28 g, 0.4 mol) in 80 ml of water is added dropwise to the hydrochloride suspension. Ice is added, when required, keeping the temperature at 0° C. Anhydrous sodium carbonate is added until the diazonium hydrochloride solution is neutral to pH paper. This is then added slowly to the cold stirring cuprous cyanide suspension, the temperature not being allowed to rise above 5° C. The reaction is then stirred at 0°-5° C. for 0.75 hr, allowed to reach room temperature over a 3 hr period and then heated on the steam bath at 50° C. After remaining at room temperature overnight, the product is steam distilled off. The distillate (3.5 l.) is extracted with benzene, dried and evaporated to give 2.8 g of the title compound, nmr (CDCl3) δ 2.55 (s, 3H) and 7.3 (m, 3H).