Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[CH:49]=[C:54]([CH3:55])[CH:53]=[CH:52][C:51]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1cccc(C)c1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccc(C)cc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of N-[2-(2-hydroxy-3-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.60 (EtOAc); Rt=5.78.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[C:5]([CH3:30])([CH3:29])[C:4]=2[CH:3]=1.[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[C:31]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:9][CH:10]=3)[C:5]([CH3:30])([CH3:29])[C:4]=2[CH:3]=1
Reactant: COc1ccc(-c2ccc3c(c2)C(C)(C)c2cc(Br)ccc2-3)c(-c2ccccc2)c1
Reactant: OB(O)c1ccccc1-c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)c2cc(-c4ccccc4-c4ccccc4)ccc2-3)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 68 %

Procedure:
A mixture of 3.4 g (7.5 mmol) of 2-bromo-7-(5-methoxybiphenyl-2-yl)-9,9-dimethyl-9H-fluorene, 2 g (10 mmol) of biphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (2.7 g, 5.1 mmol, 68%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].Cl[C:9]1[CH:10]=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1.[O-]CC.[Na+].O>C(O)C>[CH2:3]([O:4][C:9]1[CH:10]=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1)[CH3:2]
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: O=C(O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C)c2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine trifluoroacetate (W2.002b; 50 mg) was dissolved in ethanol (3.5 ml) while stirring at RT. Thereafter, sodium ethoxide was added dropwise while cooling with ice (25 mg dissolved in 1.5 ml of ethanol). After stirring at RT for 2.5 h, the mixture was heated to 60° C. and, after 2.5 h, a further equivalent of sodium ethoxide solution was added. After standing overnight, the mixture was heated again to 60° C., two further equivalents of sodium ethoxide solution were added and the mixture was stirred for 4 h. Subsequently, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 27 mg of the title compound were obtained. LC-MS rt: 0.67 min [M+H]+: 194.1 (met. a)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.Cl.[CH3:27][C:28]1([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:31]2[CH2:32][CH2:33][C:28]([CH3:27])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:30]2)=[O:10])=[N:4][CH:3]=1
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CCN(C(=O)c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid (0.150 g, 0.742 mmol) and DMF (1 drop, catalytic amount) in DCM (10 mL) was added dropwise oxalyl chloride (0.10 mL, 1.11 mmol.) at 0° C. under inert atmosphere and the mixture stirred at rt for 1 h. The solvent was evaporated under reduced pressure under an inert atmosphere and the residue taken up in THF (5 mL) followed by the addition of DIPEA (0.70 mL, 3.71 mmol) and ethyl 4-methylpiperidine-4-carboxylate hydrochloride (0.14 g, 0.89 mmol.) at 0° C. The resulting mixture was stirred at rt for 16 h. After completion of reaction (by TLC) the mixture was poured into ice cold water (100 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with water and brine, dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the crude residue purified on silica-gel eluting with 40% EtOAc in hexane to obtain the desired product as an off white semi-solid (0.10 g, 37% yield). MS: 358.01 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:44]2[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:30][CH:29]=2)[C:24]([CH3:40])=[N:23][C:22]=1[CH2:41][CH2:42][CH3:43]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:38])([CH3:39])[CH2:36][OH:37])=[CH:30][CH:29]=2)[C:24]([CH3:40])=[N:23][C:22]=1[CH2:41][CH2:42][CH3:43]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.81 g), sodium hydrogen carbonate (1.29 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.41 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.28 g, 61%).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)(=[O:23])=[O:22]
Reactant: OCCOCc1ccco1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)CCOCc1ccco1
Reaction time: 1.5 h

Procedure:
Combine fur-2-ylmethyl 2-hydroxyethyl ether (10 mmol), and N,N-diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain fur-2-ylmethyl 2-methanesulfonylethyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.C(OCC)(=O)C>[CH3:14][NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CI
Product: CNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A stirred mixture of 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (12.5 g), potassium carbonate (17.4 g) and iodomethane (22.5 g) in acetonitrile (150 ml) was heated at 80° C. for 3 hours. At this point, another portion of iodomethane (22.5 g) was added; the mixture was heated with stirring for another 2 hours. The mixture was then diluted with ethyl acetate (500 ml) and washed with water (150 ml). The organic layer was then dried over sodium sulphate, solvent removed under reduced pressure to give expected product 4-methylamino-6-chloro-3-nitro-pyridine-2-carbonitrile (13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3ccccc32)cc1)c1ccccc1Cl
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 1-H-Indole, the title compound was isolated as a yellow solid in 71% yield (98% purity by HPLC).
Reaction SMILES: CBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li][CH2:23][CH2:24][CH2:25][CH3:26].O1C2C=CC=CC=2[C:29]([C:36](=O)[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]2[N:46]=[CH:47][N:48](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:49]=2)=C1.[CH2:70]([O:72][CH2:73][CH3:74])[CH3:71]>O.C(O)(=O)C.CO>[O:72]1[C:73]2[CH:23]=[CH:24][CH:25]=[CH:26][C:74]=2[C:71]([C:36](=[CH2:29])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]2[N:46]=[CH:47][NH:48][CH:49]=2)=[CH:70]1
Reactant: [Li]CCCC
Reactant: CCOCC
Reactant: O=C(COc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1coc2ccccc12
Agent: CBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C=C(COc1ccccc1-c1c[nH]cn1)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44 %

Procedure:
To a solution of triphenylphosphine methyl bromide (0.486 mmol) in diethyl ether (15 mL) at room temperature was added nBuLi (0.486 mmol, 2.5 M) and the suspension was stirred for 2.5 h. 1-(benzofuran-3-yl)-2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethanone (0.442 mmol) was added as a solution in diethyl ether (2 mL) at room temperature. After stirring overnight the reaction mixture was diluted with water (10 mL) and the product was extracted with EtOAC (3×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the crude product. The crude was stirred in a mixture of acetic acid (1.5 mL) and MeOH at 80° C. for 2 h. After cooling to room temperature the mixture was stripped off the solvents and the crude was diluted with satd. Na2CO3 solution and the product was extracted with EtOAc (3×30 mL). The combined organic extract was dried over Na2SO4 and concentrated to afford the crude. Chromatographic purification afforded the final product. Yield 44%. 1H NMR: 5.01 (s, 2H), 5.63 (s, 1H), 5.89 (s, 1H), 7.06 (d, 1H, J=6.69 Hz), 7.08 (d, 1H, J=5.10 Hz), 7.23-7.44 (m, 5H), 7.54 (d, 1H, J=7.59 Hz), 7.74 (s, 1H), 7.81 (s, 1H), 7.84 (s, 1H)
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1.II>C(OCC)(=O)C>[C:9]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][O:1]1)(=[O:11])[CH3:10]
Reactant: OCC1CCC=CO1
Reactant: CC(=O)OC(C)=O
Agent: II
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1CCC=CO1
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of (±)-3,4-dihydro-2H-pyran-2-methanol (514 g, 4.51 mol, 1 eq) and acetic anhydride (621 g, 6.09 mol, 1.35 eq) was cooled to 0° C. To the resultant mixture was added pyridine (35.6 g, 0.45 mol, 0.1 eq) and the resultant reaction mixture was allowed to warm to room temperature with stirring. The resultant reaction mixture was allowed to stir for an additional 8 hours after reaching room temperature and was shown to be complete by thin-layer chromatography (2:1 hexanes:ethyl acetate, I2 staining). The reaction mixture was concentrated in vacuo at 35° C. and the resultant residue was diluted using ethyl acetate (2 L). The resultant mixture was transferred to a separatory funnel and sequentially washed with deionized water (3×1 L), saturated aqueous NaHCO3 (2×10 L), and brine (1.0 L). The organic layer was dried over sodium sulfate and concentrated in vacuo at 35° C. to provide (±)-3,4-dihydro-2H-pyran-2-yl-methyl acetate as a clear liquid (605.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ 1.6-2.2 (m, 4H), 2.1 (s, 3H), 4.2 (m, 3H), 4.8 (m, 1H), 6.4 (m, 1H).
Reaction SMILES: C([Li])CCC.[Li+].CC([N-]C(C)C)C.[S:14]1[C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][S:21][C:17]=2[N:16]=[N:15]1.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:25][C:20]1[S:21][C:17]2[N:16]=[N:15][S:14][C:18]=2[C:19]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1csc2nnsc12
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)sc2nnsc12
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
79 ml (201.6 mmol) of n-butyllithium (1.6M in hexane) are added at -30° C., under nitrogen, to a solution of 20.4 g (201.6 mmol) of diusopropylamine in 200 ml of tetrahydrofuran (THF). After 20 minutes' stirring at -20° C., the LDA solution so prepared is added dropwise at -90° C., under nitrogen, by means of a capillary, to a suspension of 15.0 g (80.6 mmol) of thieno[2,3-d]1,2,3-thiadiazole-6-carboxylic acid in 150 ml of THF. After 90 minutes' stirring at -50° C., a solution of 42.0 g (177.2 mmol) of hexachloroethane in 70 ml of THF is added at -90° C. and the reaction mixture is heated to room temperature within a period of 2 hours. Then the reaction mixture is poured onto 2 litres of water, the aqueous phase is extracted with diethyl ether and acidified with concentrated hydrochloric acid, and the product is isolated by filtration. There are obtained 17.55 g of light-brown solid having a melting point of 255°-265° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([C:7]1[O:20][C:10]2[C:11]([O:18][CH3:19])=[N:12][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:9]=2[CH:8]=1)([O:5][CH3:6])[CH3:4].[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23]([OH:30])[CH:22]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:27]([C:26]1[CH:21]=[CH:22][C:23]([O:16][C:15]([C:14]2[C:9]3[CH:8]=[C:7]([C:3]([O:5][CH3:6])([O:2][CH3:1])[CH3:4])[O:20][C:10]=3[C:11]([O:18][CH3:19])=[N:12][CH:13]=2)=[O:17])=[CH:24][CH:25]=1)([O-:29])=[O:28].[N+:27]([C:26]1[CH:25]=[CH:24][C:23]([O:30][C:15]([C:14]2[C:9]3[CH:8]=[C:7]([C:3](=[O:2])[CH3:4])[O:20][C:10]=3[C:11]([O:18][CH3:19])=[N:12][CH:13]=2)=[O:16])=[CH:22][CH:21]=1)([O-:29])=[O:28]
Reactant: COc1ncc(C(=O)O)c2cc(C(C)(OC)OC)oc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ncc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)(OC)OC)oc12
Product: COc1ncc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)=O)oc12

Procedure:
2-(1,1-Dimethoxyethyl)-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid (0.66 g), p-nitrophenol (0.32 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.49 g) and 4-dimethylaminopyridine (catalytic) in dry dichloromethane (40 ml) were stirred overnight at room temperature. The mixture was diluted with dichloromethane (50 ml), washed with water (100 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 33% hexane in ethyl acetate to 100% ethyl acetate gave 2-(1,1-dimethoxyethyl)-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.51 g) and 2-acetyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) as white solids.
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[N:23]=[C:24]4[C:29](=[C:30]5[C:35]=3[CH:34]=[CH:33][CH:32]=[CH:31]5)[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12][C@:11]2([C:38]([NH:40][S:41]([CH:44]3[CH2:46][CH2:45]3)(=[O:43])=[O:42])=[O:39])[CH2:37][C@H:10]2[CH2:9][C:8]([F:48])([F:47])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH3:50][N:51]1[C:55]([CH3:56])=[CH:54][C:53]([C:57](O)=[O:58])=[N:52]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[CH:44]1([S:41]([NH:40][C:38]([C@@:11]23[CH2:37][C@H:10]2[CH2:9][C:8]([F:47])([F:48])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:57]([C:53]2[CH:54]=[C:55]([CH3:56])[N:51]([CH3:50])[N:52]=2)=[O:58])[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]4[N:23]=[C:24]5[C:29](=[C:30]6[C:35]=4[CH:34]=[CH:33][CH:32]=[CH:31]6)[CH:28]=[CH:27][CH:26]=[CH:25]5)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12]3)=[O:39])(=[O:43])=[O:42])[CH2:46][CH2:45]1
Reactant: 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
Reactant: Cc1cc(C(=O)O)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a mixture of (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 20a, 12 mg, 0.017 mmol), 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2.57 mg, 0.018 mmol) and 2-(3H-[1,2,3]triazolo [4,5-b]pyridin-3-yl)-1,1,3 ,3-tetramethylisouronium hexafluorophosphate(V) (7.0 mg, 0.018 mmol)in dichloromethane (167 μl) was added N-ethyl-N-isopropylpropan-2-amine (10.18 μl, 0.058 mmol) and the mixture was stirred for 3 h at room temperature. 0.1 N HCl was added and organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The residue after solvent evaporation under reduced pressure was eluted through silica gel with 10% acetone/dichloromethane. The fractions containing the title compound were combined and the resulting crude material was purified by preparative thin layer chromatography on silica gel (20:1 dichloromethane/methanol) to provide the title compound (2R,6S,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide (8 mg 60% yield) as a white solid. MS (ESI): m/z=806.1 [M+H]. Example 21 provided a HLM stability value of <50 μl/min/mg; an EC50 of between 2.0 and 5.0 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 1b-con1 background.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl[S:13]([OH:16])(=O)=[O:14].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:1]([OH:11])=[O:10])=[CH:7][C:6]=1[S:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCOCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
p-Anisic acid (25.6 g, 168 mmol) was added neat to stirring chlorosulfonic acid (40 mL). This reaction was heated to 65° C. for 4 hours. The solution was poured very slowly into 500 mL of crushed ice, which was itself placed in a dry-ice/acetone bath to keep it cool. The water suspension that formed was allowed to stir for one hour, and it was then filtered. The solid was suspended in ether/dichloromethane (200 mL of 50/50), and excess morpholine (29 mL, 333 mmol) was added slowly. An immediate reaction occurred, but the reaction was allowed to stir overnight and then filtered and dried to provide the title compound (35 g, 69%). 1HNMR (DMSO-d6) δ13.2 (bs, 1H), 8.29 (d, J=2 Hz, 1H), 8.28 (dd, J=9 Hz, 2 Hz, 1H), 7.40 (d, J=9 Hz, 1H), 3.99 (s, 3H), 3.60 (m, 4H), 3.10 (m, 4H). MS (ES-POS): [M−H]=300.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[CH:6]1)(=[O:27])=[O:26]
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3Br)c3ccc(F)cc23)CC1

Procedure:
(32 mg, 53%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b, 30.6 mg, 0.133 mmol) and 2-bromophenylsulfonyl chloride (67.9 mg, 0.27 mmol); HRMS-FAB+ for C20H19N2SO2BrF calculated MH+ : 449.03348; found: 449.03240.
Reaction SMILES: [ClH:1].[OH:2][C:3]1([CH3:17])[CH2:8][CH2:7][CH:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1>O1CCOCC1>[ClH:1].[NH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH3:17])([OH:2])[CH2:4][CH2:5]1
Reactant: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(O)CCC(N)CC1
Reaction time: 3 h

Procedure:
4M Hydrochloric acid in dioxan (20 ml, 80 mmol) was added to a solution of the less polar diastereoisomer of tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate (610 mg, 2.66 mmol) in dioxan (5 ml). The mixture was stirred for 3 h then the solvent was removed under reduced pressure and the residue dried in vacuo to afford a single diastereoisomer of 4-amino-1-methylcyclohexanol hydrochloride (625 mg) as a gum.