Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:28])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1.O>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]1=[O:28]
Reactant: C[C@@](CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h

Procedure:
HCl (4.0 N in 1,4-dioxane, 20 mL) was added to a solution of (2R)-2-Methyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (5.15 g, 11.5 mmol) in 1,4-dioxane (100 mL) and water (20 mL). The reaction was continued for 2 hours. The reaction was concentrated in vacuo, upon concentration a white solid precipitated. The solid was triturated with 2-propanol (150 mL) at 50° C. for 30 minutes then collected by filtration. The title compound was obtained as a white solid (3.85 g, 92%) LC-MS m/z 365.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.10-2.23 (m, 1H) 2.37-2.48 (m, 1H) 3.11 (s, 3H) 3.69-3.82 (m, 1H) 4.04-4.19 (m, 1H) 6.63-6.68 (m, 1H) 6.70 (d, J=1.76 Hz, 1H) 7.41-7.55 (m, 3H) 7.68-7.75 (m, 2H) 7.77 (d, J=6.83 Hz, 1H) 11.17 (br. s., 1H). [α]58920=+33.21°.
Reaction SMILES: [NH:1]1C=CN=N1.[C@@H:6]1([N:15]2C3N=C[N:21]=[C:19]([OH:20])[C:18]=3[N:17]=[CH:16]2)[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]1[OH:8].P([O-])(O)(O)=O.[K+]>>[CH:16]1[N:15]([C@@H:6]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]2[OH:8])[N:1]=[C:18]([C:19]([NH2:21])=[O:20])[N:17]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: c1c[nH]nn1
Agent: O=P([O-])(O)O
Agent: [K+]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 24 h

Procedure:
By using a substrate solution (pH 6.0) containing 40 mM triazole as the base donor, 60 mM inosine as the saccharide residue donor and 40 mM potassium dihydrogenphosphate, reactions were carried out in the same manner as in Example 1 at respective reaction temperature (40° to 70° C.) for 24 hours to produce ribavirin. The results are shown in Table 8.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:40])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:41]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:40][C:3]1[C:2]2[N:1]=[CH:41][N:12]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:16]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc2ccccc2c2c1ncn2CCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 19.9 g of 3-amino-2-chloro-4-[2-(N-triphenylmethyl-4-piperidyl)-ethylamino]quinoline, 24.1 ml of ethyl orthoformate and 0.68 g of p-toluenesulfonic acid monohydrate in 200 ml of toluene was refluxed for 6 hours. After cooling, the precipitated crystals were collected by filtration, and washed with diisopropyl ether to give 16.4 g of colorless crystals. Recrystallization from a mixture of methanol and tetrahydrofuran gave colorless crystals having the melting point of from 229 to 234.5° C. (decomposition).
Reaction SMILES: [CH2:1]([C:5]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH:3]=C.[BH4-].[Na+].ClCCl.C[OH:34]>>[OH:34][CH2:3][CH2:2][CH2:1][C:5]1([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]1
Reactant: CO
Reactant: C=CCCC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCCO)(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 1-(1,1-dimethylethyl) 4-phenylmethyl 4-(3-butenyl)-1,4-piperidinedicarboxylate (Description 135, 1.06 g, 2.84 mmol) in dichloromethane/methanol (50:50, 20 mL) was cooled to −78° C. and oxygen was bubbled through the mixture for 10 minutes. Ozone was bubbled through the mixture until a blue coloration persisted. Oxygen was bubbled through the mixture for 10 minutes, then nitrogen for 10 minutes. Sodium borohydride (1.1 g, 28.9 mmol) was added over 5 minutes and the mixture was allowed to warm to room temperature. The solvent was evaporated under reduced pressure and water (40 mL) was added. The mixture was extracted with ethyl acetate (3×40 mL), the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (1.06 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.4–7.3 (5H, m), 5.15 (2H, s), 3.95–3.75 (2H, m), 3.52 (2H, t, J 7 Hz), 2.95–2.80 (2H, m), 2.12 (2H, br d, J 10 Hz), 1.65–1.30 (7H, m), and 1.44 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]2[NH:1][C:32](=[O:34])[N:9]([C@@H:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:3]2=[N:4][CH:5]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(Cl)cc2N)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(=O)[nH]c3cc(Cl)cnc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 189 %

Procedure:
A stirred solution of (R)-tert-butyl 3-(3-amino-5-chloropyridin-2-ylamino)pyrrolidine-1-carboxylate (680 mg, 2.2 mmol) and i-Pr2NEt (1.2 mL, 6.6 mmol0 in CH2Cl2 (50 mL) was cooled in an ice bath and solid triphosgene (213 mg, 0.72 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was concentrated to leave a black solid which was purified by chromatography on a 12-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(6-chloro-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (461 mg, 62%) as a black solid. LC-MS Method 1 tR=1.65 min, m/z=339, 283.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:29])([F:40])[F:41])[CH3:38])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Reactant: CC(O)c1ccccc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B31, 10.0 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 6.8 g of 1-[2-(trifluoromethyl)phenyl]ethanol, 12.5 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 11.0 g of di-tert-butyl azodicarboxylate in 300 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:22]=1)(=O)=O.S(=O)(=O)(O)O>CN(C)C=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:22]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCc1cn(-c2cccnc2)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2cn(-c3cccnc3)c3ccccc23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4.55 g of ethyl p-hydroxybenzoate in 50 ml of dry dimethylformamide is treated with 1.31 g of 50% sodium hydride dispersion in mineral oil under nitrogen at 0°, stirred for 30 minutes at 0°, and then at room temperature for 15 minutes. A solution of 7.55 g of 3-(methanesulfonyloxymethyl)-N-(3-pyridyl)indole in 10 ml of dry dimethylformamide is added over 5 minutes and the reaction mixture is warmed at 50° for 18 hours. The reaction mixture is poured onto ice, made acidic with concentrated sulfuric acid and extracted with diethyl ether (4×40 ml). The aqueous phase is adjusted to pH=8 and is extracted with diethyl ether (3×100 ml). The organic extracts are washed with water (4×50 ml) and brine (1×50 ml) and dried over anhydrous sodium sulfate. Evaporation and chromatography on 100 g of silica with diethyl ether as the eluent yields 3-[(p-ethoxycarbonylphenoxy)methyl]-N-(3 -pyridyl)indole.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][O:27][CH2:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[NH2:44][C:30]1[N:31]=[CH:32][C:33]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:34][C:29]=1[CH2:28][O:27][CH3:26]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COCc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Product: COCc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C(C)C)nc2C)c(=O)n4C)cnc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and 3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 168.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.20 (s, 1H), 8.06-8.01 (m, 2H), 7.85-7.80 (m, 1H), 7.53-7.50 (m, 1H), 7.44-7.41 (m, 1H), 5.99 (s, br, 2H), 4.54 (hp, 1H), 4.30 (s, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.95 (s, 3H), 1.47 (d, 6H))
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
7-Benzyl-3-methyl-3,7-dihydropurine-2,6-dione (3.18 g) was suspended in N,N-dimethylformamide (40 ml), and potassium carbonate (2.6 g) and chloromethyl pivalate (2.15 ml) were added thereto. The reaction solution was stirred at 40° C. overnight, then diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.26 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:14])[C:4]=1[F:15])#[N:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[Cl-].[Li+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:14])[C:4]=1[F:15])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: COC(=O)C(=CN(C)C)c1ccc(C#N)c(F)c1C
Temperature: 10 °C
Yield: 62.8 %

Procedure:
Combined methyl 2-(4-cyano-3-fluoro-2-methylphenyl)acetate (10.0 g, 48.3 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (17.25 g, 145 mmol), and solid lithium chloride (0.205 g, 4.83 mmol) and heated to 105° C. for 1.5 h. The mixture was cooled to 10° C. and water (210 mL) was added slowly. The solid was collected by vacuum filtration, dissolved in DCM and was purified by column chromatography to afford the title compound (7.95 g, 63%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (d, J=2.53 Hz, 3 H) 2.54-2.86 (m, 6 H) 3.50 (s, 3 H) 7.10 (d, J=7.83 Hz, 1 H) 7.62 (s, 1 H) 7.63-7.66 (m, 1 H). ESI-MS m/z [M+H]+ 263.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH:4]=[CH:5][CH2:6][OH:7].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=1>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:7][CH2:6][CH:5]=[CH:4][CH2:3][OH:8])=[CH:12][C:13]=1[CH3:18]
Reactant: OCC=CCO
Reactant: Cc1cc(CBr)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(COCC=CCO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a suspension of NaH (1.0 g, 60% oil dispersion) in 80 mL THF was slowly added but-2-ene-1,4-diol (2.0 g, 22 mmol) as a solution in 5 mL THF at room temperature. To this mixture was added dropwise 4-bromomethyl-1-fluoro-2-methyl-benzene (5.0 g, 24 mmol) and the resulting stirred for 8 h at room temperature. The reaction was quenched by the slow addition of 50 mL of saturated NH4Cl and the mixture extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (2×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 2.3 g of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@H:9]([NH2:16])[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:21]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@@H:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[NH:16][CH2:18][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-amino-4-(S)-cyclohexyl-butyric acid tert-butyl ester (5 g, 20 mmol) and 4-formyl-5-nitro-2-phenoxypyridine (6 g, 24 mmol) in methylene chloride (100 mL) was stirred at room temperature overnight. NaBH(OAc)3 (0.8 gm, 4 mmol) was added, and the solution was stirred at room temperature for 5 hours. Additional NaBH(OAc)3 (7 g, 33 mmol) was added and the solution was stirred at room temperature for another one hour. The solution was then poured into EtOAc (100 mL). The organic layer washed with aqueous NaCl, dried over MgSO4 and evaporated to yield a residue which was purified by column chromatography (10% EtOAc/Heptane) to yield 4-(S)-cyclohexyl-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyric acid tert-butyl ester as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH:14]([F:15])[F:16])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[N:9]=3)[CH:3]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)c1

Procedure:
3′-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.6) (0.43 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure III. Obtained as light yellow solid (0.62 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:16])=[CH:10][C:11]([O:13]CC)=O)[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11]([OH:13])=[CH:10][C:9]([CH3:16])=[CH:8]2
Reactant: CCOC(=O)C=C(C)Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(O)c2ccc(Cl)cc2c1
Temperature: 50 °C

Procedure:
A flask containing the crude ethyl 4-(3-chlorophenyl)-3-methylbut-2-enoate (˜25 grams) was treated with concentrated H2SO4 (120 mL) and warmed to 50° C. for 2.5 h. The reaction was poured onto ˜500 mL of crushed ice. Once the ice had melted, the brown suspension was extracted with two portions of EtOAc (500 mL and 100 mL, respectively). The two extracts were combined, washed with saturated aq. NaHCO3, dried (MgSO4), filtered, and concentrated to ˜55 mL. The residue was treated with DCM and loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product. 1H NMR (400 MHz, CDCl3) δ 8.07-8.05 (d, J=8.8 Hz, 1H), 7.69-7.68 (d, J=2.0 Hz, 1H), 7.35-7.32 (dd, J=2.0, 8.8 Hz, 1H); 7.12 (s, 1H); 6.65 (s, 1H); 5.21 (bs, 1H); 4.21-4.17 (dd, 2H); 2.41 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:27]1([CH3:36])[C:28]([C:33](Cl)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[CH3:36][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20](=[O:22])[CH3:21])=[CH:18][CH:19]=3)[C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][C:3]([C:33](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:36])=[CH:2][CH:1]=3)=[O:34]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccc(C(=O)c4ccccc4C)cc3c3cc(C(=O)c4ccccc4C)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-carbazol-9-yl-phenyl)-ethanone (2.0 g) in CH2Cl2 (100 mL) is added AlCl3 (3.3 g) and o-toluoyl chloride (2.3 g) at 0° C. After stirring overnight at room temperature, the reaction mixture is poured into ice-water. The product is extracted twice with CH2Cl2, and the combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated to give the residue, which is further dried in vacuo. The product thus obtained is used for the next reaction without further purification. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.35 (s, 6H), 2.72 (s, 3H), 7.26-7.38 (m, 6H), 7.40-7.46 (m, 4H), 7.70 (d, 2H), 7.97 (dd, 2H), 8.26 (d, 2H), 8.59 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:25][O:26][C:27](=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COC(=O)CCc1ccc(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)cc1

Procedure:
Heat 300 mg (0.891 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 642 mg (3.65 mmol) of 3-(4-hydroxyphenyl)propanoic acid methyl ester and 435.4 mg (1.34 mmol) of caesium carbonate to 120° C. for 2 h. After cooling, add water and filter off the precipitated crude product. Dissolve the solid in ethyl acetate and wash the solution twice with buffer solution (pH 7), dry over magnesium sulphate and concentrate again. After treating the residue with methanol, a solid precipitates out. Filter it off, wash with a little methanol and dry under reduced pressure. 160 mg (36.3% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N:11]1([C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CC=C(N2CCCC2)CC1

Procedure:
A mixture of 4.95 mL (40 mmol) of 1-acetyl-4-piperidinone, 3.64 mL (44 mmol) of pyrrolidine, 15 mL of toluene and a catalytic quantity of p-toluenesulfonic acid was heated for 12 h with refluxing on a water separator. After removal of the solvent under a vacuum, 7.7 g (99% of theoretical) of the desired product 1-(4-pyrrolidin-1-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (A) were obtained in the form of a brown-red oil.