Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@:35]2([CH3:36])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:30])[CH2:15][CH2:16][C@H:17]([O:21]C(=O)C2C=CC=CC=2)[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:38]C(=O)C2C=CC=CC=2)[CH2:3]1.O[C@@H]1[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(OC(=O)C2C=CC=CC=2)C(C)C)C[C@@H](OC(=O)C2C=CC=CC=2)C1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[OH:1][C@@H:2]1[C@@:35]2([CH3:36])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:30])[CH2:15][CH2:16][C@H:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:38])[CH2:3]1
Reactant: CC(C)[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1
Agent: CC(C)C(CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)[C@@H](O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1α-Hydroxy-3β,24(S)-dibenzoyloxy-cholest-5-ene prepared in the same way as in Example 4, (B) was reduced with LiAlH4 in dry diethyl ether to form 1α,3β,24(S)-trihydroxy cholest-5-ene. This product (180 mg) was then reacted with 24 ml. of acetic anhydride and 75 ml. of pyridine at 95° C. for 3.5 hours. The product was treated in the same way as in Example 3, (A), and chromatographed through a column containing silica gel as a carrier to afford 195 mg of 1α,3β,24(S)-triacetoxy-cholest-5-ene.
Reaction SMILES: [C:1]([NH:3][C:4](SC)=[N:5][CH3:6])#[N:2].C(N(CC)CC)C.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][S:22][CH2:23][CH2:24][NH2:25]>CN(C)C=O.CO.[N+]([O-])([O-])=O.[Ag+]>[C:1]([NH:3][C:4]([NH:25][CH2:24][CH2:23][S:22][CH2:21][C:17]1[O:16][CH:20]=[CH:19][CH:18]=1)=[N:5][CH3:6])#[N:2]
Reactant: CN=C(NC#N)SC
Reactant: NCCSCc1ccco1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN=C(NC#N)NCCSCc1ccco1
Yield: 34.7 %

Procedure:
A solution of silver nitrate (8.25 g) in dimethylformamide (50 ml) was added dropwise to a solution of N-cyano-N'-methylcarbamimidothioic acid, methyl ester (6.1 g), triethylamine (4.8 g) and 2-[[[2-furanyl]methyl]thio]ethanamine (7.8 g) in methanol (150 ml). After 42 hr at 50° the mixture was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate and water. The organic layers were dried and evaporated to give an oil which yielded crystalline N-cyano-N'-[2-[[[2-furanyl]methyl]thio]ethyl]-N"-methylguanidine (3.9 g) m.p. 78°-82°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15].[Cl:17][C:18]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C(#N)C>[Cl:17][C:18]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:19]=1[C:20]([NH:22][C:23](=[O:24])[NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15])=[O:21]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Amino-5-(4-fluorophenyl)thiophene-2-carboxylic acid (50 mg) is initially charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added and the mixture is stirred at RT. After 3 hours, the solid is filtered off with suction, stirred once more with methanol, filtered off with suction and dried under reduced pressure.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CC(C)OC(=O)c1ccc(CCBr)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1ccc(CCN=[N+]=[N-])s1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
Sodium azide (697 mg, 10.7 mmol) was added to a solution of the bromide from step 2 (2.7 g, 9.7 mmol) in DMF (39 mL) at room temperature. After 18 h at room temperature, the reaction mixture was diluted with EtOAc (300 mL) and washed with water (3×100 mL) and brine (50 mL). The organic phases was dried (Na2SO4), filtered and concentrated in vacuo to afford 2.24 g (96%) of isopropyl 5-(2-azidoethyl)thiophene-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:21])[C:3]=1[C:22]([NH:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[O:23]>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:18])([F:20])[F:19])[CH:15]=2)[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[C:4](=[O:21])[C:3]=1[C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C2(CCOCC2)C1=O
Reaction time: 0.42 h

Procedure:
A solution of 1,1-dimethylethyl N-((4-hydroxy-2-oxo-6-(trifluoromethyl)-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (500 mg, 1098 μmol) in TFA (4 mL) was stirred at 23° C. After 25 minutes, the reaction was concentrated in vacuo and azeotroped with DCM (2×10 mL). The crude solid was washed with diethyl ether affording 356 mg of N-((4-hydroxy-2-oxo-6-(trifluoromethyl)-2′,3′,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycine. MS m/e=400.1 (M+H)+. Calculated for C18H16F3NO6 399.09.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:10](=[CH:18]\[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)/C(OC(C)(C)C)=O)=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[C@H:18]1[CH2:10][C:8](=[O:9])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(C)(C)OC(=O)/C(=C/c1ccc2ccccc2c1)C(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: O=C1C[C@H](c2ccc3ccccc3c2)Oc2ccccc21
Yield: 89.3 %

Procedure:
Prepared according to general procedure using (E)-tert-butyl 2-(2-hydroxyphenylcarbonyl)-3-(naphthalen-2-yl)prop-2-enoate (77 mg, 0.20 mmol), thiourea catalyst III (14 mg, 0.020 mmol) in 2.0 mL toluene for 38 h at −25° C. and p-toluenesulfonic acid (19 mg, 0.10 mmol) for 10 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 49 mg (89%) of 9 as a white solid in 91% ee. [α]D: +56.3 (EtOH, c=0.5). Analytical data for 9: IR (film) 1690.9, 1607.9, 1464.8, 1304.4, 1226.9 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.99-7.89 (m, 5H), 7.63-7.54 (m, 4H), 7.13-7.09 (m, 2H), 5.68 (dd, J=13.1, 2.4 Hz, 1H), 3.22 (dd, J=16.8, 13.4 Hz, 1H), 3.00 (dd, J=16.8, 2.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 192.2, 161.8, 136.5, 136.3, 133.6, 133.4, 129.0, 128.4, 128.0, 127.3, 126.8 (x2), 125.6, 123.9, 121.9, 121.2, 118.4, 79.9, 44.9; LRMS (electrospray): Exact mass calcd. for C19H14O2 [M]+, 274.10. Found [M]+, 273.8.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+].BrN1C(=O)CCC1=O.[CH2:19]([OH:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>O.C1COCC1.CN(C1C=CN=CC=1)C>[C:6]([O:9][CH:23]1[CH:22]=[CH:21][C:19](=[O:25])[CH2:20][O:24]1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: OCc1ccco1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1C=CC(=O)CO1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
2055 g of sodium hydrogen carbonate and 1004 g of sodium acetate were dissolved in a mixed solvent of 1.8 L of water and 15 L of THF. The resultant was cooled to −15° C., and 1.2 L of THF solution containing 2257 g of N-bromosuccinimide was added while maintaining the temperature at 0° C. or lower. Furthermore, 1200 g of furfuryl alcohol (Compound 1) was added while maintaining the temperature at 0° C. or lower, and agitated at the same temperature for 10 minutes. After confirming the end of the reaction by thin-layer chromatography, 299 g of DMAP and 2498 g of acetic anhydride were added while maintaining the temperature at 0° C. or lower. The reaction solution was heated to 30° C. and agitated at that temperature for 3.5 hours. After confirming the end of the reaction by thin-layer chromatography, the solution was cooled to 5° C., and added with 9.5 L of 2 N aqueous sodium hydroxide solution to prepare a solution of pH 6.5. This reaction solution was extracted with ethyl acetate and washed with a saturated sodium bicarbonate solution to obtain the organic layer. The solvent was distilled away under reduced pressure to obtain 1263 g of a crude product (±) 4 as a clear brown oily product (crude yield: 71.1%).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([S:20]([NH:23][C:24]2[C:29]([O:30][CH3:31])=[N:28][C:27]([CH3:32])=[CH:26][N:25]=2)(=[O:22])=[O:21])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)=[CH:9][CH:10]=1)C(C)C>CO.O.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[C:7]([S:20]([NH:23][C:24]3[C:29]([O:30][CH3:31])=[N:28][C:27]([CH3:32])=[CH:26][N:25]=3)(=[O:21])=[O:22])=[CH:6][CH:5]=[CH:10][CH:9]=2)[CH:16]=[CH:15][C:14]=1[CH2:7][CH:8]([CH3:11])[CH3:9]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cc(CC(C)C)ccc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)c(N)c1
Yield: 65.7 %

Procedure:
4-Isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-3'-nitro-2-biphenylsulphonamide (0.456 g) was dissolved in methanol/water (1:9 v/v; 10 ml) and the solution was catalytically hydrogenated over 10% Pd-C (0.046 g). The catalyst was removed by filtration through diatomaceous earth and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting foam was recrystallised from ether to give 3'-amino-4'-isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-biphenylsulphonamide (0.14 g), m.p. 160-162° C.; mass spectrum (+ve FAB, DMSO/methanol/NBA): 427 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21](O)=[O:22])=[O:15])[CH2:7]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:15])[CH2:7]2
Reactant: Cc1cc(C)c2c(c1)CC(CC(=O)C1SCN[C@@H]1C(=O)O)CC2
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: Cc1cc(C)c2c(c1)CC(CC(=O)C1SCN[C@@H]1C(=O)N1CCCC1)CC2
Yield: 60 %

Procedure:
A colorless oil of 1-[3-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 3-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline prepared in Reference Example 25 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 60%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.CO.[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:17])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCCC2=O
Yield: 99.8 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (10.0 g, 52.6 mmol) in THF (52.6 mL) and MeOH (10.64 mL, 263 mmol) at rt was added trimethylsilyldiazomethane (2.0 M in diethyl ether, 79 mL, 158 mmol) dropwise until the solution turned yellow and gas evolution ceased. The reaction was then concentrated under reduced pressure to give methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (10.72 g, 52.5 mmol, 100% yield) as a brown solid. MS ESI calcd for C12H12O3 [M+H]+ 205, found 205. 1H NMR (500 MHz, DMSO) δ 7.94 (d, J=8.1 Hz, 1H), 7.91 (s, 1H), 7.85 (dd, J=8.1, 1.6 Hz, 1H), 3.86 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.66-2.61 (m, 2H), 2.09-2.00 (m, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Cl:23]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:23][C:12]1[S:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[CH:13]=1
Reactant: CSc1ccc(-c2ccsc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1ccc(-c2cc(Cl)sc2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
A mixture of 3-[4-(methylthio)phenyl]-2-(4-nitrophenyl)thiophene (0.33 g) and N-chlorosuccinimide (0.15 g) in acetic acid (5 ml) was heated at 80° C. for 3 hours. The mixture was poured into an ice-cooled solution of sodium bicarbonate, and the precipitates were collected to give a powder of 5-chloro-3-[4-(methylthio)phenyl]-2(4-nitrophenyl)thiophene (0.31 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([C:20]4[S:21][C:22]([CH2:25][NH:26]S(C)(=O)=O)=[CH:23][CH:24]=4)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:32])([CH3:31])[NH:3]1.C(N(CC)CC)C.[CH3:41][O:42][CH2:43][C:44](Cl)=[O:45]>C1COCC1>[CH3:41][O:42][CH2:43][C:44]([NH:26][CH2:25][C:22]1[S:21][C:20]([C:18]2[S:19][C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:1])([CH3:33])[NH:3][C:4]([CH3:31])([CH3:32])[CH2:5]4)[N:14]=3)=[CH:16][CH:17]=2)=[CH:24][CH:23]=1)=[O:45]
Reactant: COCC(=O)Cl
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccc(CNS(C)(=O)=O)s4)s3)n2)CC(C)(C)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1ccc(-c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound of Example 68 (133 mg, 0.31 mmol) was dissolved in 7 ml THF and 0.2 ml triethylamine and 37 mg (0.35 mmol) methoxyacetylchloride added. This mixture was stirred at room temperature for 3 hours. Afterwards the solution was evaporated and the crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:95/5/0.5). Yield: 137 mg (88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CO.O>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:12]/[C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
(E)-4-(4-Methoxyphenyl)but-3-en-2-one (1 g, 5.7 mmol) was dissolved in MeOH (18 mL) and stirred for 5 min at room temperature. A solution of NaOH (500 mg, 12.5 mmol) in H2O (34 mL) was added and the reaction mixture was stirred for further 1 h. After the dropwise addition of 4-(trifluoromethyl)-benzaldehyde (822 μl, 6.0 mmol), the mixture was stirred overnight at ambient temperature. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW336.2 as a pale yellow solid (1.75 g, 92%). mp: 144-146° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.66 (d, 3J=15.9 Hz, 1H, Hvin), 7.64 (d, 3J=15.5 Hz, 1H, Hvin), 7.63 (d, 3J=9.0 Hz, 2H, HAr), 7.58 (d, 3J=8.6 Hz, 2H, HAr), 7.50 (d, 3J=8.8 Hz, 2H, HAr), 7.06 (d, 3J=16.0 Hz, 1H, Hvin), 6.87 (d, 3J=16.0 Hz, 1H, Hvin), 6.86 (d, 3J=8.8 Hz, 2H, HAr), 3.78 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.4 (C), 161.9 (C), 143.9 (CH), 140.8 (CH), 138.4 (q, 4J(C, F)=1.3 Hz, CH), 131.7 (q, 2J(C, F)=32.7 Hz, C), 130.3 (CH), 128.4 (CH), 127.6 (CH), 127.3 (C), 125.9 (q, 3J(C, F)=3.8 Hz, CH), 123.9 (q, 1J(C, F)=272.2 Hz, C), 123.2 (CH), 114.5 (CH), 55.5 (OCH3). MS (FAB) m/z: 333.1 (M+). Anal. calcd for C19H15F3O2: C, 68.67; H, 4.55. Found: C, 68.81; H, 4.63%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:22])[NH:17][CH2:18][N:19]=[C:20]=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:23](=[C:25]1[N:29]=[CH:28][N:27]=[C:26]1[C:30]([NH2:32])=[O:31])=[N-:24]>CS(C)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:22])[NH:17][CH2:18][N:19]3[C:20](=[O:21])[N:29]4[CH:28]=[N:27][C:26]([C:30](=[O:31])[NH2:32])=[C:25]4[N:23]=[N:24]3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: O=C=NCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CS(C)=O
Product: NC(=O)c1ncn2c(=O)n(CNC(=O)OCC3c4ccccc4-c4ccccc43)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Isocyanatomethyl-carbamic acid 9H-fluoren-9-ylmethyl ester (1.13 g, 3.83 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.5 g, 3.65 mmol) in dry dimethylsulfoxide (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the pouring onto crushed ice. The resultant precipitate was collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a white solid (600 mg, 33.9%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.86 (1H, s), 8.61 (1H, t-broad), 7.89-7.26 (9H, m), 5.55 (2H, t, J=6.8 Hz), 4.40-4.19 (5H, m), 2.01 (2H, s).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[CH:25]N(C)C)[C:21](OC)=[O:22])=[C:16]([CH3:29])[C:15]=1[F:30])#[N:13].Cl.C(N(C(C)C)C(C)C)C>O.CC(O)C>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[N:2][N:1]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=3)[C:21]=2[OH:22])=[C:16]([CH3:29])[C:15]=1[F:30])#[N:13]
Reactant: NNc1ccc(C(=O)O)cn1
Reactant: COC(=O)C(=CN(C)C)c1ccc(C#N)c(F)c1C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Combined 6-hydrazinylnicotinic acid (1.10 g, 7.18 mmol), methyl 2-(4-cyano-3-fluoro-2-methylphenyl)-3-(dimethylamino)acrylate (2.072 g, 7.90 mmol), 2-propanol (18 mL), and 0.5M aqueous hydrochloric acid (17.24 mL, 8.62 mmol). After 2 hours, N-ethyl-N-isopropylpropan-2-amine (6.26 mL, 35.9 mmol) was added. After another hour the reaction mixture was diluted with water and washed twice with IPAc. The aqueous phase was acidified to ˜pH=3.5 and stirred for 30 minutes to give a solid which was collected by filtration, washed with water, ethanol, and heptanes, and dried overnight under vacuum to give the title compound (1.60 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (d, J=2.27 Hz, 3 H) 7.64 (d, J=8.08 Hz, 1 H) 7.69-7.80 (m, 1 H) 8.26 (br. s., 1 H) 8.48 (br. s., 2H) 8.98 (t, J=1.52 Hz, 1 H) 13.45 (br. s., 2 H). ESI-MS m/z [M+H]+ 339.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CCOC(=O)N1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-amino-piperidine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.19 (m, 5 H), 1.43-1.70 (m, 8 H), 2.79 (s, 2 H), 3.23-3.28 (m, 4 H), 3.70-3.98 (m, 5 H), 6.16-6.34 (bd, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.10-7.20 (m, 2 H), 7.38 (d, J=8.0 Hz, 1 H), 7.42 (s, 1 H), 7.53-7.60 (m, 3 H), 7.79 (d, J=7.7 Hz, 1 H), 7.96 (d, J=8.0 Hz, 1 H), 8.21 (s, 1 H), 10.40 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F-:12].[K+]>[Cl-].C[N+](C)(C)C.ClC1C=CC=CC=1C>[F:12][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: [F-]
Agent: C[N+](C)(C)C
Agent: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Cl-]
Solvent: Cc1ccccc1Cl
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 180 °C
Yield: 57 %

Procedure:
20 g of tetramethylammonium chloride are dissolved at 70° C. in 100 g of 2-chlorotoluene. 1230 g (6.5 mol) of 2,3-dichloronitrobenzene are added to the solution. After addition of 290 g (5 mol) of potassium fluoride, the resulting suspension is heated for 14 hours at 180° C. with stirring and under nitrogen. During this time, some of the 2-chlorotoluene is continuously distilled off. The reaction suspension is then quickly filtered off using suction, the filter cake is washed with 2-chlorotoluene and the combined filtrates are fractionated in vacuo. In this manner 505 g (57% of theory) of 2-fluoro-3-chloronitrobenzene and 437 g of unreacted 2,3-dichloronitrobenzene are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1cc(C)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)c(C)o1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 93.8 %

Procedure:
To a 0° C. solution of methyl 2,5-dimethyl-3-furanoate (2.0 g, 13.0 mmol) in THF (130 mL) under N2 was added lithium aluminum hydride (39 mL of a 1.0 M solution in THF, 38.9 mmol) dropwise. The reaction was stirred at 0° C. for 3.5 h, at which time it was quenched cautiously with saturated aqueous Na2SO4 solution and allowed to warm to room temperature. The reaction mixture was filtered and rinsed with ethyl acetate, the filtrate was diluted with more ethyl acetate and the layers separated. The organic layer was washed with saturated aqueous NH4Cl, water and brine and dried over Na2SO4. The solution was filtered and concentrated to afford the title compound as a clear liquid (1.54 g, 12.2 mmol, 94%). 1H NMR (300 MHz, DMSO-d6): δ 5.93 (s, 1H); 4.18 (s, 2H); 2.17 (s, 3H); 2.15 (s, 3H).