Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2C1CCCCO1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a flask (1 L) under N2 at room temperature, were added 3,6-dibromocarbazole (50 g), dichloromethane (500 mL), 3,4-dihydro-2H-pyran (40 g), p-toluenesulfonic acid monohydrate (1 g). The reaction was stirred overnight. NaHCO3 (3 g) was added, and the reaction was stirred for 1 h. After filtration, the solvent in the filtrate was removed by evaporation. MeOH (1 L) was added for reflux under N2 for 2 h. Filtration when it was warm gave 37.5 g product. The MeOH (800 mL) was removed by evaporation, and solid came out. Filtration gave 12.5 g product. Both products are white, single spot on TLC, and GS-MS and 1H NMR showed they are pure product. The overall yield is 80%. Second and Third Reactions following the reaction scheme above produce compound (2) and (3), respectively, according to the scheme below:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:6]([CH:8]=[C:9]([CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[N:10]=2)[N:7]=1.C([O-])=O.[NH4+]>C1COCC1.CO.CCOC(C)=O.[Pd]>[O:25]1[CH2:24][CH2:23][N:22]([C:4]2[C:5]3[N:6]([CH:8]=[C:9]([CH:11]4[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]4)[N:10]=3)[N:7]=[CH:2][CH:3]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3nc(Cl)cc(N4CCOCC4)c3n2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2cn3nccc(N4CCOCC4)c3n2)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Compound 19b (430 mg, 1.09 mmol) and ammonium formate (344 mg, 5.45 mmol) were placed in a 20 mL vial equipped with a stir bar and dissolved in a mixture of THF (8 mL) and MeOH (4 mL). 10% Pd/C (116 mg, 0.109 mmol) was then added. The reaction mixture was stirred at 70° C. for 3 h, cooled to rt, and filtered through a pad of diatomaceous earth. The solids were washed with MeOH (2×10 mL). The combined filtrates were concentrated under reduced pressure and the residue obtained was dissolved in EtOAc (100 mL) and washed with water (2×25 mL) and brine (25 mL). The combined aqueous washings were extracted once with EtOAc (25 mL) and the organic extracts were combined, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to obtain compound 19c. Mass Spectrum (LCMS, ESI pos.): Calcd. for C19H25N5O3: 360.2 (M+H). found: 360.3.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([S:9][C:10](=S)OCC)[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl.[BH4-].[Na+].[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34](CBr)=[CH:33][CH:32]=1>CCO.CCOC(C)=O.CN(C=O)C>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:10][S:9][C:7]2[CH:6]=[CH:5][C:4]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:8]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=S)Sc1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of dithiocarbonic acid O-ethyl ester S-(2-trifluoromethyl-biphenyl-4-yl) ester (128 mg, 0.3738 mmol) in EtOH (5 mL) is added aqueous NaOH (1 N, 5 mL). The mixture is heated at 65° C. for 3 h. After cooling to room temperature, 1 N HCl (aq) is added until the reaction pH is adjusted to ca. pH=5. The reaction is diluted with EtOAc and washed with H2O followed by saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the crude 2-trifluoromethyl-biphenyl-4-thiol product obtained (64 mg, 0.2519 mmol) is dissolved in EtOH (5 mL). NaBH4 (19 mg, 0.5039 mmol, 2 eq.) is added to this solution. The resulting mixture is stirred at room temperature for 25 min at which point methyl-4-(bromomethyl)benzoate (58 mg, 0.2519 mmol, 1 eq.) in DMF (1.5 mL) is added to the reaction. The mixture is stirred at room temperature an additional 30 min. The EtOH is removed under vacuum. The resulting DMF solution is diluted with EtOAc and washed with H2O followed by saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (3:1 hexanes/EtOAc) to give 4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzoic acid methyl ester. [MS: (ES+) 425.1 (M+23)+].
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][C:8]=2[CH3:20])[CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](OC)=O)=[CH:31][CH:30]=1)[CH3:27]>C1COCC1>[CH:1]1([CH2:5][N:6]2[C:7]3=[N:12][CH:11]=[C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:9]=[C:8]3[CH:20]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(NC(=O)C(C)(C)C)cnc1NCC1CCC1
Reactant: CCOc1ccc(CC(=O)OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc3cc(NC(=O)C(C)(C)C)cnc3n2CC2CCC2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a solution of N-[6-[(cyclobutylmethyl)amino]-5-methyl-3-pyridinyl]-2,2-dimethyl-propanamide (2.0 g, 7.26 mmol) in THF (70 ml) at −78° C. was added n-butyl lithium (12.7 mL of 2.0 M solution in cyclohexane, 25.4 mmol). The mixture was stirred for one hour at −20° C. and then cooled to −78° C. To this reaction mixture was cannulated to a solution of methyl 4-ethoxy-benzeneacetate (2.3 g, 11.6 mmol) in THF (50 mL) at −78° C. After stirring for 3 hours at room temperature, the mixture was quenched with NaHCO3 saturated aqueous solution (200 ml) and diluted with EtOAc (100 mL). The phases were separated and the aqueous phase was back-extracted with additional EtOAc (100 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3% MeOH+0.5% NH4OHaq] in CH2Cl2) to provide 650 mg of the title compound N-[1-(cyclobutylmethyl)-2-[(4-ethoxyphenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2,2-dimethyl-propanamide. 1H NMR (400 MHz, DMSO-D6) δ 1.21 (s, 9 H) 1.29 (t, J=7.03 Hz, 3 H) 1.77 (m, 6 H) 2.69 (m, 1 H) 3.97 (q, J=7.03 Hz, 2 H) 4.06 (s, 2 H) 4.15 (d, J=7.23 Hz, 2 H) 5.99 (s, 1 H) 6.86 (d, J=8.59 Hz, 2 H) 7.14 (d, J=8.59 Hz, 2 H) 7.98 (d, J=2.34 Hz, 1 H) 8.21 (d, J=2.34 Hz, 1 H) 9.21 (s, 1 H). MS (ESI) (M+H)+: 421.
Reaction SMILES: [BH4-].[Na+].[C:3]1([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][C:20](=[O:30])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)[C:12](=[O:31])[NH:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>C(O)C.O>[C:3]1([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:15][CH2:14]3)[C:12](=[O:31])[NH:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(COc1ccc(F)cc1)CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(CC(O)COc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 0.2 g of sodium borohydride in 10 ml of ethanol is added dropwise a solution of 2 g of 1-phenyl-8-[3-(p-fluorophenoxy)-2-oxopropyl]-4-oxo-1,3,8-triazaspiro[4,5]decane in 20 ml of ethanol. The mixture is stirred at room temperature for five hours. The resulting mixture is decomposed with 2N hydrochloric acid, diluted with water, made alkaline with sodium hydroxide and diluted again with water. After cooling, the precipitate is collected by filtration and dried to give 1-phenyl-8-[3-(p-fluorophenoxy)-2-hydroxypropyl]-4-oxo-1,3,8-triazaspiro[4,5]decane, m.p. 152° - 154° C. Recrystallization from iso-propanol gives pale yellow crystals, m.p. 164° - 166° C.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.P(=O)(O)(O)O>O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=P(O)(O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 24 h

Procedure:
9α-Hydroxyandrostenedione (9.06 g.) is added to phosphoric acid (85%, 25 ml.) and stirred at 45°-55° for 24 hours. Water (75 ml.) is added, the mixture stirred for 2 hours and the solids are collected by filtration. The solids are washed with water (200 ml.) and air-dried to give androsta-4,9(11)-diene-3,17-dione, 8.11 g., (95.1% chemical yield); m.p. 193°-195°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH2:24][CH2:25][C:26]5[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[N:28]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](O)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>>[C:36]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH2:24][CH2:25][C:26]5[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[N:28]=4)[CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCC(=O)O
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCCN4CCNCC4)cc3)CC1)CC2
Product: CCCCC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 66 %

Procedure:
Obtained in 66% yield by an analogous method to Example 4.1, starting from 6-[4-[4-[3-(piperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine and pentanoic acid.
Reaction SMILES: O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2[C:27]2[C:32](OC)=[CH:31][CH:30]=[CH:29][C:28]=2[O:35][CH3:36])CCCCC1.Cl[CH2:44][Cl:45]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:45][C:44]1[CH:27]=[CH:32][CH:31]=[C:30]2[C:29]=1[CH2:28][O:35][CH2:36]2
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: ClCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cccc2c1COC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
To the mixture of sodium 2,6-dichlorobenzyloxymethyl trifluoroborate (41 mg, 0.15 mmol) synthesized in Example 10 and 1,4-dioxane (1.5 ml), water (0.15 ml), cesium carbonate (170 mg, 0.51 mmol), palladium(II) acetate (3.3 mg, 0.015 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12 mg, 0.030 mmol) were added at room temperature, and the obtained reaction mixture was then stirred at 100° C. (an outer temperature) for 4 hours. The reaction mixture was cooled to room temperature, and then dichloromethane was added thereto. The organic layer was then separated and the solvents were evaporated under reduced pressure from the organic layer. The obtained residue was purified with silica gel column chromatography (hexane: diethyl ether=100:0→91:9→80:20), thereby obtaining the entitled compound (3.7 mg, 17%).
Reaction SMILES: [CH2:1]([C:4]1([S:7]([N:10]2[C:14]3=[CH:15][C:16]4[S:20][N:19]=[N:18][C:17]=4[C:21]([F:22])=[C:13]3[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=3[Cl:30])C2=O)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[O-].[K+]>C1COCC1>[CH2:1]([C:4]1([S:7]([NH:10][C:14]2[C:13]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=3[Cl:30])=[C:21]([F:22])[C:17]3[N:18]=[N:19][S:20][C:16]=3[CH:15]=2)(=[O:8])=[O:9])[CH2:5][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4nnsc4cc32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)Nc2cc3snnc3c(F)c2Nc2ccc(Br)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.09 mmol) in THF (5 mL) was added potassium trimethylsilanolate (12 mg, 0.09 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (45 mg, 94.5% yield). 1H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.65-7.57 (m, 2H), 7.33 (m, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 5.72-5.57 (m, 1H), 5.05 (m, 2H), 2.79-2.72 (m, 1H), 2.12-2.05 (m, 1H), 1.76-1.71 (m, 2H), 1.21-0.98 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21].C(O)C>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])=[C:3]([C:10]([F:11])([F:12])[F:13])[CH:4]=1)=[O:7]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1ccc(C=O)cc1C(F)(F)F
Yield: 59.9 %

Procedure:
The compound was prepared according to general procedure E with 4-hydroxy-3-(trifluoromethyl)benzaldehyde (1.3 mmol) in dry acetone (20 ml), anhydrous K2CO3 (1.7 mmol), and ethylbromoacetate (2.2 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. The crude product was purified by silica gel chromatography (eluent dichloromethane). 215 mg of purified compound were obtained (59% yield). 1H NMR (250 MHz, CDCl3): δ 1.30 (t, J=7.0 Hz, 3H), 4.28 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.02 (d, J=8.7 Hz, 1H), 8.04 (dd, J=8.9 and 2.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H) 9.95 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 13.8, 61.6, 65.5, 112.9, 120.5 (d, J=32.0 Hz), 122.8 (d, J=273 Hz), 128.9, 129.6, 135.0, 160.1, 167.2, 189.6 MS (ESI): m/z 573.1 [2M+Na]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:11][C:12]([O:14]N=C(C1C=CC=CC=1)C#N)=O)([CH3:10])([CH3:9])[CH3:8].C[O-].[Na+]>CCOCC>[C:7]([O:11][C:12]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH3:6])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CNCCNC
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CNCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
8.8 g of N,N'-dimethylethylenediamine were dissolved in 50 ml of ether and the solution was cooled to 0° C. 18.5 g of BOC-ON [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile] were slowly added dropwise and the mixture was stirred at RT for 16 hours. 6 g of sodium methylate were added and stirring was continued at RT for 18 hours. The substance which had precipitated out was filtered off with suction and washed with ether. The combined ether solution was concentrated in vacuo and the residue was distilled (boiling point 58°-60° C./0.5 mbar). 11.3 g were obtained as a colorless oil. MS(Cl): 189 (M+H)⊕, 133
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14](O)[C:15]#[CH:16].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[CH2:16]([O:12][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:15]#[CH:14]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C#CCOC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N-Boc-β-alanine (1.91 g, 10.1 mmol) and propargyl alcohol (0.675 g, 12 mmol) were dissolved in EtOAc (25 mL). Dicyclohexyl-carbodiimide (DCC, 2.06 g, 10 mmol) was added to the solution and after 16 h of stirring at room temperature, the reaction mixture was filtered and evaporated to dryness under vacuum. Crude product yield
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][NH2:15])[CH2:9][CH2:8][CH2:7]2.[CH:16](OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[ClH:1].[CH3:16][NH:15][CH2:14][CH:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)CCCC2CN
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNCC1CCCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 2 was converted to the free base (15 g) then dissolved in toluene (40 ml). Ethyl formate (70 ml) was added and the reaction refluxed for 2 hr. The solvent was evaporated giving an oil. This was dissolved in dry tetrahydrofuran (THF) (100 ml) and added dropwise to lithium aluminum hydride (3.23 g) in THF, with cooling. Upon complete addition, the reaction was refluxed for 2 1/2 hr. then stirred an additional 24 hr at room temperature, followed by an additional 3 hrs refluxing. The mixture was cooled in an ice bath, then quenched with H2O (3.3 ml), 15% aq. KOH (3.3 ml) and H2O (9.9 ml) added dropwise. After stirring for 1 hr at room temperature, the reaction was filtered, and evaporated to dryness. The residue was converted to the HCl salt with ethereal/HCl giving 12.9 g desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][NH2:25]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([NH:25][CH2:24][C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: NCc1ccco1
Product: CC(C(=O)NCc1ccco1)c1ccc(-c2ccccc2)c(F)c1
Yield: 75 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(2-fluorobiphenyl-4-yl)propanoic acid and furan-2-ylmethanamine. Yield: 75%. 1H NMR (500 MHz, CDCl3): δ 1.55-1.56 (d, 3H), 3.56-3.58 (m, 1H), 4.35-4.40 (dd, 1H, J1=5.3 Hz, J2=15.5 Hz), 4.45-4.49 (dd, 1H, J1=5.7 Hz, J2=15.6 Hz), 5.72 (s br, 1H), 6.16 (d, 1H, J=2.7 Hz), 6.39 (m, 1H), 7.10-7.15 (m, 2H), 7.25-7.45 (m, 5H), 7.54 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](I)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:15]#[N:16])[CH3:2].C([SiH](CCCCCC)CCCCCC)CCCCC.CN(C)[CH:38]=[O:39]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:38]=[O:39])[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:15]#[N:16])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(I)cc12
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Product: CCOc1c(C#N)cnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
A mixture of 4-ethoxy-6-iodo-quinoline-3-carbonitrile (example 14d, 6.4 g, 20 mmol), trethylamine (6.9 mL, 50 mmol), diphenylpropylphosphine (dpp, 0.23 uL, 1 mmol) and palladium(II) acetate (0.22 g, 1 mmol) in dry N,N-dimethylformamide (120 mL) in pressure tube was stirred under carbon monoxide at 75 psi at room temperature for 10 min. After addition of trihexylsilane (14 mL, 40 mmol), the mixture was then stirred under carbon monoxide at 75 psi at 80° C. for 3 h. The reaction was allowed to cool to 25° C. and then extracted with ethyl acetate (2×200 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 5%-40% ethyl acetate in hexanes in 30 min) afforded 4-ethoxy-6-formyl-quinoline-3-carbonitrile (2.3 g, 51%) as a white solid. LC-MS m/e 227 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=[O:29])[C:23]2[CH:24]=[CH:25][N+:26]([O-:38])=[CH:27][CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide (191 g) in dichloromethane (3000 mL) was added m-chloroperbenzoic acid (65%, 146 g) at 0° C., and the mixture was stirred for 30 min. The mixture was warmed to room temperature and stirred for 16 hr. The mixture was cooled to 0° C., 10% aqueous sodium dithionite solution (630 mL) was added, and the mixture was stirred for 30 min and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (500 mL) and saturated brine (500 mL). The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (NH, chloroform) to give the object 4-tert-butyl-N-[4-chloro-2-(1-oxidoisonicotinoyl)phenyl]benzenesulfonamide (181 g, pale-yellow solid).
Reaction SMILES: N/C(/C#N)=C(\N[C:7]([NH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[F:18])=[O:8])/C#N.FC1C=CC(OC)=CC=1C(O)=O.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.CN(C=O)C.O.O1CCOCC1>[F:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[N:9]=[C:7]=[O:8]
Reactant: COc1ccc(F)c(NC(=O)N/C(C#N)=C(\N)C#N)c1
Agent: COc1ccc(F)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(F)c(N=C=O)c1
Reaction time: 0.25 h

Procedure:
(Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-fluoro-5-methoxyphenyl)urea. 2-Fluoro-5-methoxybenzoic acid (0.62 g, 3.62 mmol) was dissolved in CH2Cl2 (15 mL) and DMF (0.5 mL). Oxalyl chloride (0.38 mL, 4.32 mmol) was added dropwise. The mixture was stirred for another 15 min. The reaction was concentrated and then taken up in dioxane (10 mL). Sodium azide (0.26 g, 3.96 mmol) in water/dioxane (1:1 v/v, 10 mL) was added to the acid chloride at 0° C. The mixture was stirred for 10 min. The reaction was partitioned between EtOAc and water. The layers were shaken and separated. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude acyl azide was filtered through a silica gel plug (90% Hexanes in EtOAc. The filtrate was concentrated. The purified acyl azide was dissolved in toluene and stirred at 100° C. for 1 h. The toluene solution was concentrated to afford 1-fluoro-2-isocyanato-4-methoxybenzene in quantitative yield. 1-Fluoro-2-isocyanato-4-methoxybenzene (0.6 g, 3.62 mmol) was reacted with 2,3-diaminomaleonitrile (0.39 g, 3.62 mmol) according to General Procedure A to afford the title compound. MS (ESI) m/z 276.4 [M+1]+.