Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH2:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CO/[CH:22]=[C:23](\[C:30]([O:32][CH3:33])=[O:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9]/[CH:22]=[C:23](\[C:30]([O:32][CH3:33])=[O:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]
Reactant: CO/C=C(/C=C/C(=O)OC)C(=O)OC
Reactant: Nc1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/C(=C/Nc1c(Cl)cccc1Cl)C(=O)OC
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a solution of (2,6-dichlorophenyl)amine (12.8 g) in THF (73 mL) was added an 1 M THF solution of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (79.8 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To this solution was added a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (14.52 g) in THF (35 ml) at once, and the resulting mixture was stirred at 0° C. for 3 hr. The reaction mixture was diluted with EtOAc (150 mL) and washed with a mixture of 1 M HCl (200 mL) and brine (150 mL), saturated aqueous NaHCO3 (150 mL) and brine successively, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with a mixture of EtOAc and hexane (1:2) and collected by filtration to give dimethyl (2E,4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-pentenedioate (9.28 g). The filtrate was evaporated in vacuo and the residue was purified by silica gel (200 g) column chromatography eluting with EtOAc-hexane (1:2) followed by triturating the isolated material with EtOAc-hexane (1:2) to afford dimethyl (2E,4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-pentenedioate (1.30 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:20][C:10]3[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:12][CH:13]=[C:8]([N:6]4[CH2:5][CH2:4][O:3][C@H:2]([CH3:1])[CH2:7]4)[CH:9]=3)=[C:23]([CH3:39])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: C[C@@H]1CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCO[C@H](C)C2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using (R)-5-(2-methylmorpholino)-2-morpholinopyridin-3-amine (68 mg, 0.25 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (67 mg, 0.25 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (60 μL, 0.25 mmol), and NMP (280 μL, 3.0 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded 7-fluoro-3-methyl-N-(5-((2R)-2-methyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine as a yellow solid (absolute configuration of stereocenter not determined) 1H NMR (500 MHz, chloroform-d) δ ppm 8.68-8.76 (1H, m), 7.84-7.94 (2H, m), 7.75-7.84 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.39 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 7.28 (1H, ddd, J=9.2, 8.0, 2.6 Hz), 6.76 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.82-3.97 (5H, m), 3.56-3.72 (2H, m), 3.22 (4H, m), 3.14 (1H, m), 2.97-3.10 (1H, m), 2.60-2.72 (1H, m), 2.29-2.42 (4H, m), 1.15 (3H, d, J=6.4 Hz). Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:1][NH2:2])=[CH:7][CH:6]=1
Reactant: CN
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: NC=Cc1ccc(C(F)(F)F)cc1

Procedure:
Methylamine was passed into a solution of about 10.1 g of 4-(trifluoromethyl)benzaldehyde in about 100 ml of benzene over MgSO4 for four hours with stirring. The solution was filtered, and then the solvent was evaporated to give N-[4-(trifluoromethyl)benzylidene]methylamine as an oil. This was taken up in benzene and catalytically (5% Pd/C) hydrogenated to give the title product.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:4]=1.Cl.[CH3:20]O>>[ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:20])=[O:11])=[C:5]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:4]=1
Reactant: Nc1ccc(CC(=O)O)c(OCC(F)(F)F)c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(N)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Into a stirred solution of 4-amino-2-(2,2,2-trifluoroethoxy)phenylacetic acid hydrochloride (0.95 g, 3.5 mmol) from Step 6 above in MeOH (25 mL) at 0° C. was bubbled HCl gas for 10 min. The resulting solution was warmed to ambient temperature and stirred for 14 h. The solvent was removed under reduced pressure to give methyl 4-amino-2-(2,2,2-trifluoroethoxy)phenylacetate hydrochloride as a solid (HPLC retention time=5.6 min (method A)).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:15])([CH3:14])[O:7]2.Cl[C:17]1[C:18]([C:30]([OH:32])=[O:31])=[CH:19][C:20]2[C:25]([C:26]=1[N+:27]([O-:29])=[O:28])=[CH:24][CH:23]=[CH:22][CH:21]=2.C([O-])(=O)C.[K+].CC(O)C>CC([O-])=O.CC([O-])=O.[Cu+2].O.C(N(CC)CC)C>[CH3:14][C:6]1([CH3:15])[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[NH:1][C:17]2[C:18]([C:30]([OH:32])=[O:31])=[CH:19][C:20]3[C:25]([C:26]=2[N+:27]([O-:29])=[O:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:7]1
Reactant: COc1cc(N)c2c(c1)OC(C)(C)C=C2
Reactant: O=C(O)c1cc2ccccc2c([N+](=O)[O-])c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1cc(Nc2c(C(=O)O)cc3ccccc3c2[N+](=O)[O-])c2c(c1)OC(C)(C)C=C2

Procedure:
To 3.3 g of 5-amino-7-methoxy-2,2-dimethylchromene there are added 3 g of the compound obtained in Step 3 above, 3.4 g of potassium acetate, 375 mg of Cu(OAc)2.H2O and 120 ml of 2-propanol containing 3.8 ml of triethylamine. The solution is refluxed for 5 days and is then evaporated under reduced pressure. The residue is taken up in a 1/1 mixture of dichloromethane and 1N aqueous HCl solution. After extraction of the aqueous phase, the combined organic phases are treated in customary manner. Chromatography over silica gel (dichloromethane/methanol: gradient from 0.1 to 1%) allows the expected product to be isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[CH:28]=[C:29]([N:33]4[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:35][CH2:34]4)[CH:30]=[N:31][CH:32]=3)=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]2=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[CH:28]=[C:29]([N:33]4[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH2:35][CH2:34]4)[CH:30]=[N:31][CH:32]=3)=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3)c3nc(-c4ccccc4F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5ccccc5F)nc34)c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A solution of tert-butyl 1-(5-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (125 mg, 0.195 mmol) in THF (3 mL) was treated with NaOH 10N (0.195 mL, 1.948 mmol). The reaction was heated to reflux at 80° C. After 4 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-5% MeOH/DCM), affording tert-butyl 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (69 mg, 73%). MS (ESI, pos. ion) m/z: 488.2 (M+1). A solution of tert-butyl 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (64 mg, 0.131 mmol) in MeOH (3 mL) and DCM (0.500 mL) was treated with HCl, 36.5-38.0% (0.109 mL, 1.313 mmol). The reaction was heated to 50° C. After 2 h 30 min, the reaction was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 388.3 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]=O.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]=[N:14][OH:15]
Reactant: O=Cc1sccc1C1OCCO1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1sccc1C1OCCO1

Procedure:
3-(1,3-Dioxolan-2-yl)thiophene-2-carbaldehyde (13.1 g, 71.11 mmol), prepared by a method described by Hibino (S. Hibino et al., J. Org. Chem. 1984, 49, 5006), was dissolved in ethanol (80 ml). At room temperature a solution of hydroxylamine hydrochloride (two equivalents) and sodium hydrogencarbonate (one equivalent) in water (130 ml) was added and the resultant mixture stirred at this temperature for two hours. The ethanol was removed under reduced pressure and the aqueous phase extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation after filtration afforded 3-(1,3-dioxolan-2-yl)thiophene-2-carbaldehyde oxime as an off-white solid (quantitative). 1H NMR (2 isomers, 1:1) (CDCl3): δ 8.56 (1H, s), 8.45 (1H, s), 7.50 (1H, d, J 5.26), 7.25 (1H, d, J 5.2), 7.21 (1H, d, J 5.28), 7.12 (1H, d, J 5.2), 6.09 (1H, s), 5.99 (1H, s), 4.17–4.00 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[O:19]1[CH:23]=[N:22][N:21]=[C:20]1[CH2:24][CH2:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([CH2:25][CH2:24][C:20]3[O:19][CH:23]=[N:22][N:21]=3)=[CH:27][CH:28]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnccc1-c1ccc(F)cc1
Reactant: Nc1ccc(CCc2nnco2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1cnccc1-c1ccc(F)cc1)Nc1ccc(CCc2nnco2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.5 %

Procedure:
A mixture of (2E)-3-[4-(4-fluorophenyl)pyridin-3-yl]prop-2-enoic acid (18.0 g), 4-[2-(1,3,4-oxadiazol-2-yl)ethyl]aniline (14.0 g), triethylamine (14.97 g), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (18.84 g) and dichloromethane (2.5 L) was stirred at room temperature for 17 hr. The reaction mixture was washed successively with water and 1 M aqueous sodium hydroxide solution. Methanol (600 mL) was added thereof, and the mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid. The obtained solid was recrystallized with ethanol to give the title compound (25.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[C:22][Si](C)(C)C)[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 119.6 %

Procedure:
To a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[(trimethylsilyl)ethynyl]pyridine (500 mg, 1.3 mmol) in anhydrous THF (43 mL) was added at 0° C. 1.0M tetra-n-butylammonium fluoride solution in THF (4.0 mL, 4.0 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched by addition of saturated aqueous NH4Cl solution. The mixture was extracted with CH2Cl2, and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC on SiO2 eluting with EtOAc/hexane 1:4 to give 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-ethynylpyridine (470 mg, 98%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[C:5]=2[CH2:4][CH2:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.O1CCCC1.CN(C)C=O>O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:6]3[C:5]4[CH2:4][CH2:3][C:2](=[O:1])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)=[CH:19][CH:18]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Oc2ccnc3c2CCC(=O)N3)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2N1

Procedure:
4-[(7-Oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-4-yl)oxy]aniline (43 mg), p-fluorophenyl isocyanate (28 mg), tetrahydrofuran (5 ml) and dimethylformamide (2 ml) were stirred at room temperature for 30 minutes. Water was added dropwise at room temperature until precipitation of crystals, and these were filtered out to obtain 48 mg of the target substance as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([O:20]C)=O)=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.C1COCC1.[C:27]([Li])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18](=[O:20])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: [Li]C(C)(C)C
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)C(C)(C)C)c1
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a stirred solution of methyl 2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-carboxylate 66.13E (2.00 g, 7 mmol) in THF (138 mL, 7 mmol) at −78° C. was added t-butyllithium (1.7 M in pentane, 9 mL, 14 mmol). Stirring was continued for 3 hours. A saturated solution of ammonium chloride was added to quench the reaction, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 1-(2′-Fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanone 66.13F as a clear oil (2.00 g, 92% yield). MS ESI (pos.) m/e: 334.1 (M+H2O)+, 317.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1.C1C=CN=CC=1.[FH:26]>CCOCC>[Br:19][C:3]1[C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[F:26]
Reactant: F
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc2occc2c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=Cc1ccc2oc(F)c(Br)c2c1
Temperature: 25 °C

Procedure:
Benzofuran-5-carbaldehyde (100 mg, 0.68 mmol) in ether (1 mL) was added to a cold solution (−78° C.) of NBS (158 mg, 1.3 eq) and pyridinium poly(hydrogen fluoride) 70% (0.850 mL) in ether (4 mL) in a polypropylene tube. The reaction was allowed to warm up to room temperature overnight. The reaction mixture was poured into ice water and extracted with ether. The ether phase was washed with aqueous bicarbonate, dried over sodium sulfate, filtrated and evaporated to give 3-bromo-2-fluoro-benzofuran-5-carbaldehyde (141.6 mg). It was purified on reverse phase HPLC (solvents gradient H2O/CH3CN 0.1% TFA) affording the title compound (62 mg, 37%), which was used in the next step.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3SC=C[CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].[CH3:37][O:38][C:39]1[CH:44]=CC(S(Cl)(=O)=O)=[CH:41][CH:40]=1>>[CH3:37][O:38][C:39]1[CH:44]=[CH:35][C:31]([S:28]([N:10]2[CH2:9][C:8]3[CH:36]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[NH:13][CH2:12][C@H:11]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:29])=[O:30])=[CH:41][CH:40]=1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)N2Cc3cc(C#N)ccc3NC[C@H]2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from Compound A of Example 23 and 4-methoxyphenylsulfonyl chloride following the procedure of Compound B of Example 23.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([CH3:21])([CH3:20])[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:11]([CH3:20])([CH3:21])[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(c2ccccc2)C(C)(C)C(=O)Nc2nccs2)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(O)c1ccc(C(c2ccccc2)C(C)(C)C(=O)Nc2nccs2)cc1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of the title compound of Example 368 (20 mg, 0.053 mmol) in ethanol (1 ml) was added sodium borohydride (2 mg, 0.053 mmol) at ° C. The reaction mixture was stirred for 2 h. It was diluted with DCM and saturated aqueous NaHCO3. After separation, the organic extract was washed (brine), dried (MgSO4) and concentrated. The crude product was purified by silica gel flash chromatography using 0 to 50% ethyl acetate in heptane to afford the title compound of Example 371 as a white solid (18 mg, 89% yield). LC/MS (m/z) 381.19 [(M+1)+]; HPLC Rt: 3.246 min. 1H NMR (400 MHz, MeOD) δ ppm 7.36-7.40 (5H, m) 7.28-7.23 (4H, m) 7.20-7.16 (1H, m) 7.06 (1H, s) 4.79-4.75 (1H, m) 4.64 (1H, s) 1.4-1.39 (9H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12]1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[CH:12]3)[CH:4]=2)[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(-c2cccnc2)c1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cnc(-c4cccnc4)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzoic acid (15 mg; 0.054 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (29 mg; 0.11), and HATU (49 mg; 0.11 mmol) were dissolved in 1 mL of DMF, and the mixture was chilled to 0° C. Diisopropylethylamine (19 μL; 0.11 mmol) was then added, the cold-bath was removed, and the mixture was stirred overnight. The mixture was then poured into water and extracted with EtOAc. The organic portion was washed with NaHCO3 and brine, and the washes were extracted once with EtOAc. The extracts were combined, dried with Na2SO4, filtered, and concentrated. Chromatography (0–6.5% MeOH/0.5% NH4OH in CH2Cl2) provided 23 mg (0.043 mmol; 80%) of Example 160. ESI MS m/z 534 [C28H31N5O4S+H]+.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([C:22]1[C:26]([O:27][C:28]2[CH:29]=[C:30]([C:36]#[N:37])[CH:31]=[C:32]([CH:35]=2)[C:33]#[N:34])=[C:25]([CH3:38])[N:24]([CH2:39][CH2:40]O)[N:23]=1)([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:66]=N/C(OCC)=O)=O.O>O1CCCC1>[NH3:15].[NH2:66][CH2:40][CH2:39][N:24]1[C:25]([CH3:38])=[C:26]([O:27][C:28]2[CH:29]=[C:30]([C:36]#[N:37])[CH:31]=[C:32]([CH:35]=2)[C:33]#[N:34])[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[N:23]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1c(Oc2cc(C#N)cc(C#N)c2)c(C(C)(C)C)nn1CCO
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Oc2cc(C#N)cc(C#N)c2)c(C(C)(C)C)nn1CCN
Product: N
Reaction time: 18 h
Yield: 30.9 %

Procedure:
Diphenylphosphorylazide (305 mg, 1.10 mmol) was dissolved in tetrahydrofuran (5 ml) and added to a solution of the pyrazole from Example 157 (180 mg, 0.55 mmol), triphenylphosphine (291 mg, 1.10 mmol) and diethylazodicarboxylate (193 mg, 1.10 mmol) in tetrahydrofuran (20 ml) under nitrogen at room temperature. The reaction was stirred for 18 hours then triphenylphosphine (291 mg, 1.10 mmol) was added, and the reaction was stirred for a further 18 hours. Water (180 μl, 10.0 mmol) was then added and the reaction was stirred for 64 hours. The solvent was removed under reduced pressure and the residual white paste was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:4.5:0.5, by volume) to provide the title compound (55 mg) as a colourless oil.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH:5]([C:7]([S:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1)=[S:8])[NH2:6].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:24][C:21]([C:12]1[CH:11]=[C:10]([S:9][C:7]2[S:8][C:1](=[S:2])[NH:6][N:5]=2)[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]=1[OH:20])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(SC(=S)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Sc2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
Thiophosgene (0.37 mL, 4.8 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl hydrazinecarbodithioate (1.5 g, 4.8 mmol) in tetrahydrofuran (150 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a solid which is crystallized from ethyl acetate/hexane to afford 1.5 g (88%) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1,3,4thiadiazole-2(3H)-thione, mp 181.0°-185.5° C.