Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:9][N:8]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=[C:7]3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>>[OH:34][C@:30]([C:27]1[CH:26]=[C:25]([CH3:24])[O:29][N:28]=1)([CH3:31])[C:32]#[C:33][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:9][N:8]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=[C:7]3[C:6]=2[CH:23]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(C(C)(C)O)C2
Product: COC(=O)c1cn2c(n1)-c1cc(C#C[C@@](C)(O)c3cc(C)on3)ccc1OC(C(C)(C)O)C2

Procedure:
Similar to as described in General Procedure G, racemic methyl 10-bromo-6-(2-hydroxypropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give methyl 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(2-hydroxypropan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate. M+1=452. A solution of the above compound (100 mg, 0.22 mmol, 1.00 equiv) in methanol (Saturated with ammonia, 20 mL) was stirred for 3 days at 60° C. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (19:1) to give a mixture of diastereoisomers. The two diasteromers were separated by Chiral-Prep-HPLC with the following conditions (Prep-HPLC-004): Column, Chiralpak IC, 2*25 cm, 5 um; mobile phase, Hex and ethanol (hold 40.0% ethanol in 25 min); Detector, UV 254/220 nm to give 12.2 mg (13%) Compound 1 as a off-white solid, Chiralpak IC-3, 25° C., 254 nm, 60:40 Hex (0.1% TEA):EtOH, 1 mL/min, tR=2,7 min; and 11.5 mg (12%) of Compound 2 as an off-white solid, Chiralpak IC-3, 25° C., 254 nm, 60:40 Hex (0.1% TEA):EtOH, 1 mL/min, tR=5.0 min.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[N:26]([CH3:30])[N:27]=[CH:28][CH:29]=2)[C:22]([CH:31]([CH3:33])[CH3:32])=[CH:21][C:20]=1[NH:34][C:35](OC1C=CC(Cl)=CC=1)=[O:36]>O1CCOCC1>[CH:31]([C:22]1[CH:21]=[C:20]2[C:19]([C:18](=[O:17])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:35](=[O:36])[NH:34]2)=[CH:24][C:23]=1[C:25]1[N:26]([CH3:30])[N:27]=[CH:28][CH:29]=1)([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C(C)C)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc2[nH]c(=O)n(NS(C)(=O)=O)c(=O)c2cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
CH3SO2NHNH2 (79.5 mg, 1.1 equiv) and i-Pr2NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH/DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]+, rt 4.20 min).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH:23][C:31](=[O:33])[CH3:32])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (1.5 g, 0.005 mol), triethylamine (0.76 mL, 0.0054 mol) and N,N-dimethylaminopyridine (catalytic amount) in 50 mL of dichloromethane is cooled to 0° C. and acetyl chloride (0.42 mL, 0.006 mol) is added dropwise. The cold bath is removed and the solution is stirred at room temperature for 1 hour. The reaction is quenched with saturated aqueous sodium bicarbonate, the organic layer is washed with water and dried (sodium sulfate), and the solvent is removed under reduced pressure. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound, containing 0.35 mol of water; mp 158.5°-159.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Temperature: 120 °C
Yield: 19.5 %

Procedure:
A solution of 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (prepared according to WO2007/109279, 0.141 g, 0.43 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.092 g, 0.44 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and then heated at 120° C. for 5 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc) followed by trituration with MeOH afforded the title compound as white solid (0.042 g, 20%).
Reaction SMILES: Cl.Cl.[F:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.Br[CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH:4]([F:3])[CH2:5]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: FC1CCNC1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCN1CCC(F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 3-Fluoro-pyrrolidine dihydrochloride salt (448 mg, 3.584 mmol) in anhydrous acetonitrile (24 mL) was treated with bromopropoxy-tert-butyldimethyl silane (0.83 mL) and then with K2CO3 (2.5 g, 5 equiv.). The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was subsequently diluted with water (75 mL) and extracted with a 6:1 mixture of Hexane and diethyl ether (2×100 mL). The organic layer was washed with NaHCO3(aq) (100 mL) and brine (100 mL) then dried over anhydrous K2CO3. Following filtration and concentration of the filtrate in vacuo the crude product was purified by flash silica gel chromatography (MeOH:EtOAc, 1:20). By 1H NMR the resulting clear oil (0.8 g) was the desired 1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-3-fluoro-pyrrolidine in a 10:1 ratio with the t-butyldimethylsilanol by-product. This residue was carried on without further purification.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:15][CH2:14]1.C([N:30]([CH2:33]C)CC)C.ClC(Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl.N>ClCCl>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:22][CH2:23][C@H:24]([NH:27][C:33]([NH2:30])=[O:38])[CH2:25][CH2:26]2)[CH2:15][CH2:14]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c(Cl)c1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: ClCCl
Product: COc1ccc(N2CCN(CC[C@H]3CC[C@H](NC(N)=O)CC3)CC2)c(Cl)c1Cl
Reaction time: 20 h

Procedure:
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine 1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature ammonia (20% solution in methanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave 0.86 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.37 g of title compound, melting at 195-8° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](=[O:6])[CH3:5].[CH2:8](Br)[CH:9]=C.[In].[CH3:13]O.Cl>>[CH3:1][O:2][C:3](=[O:7])[C:4]([OH:6])([CH3:13])[CH2:5][CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: COC(=O)C(C)=O
Reactant: CO
Agent: Cl
Agent: [In]
Product: C=CCC(C)(O)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring solution of 2-oxopropionic acid methyl ester (1.0 g, 0.903 mmol), allyl bromide (1.8 mL, 21.32 mmol) in MeOH/HCl (1:4, 10 mL), is added indium powder (1.12 g, 9.76 mmol). The mixture is stirred for 3 days at room temperature. The mixture is quenched with NaHCO3 and extracted with DCM (3×50 mL). The organic layers are washed with water (2×50 mL) and brine. The combined organic layers are dried with MgSO4 and concentrated to afford 2-hydroxy-2-methylpent-4-enoic acid methyl ester: (M+H)+=145.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[N:22]1([C:28]2[N:32]=[C:31]([NH2:33])[O:30][N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:33][C:31]3[O:30][N:29]=[C:28]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[N:32]=3)[CH:3]=2)[N:8]=1
Reactant: Nc1nc(N2CCCCC2)no1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Product: COc1ccccc1CNc1ccc2cc(Nc3nc(N4CCCCC4)no3)ccc2n1

Procedure:
The title compound, light brown foam, MS: m/e=431.3 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and 3-(piperidin-1-yl)-[1,2,4]oxadiazol-5-yl-amine [CAS-No. 75565-19-4].
Reaction SMILES: N[C:2]1[C:3]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[BH3-][C:21]#[N:22].[Na+].[OH-].[Na+].[C:26](O)(=O)C>>[CH2:13]([O:12][C:3]1[C:2]([N:22]([CH3:21])[CH3:26])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(N)c1OCc1ccccc1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cccc(N(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-amino-2-(benzyloxy)benzoate (17 g, 66.07 mmol, 1.00 equiv), acetic acid (360 mL) and (CHO)n (11.91 g, 6.00 equiv). This was followed by the addition of NaBH3CN (25 g, 6.00 equiv) in several batches at 0° C. The resulting solution was stirred overnight at 25° C. The pH value of the solution was adjusted to 7 with sodium hydroxide (cooled) (1 mol/L). The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 16 g (85%) of methyl 2-(benzyloxy)-3-(dimethylamino)benzoate as yellow oil. MS (ESI) m/z 286 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3](O)([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.C(N(S(F)(F)[F:40])CC)C.O>ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]([F:40])([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(CCCc1cccc(Oc2ccccc2)c1)(c1ccc(OC(F)(F)F)cc1)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(C(F)(CCCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1,1,1-trifluoro-2-hydroxy-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)pentane (0.18 g) in dichloromethane (6 cm3) was cooled to -78° C. and diethylaminosulphur trifluoride (0.1 g) was added. The mixture was allowed to warm to room temperature, stirred for a further 20 minutes and poured into water. The products were extracted into dichloromethane. The combined organic extracts were dried and the solvent evaporated under reduced pressure to leave an oil. The oil was purified by chromatography to give 1,1,1,2-tetrafluoro-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)pentane.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([Li])CCC.[S:25](=[O:27])=[O:26].C([O-])(=O)C.[Na+].[NH2:33]OS(O)(=O)=O>O.O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:25]([NH2:33])(=[O:27])=[O:26])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOS(=O)(=O)O
Reactant: O=S=O
Reactant: Cc1onc(-c2ccc(Br)cc2)c1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-[5-Methyl-4-phenylisoxazol-3-yl]bromobenzene from Step 3 (1.73 g, 5.5 mmol) and tetrahydrofuran (100 mL) were stirred at -78° C. under nitrogen. Butyllithium (1.6M in hexanes, 4.1 mL, 6.6 mmol) was added dropwise, maintaining the temperature below -60° C. After stirring at -78° C. for 0.5 hour, sulfur dioxide gas was passed through a stainless steel needle above the surface of the solution. After 1 minute, the solution changed color from orange to clear, and after 10 minutes pH paper indicated an acidic reaction. Gas addition was ceased and the cooling bath was removed. After 1 hour, the mixture was concentrated to 25 mL and hexane (100 mL) was added. A white precipitate formed which was isolated by filtration. This solid was dissolved in water (50 mL) and sodium acetate (4.5 g, 55 mmol), and hydroxylamine-O-sulfonic acid (0.75 g, 6.6 mmol) were added. The resulting mixture was stirred at room temperature overnight and extracted with ethyl acetate (2×50 mL). The combined extract was washed with brine, dried over MgSO4, and concentrated. A white solid was recrystallized from dichloromethane/hexane (0.8 g, 46%): mp 150.9°-152.3° C. 1H NMR (acetone-d6 /300 MHz) 7.9 (d, J=9.7 Hz, 2H), 7.6 (d, J=9.7 Hz, 2H), 7.4 (m, 3H), 7.3 (m, 2H), 6.7 (bs, 2H), 2.5 (s, 3H). Anal. Calc'd. for C16H14N2O3S: C, 61.13; H, 4.49; N, 8.91. Found: C, 61.18; H, 4.52; N, 8.85. High resolution mass spectrum calc'd. (M+H): 315.0803. Found : 315.0793.
Reaction SMILES: CC([O-])(CC)C.[Na+].Cl[C:9]1[N:14]=[C:13]2[O:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:17]([C:18](=[O:21])[NH:19][CH3:20])[C:12]2=[CH:11][C:10]=1[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45]>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[O:15][C:13]3=[N:14][C:9]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[C:10]([C:29]4[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=4)[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH:11]=[C:12]3[C:17]=2[C:18](=[O:21])[NH:19][CH3:20])=[CH:27][CH:26]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Reactant: NCC(F)(F)F
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
Sodium 2-methylbutan-2-olate (229 mg, 2.08 mmol), tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (200 mg, 0.416 mmol), 2,2,2-trifluoroethanamine (206 mg, 2.08 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (33 mg, 0.042 mmol) was combined, degassed, and taken up in dioxane (8.3 ml) at rt and then was heated to 80° C. LCMS at 30 min showed major peak with M+H matching that of the expected product. The mixture was diluted with EtOAc and washed with 1M HCl aq, and sat NaCl aq. The organic phase was concentrated and triturated with DCM to give the expected product tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoate (130 mg, 0.239 mmol, 58% yield) consistent by LCMS. LC-MS retention time: 2.13 min; m/z (MH+): 544. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:10][C:9]=1[OH:21])=[O:7].[CH3:23]CN(CC)CC.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>ClCCl.O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]([C:8]1[C:9]([O:21][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30])=[CH:10][C:11]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:12][C:13]=1[CH3:23])=[O:7]
Reactant: CCN(CC)CC
Reactant: COC(=O)CCC(=O)c1ccc(OC2CCCCO2)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(=O)c1c(C)cc(OC2CCCCO2)cc1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of 4-[2-hydroxy-4-(tetrahydro-pyran-2-yloxy)-phenyl]-4-oxo-butyric acid methyl ester (2.87 g, 8.91 mmol) and Et3N (3.71 mL, 26.73 mmol) in dichloromethane (30 mL) was added Tf2O (2.30 mL, 13.37 mmol) at −78° C. The mixture was stirred at −78° C. for 2 hours, diluted with H2O and extracted with dichloromethane. The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was dissolved in Hexane-EtOAc(4:1), filtered through a plug of silica gel and filtrate was concentrated to give 4-[2-methyl-4-(tetrahydro-pyran-2-yloxy)-6-trifluoromethanesulfonyloxy-phenyl]-4-oxo-butyric acid methyl ester (2.56 g, 63%). 1HNMR (400 MHz, CDCl3): 6.95 (s, 1H), 6.90 (s, 1H), 5.45 (s, 1H), 3.82 (m, 1H), 3.77 (s, 3H), 3.65 (m, 1H), 3.10 (t, J=6.5 Hz, 2H), 2.75 (t, J=6.5 Hz, 2H), 2.30 (s, 3H), 2.05-1.50 (m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[CH:8][N:7]=1.C1C(=O)N([Cl:20])C(=O)C1>CC(O)=O>[Cl:20][C:9]1[C:10]([OH:12])=[N:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccnc(-c2cccs2)n1
Solvent: CC(=O)O
Product: Oc1nc(-c2cccs2)ncc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
To the solution of 2-(thiophen-2-yl)pyrimidin-4-ol (100 mg, 0.56 mmol) in HOAc (3 mL) was added NCS (90 mg, 0.67 mmol, 1.2 equiv.) portionwise. The reaction mixture was stirred at 60° C. for 4 h and partitioned between brine and ethylacetate. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to give 5-chloro-2-(thiophen-2-yl)pyrimidin-4-ol (90 mg, 75%). LC-MS (m/z)=213.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.ClC([C:17]1[CH:18]=[C:19](C(C)C#N)[CH:20]=[CH:21][CH:22]=1)=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C#N)c1cccc(C(=O)c2ccccc2)c1

Procedure:
3-Carboxybenzyne prepared from 2-chlorobenzoic acid in the presence of a strong base is reacted with propionitrile to produce alpha-(m-carboxyphenyl)propionitrile (R. Biehl et al., J. Org. Chem., 31, 602 (1966)). The alpha-(m-carboxyphenyl)propionitrile is converted to alpha-(m-chlorocarbonylphenyl)propionitrile by using thionyl chloride. Friedel-Crafts reaction of alpha-(m-chlorocarbonylphenyl)propionitrile with benzene using aluminum chloride affords alpha-(m-benzoylphenyl)propionitrile. Hydrolysis of the alpha-(m-benzoylphenyl)propionitrile with methanol/sodium hydroxide gives alpha-(m-benzoylphenyl)propionic acid (see British Pat. No. 1,360,560).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[CH2:4].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH:3]=[CH2:4])[CH:10]=[CH:11]1)[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=Cc1cccc2cc[nH]c12
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCCCn1ccc2cccc(C=C)c21
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
Add sodium hydride (60% dispersion in mineral oil) (3.5 g, 87.3 mmol) to a 0° C. solution of 7-vinylindole (5.0 g, 34.9 mmol) in 140 mL of dimethylformamide. Warm the resulting mixture to 20-24° C. and stir an additional 30 minutes. Add 5-bromo-1-pentene (20 mL, 175 mmol) dropwise and stir for 3 hours. Pour the reaction mixture into a mixture of 150 mL of water and 150 mL of ethyl acetate. Wash the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers, wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5-10% ethyl acetate in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as a clear oil (5.39 g, 73%).