Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]2[CH:19]=[CH:20][N:21]=[C:15]2[CH:14]=1)=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]2[C:19]([I:8])=[CH:20][N:21]=[C:15]2[CH:14]=1)=[O:12]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccn2ccnc2c1
Solvent: CC#N
Product: COC(=O)c1ccn2c(I)cnc2c1
Reaction time: 8 h
Yield: 88 %

Procedure:
NIS (1.5 eq, 1.06 mmol, 238 mg) was added in one portion to a stirred solution of imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (0.705 mmol, 124 mg) in acetonitrile (3 mL). The resulting mixture was stirred overnight. The resulting precipitate was filtered and washed with ethyl acetate. Drying in vacuo at room temperature afforded 3-iodo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester in 88% yield. m/z (M+H)=303.1.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[C:1]([NH:8][CH2:9][CH2:10][N:12]=[N+:13]=[N-:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Temperature: 110 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
BocNHCH2CH2Br (10.00 g, 44.62 mmol) was dissolved in DMF (200 mL). NaN3 (14.48 g, 223.1 mmol) was added, and the mixture was stirred at 110° C. for 12 h. The solvent was removed under reduced pressure, and the residue was dissolved in water (200 mL). The resulting aqueous solution was extracted with ethyl acetate (2×200 mL). The organic layers were combined and dried over anhydrous MgSO4(s). After filtering, the organic layer was concentrated under reduced pressure and the residue was dissolved in methylene chloride (10-20 mL) and purified by flash chromatography (silica gel, methylene chloride). BocNHCH2CH2N3 (6.60 g, 80%) was isolated as a colorless oil. HRMS (ESI) [M+Na]+ calcd for C7H14N4O2Na, 209.1014; found, 209.1010; 1H NMR (400 MHz, CDCl3) δ 4.88 (bs, 1H), 3.42 (t, J=5.3 Hz, 2H), 3.34-3.26 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.8, 79.8, 51.4, 40.2, 28.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:28]([F:31])([F:30])[F:29])[CH2:3][CH2:2]1.[C:32](=O)([O:34]C1C=CC=CC=1)[NH2:33].CCN(CC)CC.FC(F)(F)C(O)=O>CO>[NH2:33][C:32]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:28]([F:29])([F:30])[F:31])[CH2:3][CH2:2]1)=[O:34]
Reactant: N=C(N)c1ccc(O)c(C=CCNc2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Reactant: NC(=O)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(O)c(C=CCNc2ccc(OC3CCN(C(N)=O)CC3)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine (75 mg) in MeOH was added phenyl carbamate (37 mg) and Et3N (0.073 mL). The reaction mixture was stirred at ambient temperature for 3 hours, acidified with trifluoroacetic acid and purified on HPLC (10-40% acetonitrile in water with 0.1% trifluoroacetic acid). The corresponding peak was collected and freezed dried to afford 4-(N′-(aminocarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:34]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:38]([CH:34]4[CH2:37][CH2:36][CH2:35]4)=[O:39])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Reactant: O=C(Cl)C1CCC1
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)C4CCC4)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and cyclobutancarbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(O)C>[OH-].[Na+]>[C:9]1([CH3:8])[CH:14]=[CH:13][C:12]([S:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1

Procedure:
Aniline (5 g, 54 mmol) was reacted with p-toluenesulfochloride (15 g, 78 mmol) in 10% sodium hydroxide solution under standard conditions (Vogel, Id, at p. 1275). The product (8.9 g, 36 mmol) was twice recrystallized from ethanol; the melting point was 102°-103° C., yield, 67%.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Fc1ncccc1-c1ccnc(C(F)(F)F)c1
Temperature: 95 °C

Procedure:
A mixture of 2-fluoropyridin-3-ylboronic acid (0.748 g, 5.3 mmol), 4-bromo-2-(trifluoromethyl)pyridine (1.00 g, 4.4 mmol), Pd(PPh3)2Cl2 (0.155 g, 0.22 mmol) and sodium carbonate (0.797 g, 13.3 mmol) in DME (6.5 mL), ethanol (1.9 mL) and water (0.47 mL) was heated to 95° C. for 2 h. After cooling to room temperature, the mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (EtOAc/Hexanes=0→20%) to give the title compound. MS (ESI, pos. ion) m/z: 243 (M+1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].C(O)(=O)C.[Cl:16]N1C(=O)CCC1=O>O>[Cl:16][C:10]1[CH:9]=[C:6]([O:7][CH3:8])[C:4]([OH:5])=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Cl)cc(C=O)c1O
Temperature: 105 °C
Reaction time: 0.12 h
Yield: 52 %

Procedure:
o-Vanillin (100.5 g, 660 mmol), acetic acid (504 mL) and N-chlorosuccinimide (83.8 g, 627 mmol) were mixed and heated to 105° C. over 30 minutes. A rapid exotherm from 55 to 105° C. occurred over 7 minutes. The mixture refluxed for a few minutes and was allowed to cool slowly to room temperature (2.5 h). Water (1 L, 2 volume equivalents) was added to the mixture slowly over 10 minutes. The mixture was stirred for 5 minutes, filtered and the crude product air dried to afford 146.9 g of wet cake as a light yellow powder with 90% product, 3% o-vanillin and 7% dichlorovanillin Recrystallization from 200 g ethanol afforded 61 g (52% yield).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.C1C(=O)N([Cl:27])C(=O)C1>CC(O)=O>[Cl:27][C:10]1[C:11]2[C:2](=[O:1])[NH:3][CH2:4][CH2:5][C:6]=2[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(OC(C)C)cc2c1CCNC2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC(C)C)c(Cl)c2c1CCNC2=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of methyl 1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (Cpd E, 400 mg, 1.52 mmol) in AcOH (5 mL) was added NCS (416 mg, 3.04 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under vacuum and the residue was diluted with H2O and NaHCO3 (sat., aq.). The aqueous layer was extracted with EtOAc and the organic layer purified by column chromatography (50% EtOAc/heptanes) to give the title compound (Cpd F, 180 mg, 40%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 1.40 (s, 3H) 1.42 (s, 3H) 3.27-3.36 (m, 2H) 3.37-3.47 (m, 2H) 3.88-3.95 (m, 3H) 4.62 (dt, J=12.07, 6.13 Hz, 1H) 6.06 (br. s., 1H) 7.61 (s, 1H); MS 298.0 [M+H].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:4][CH2:3]1.[O:30]=[C:31]1[CH2:36][O:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH3-]C#N.[Na+]>CO>[C:27]([C:24]1[CH:25]=[CH:26][C:21]2[O:20][CH2:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:41][C:39]4[CH:38]=[CH:37][C:34]5[O:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=5[N:40]=4)[CH2:7][N:6]3[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C:22]=2[CH:23]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](NCc2ccc3c(n2)NC(=O)CO3)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl(2R,5S)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (Intermediate 183, 0.14 g), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg) and 3 Å molecular sieves powder (70 mg) in methanol (8 mL) was heated at 80° C. for 1 hour. The solution was cooled to 0° C. and NaCNBH3 (33 mg) was added. After stirring at room temperature overnight, the reaction was filtered and concentrated. The residue was purified chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride to give 0.14 g.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([NH:6][CH2:7][CH:8]2[CH2:10][CH2:9]2)=[C:4]([N+:13]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:6][CH2:7][CH:8]2[CH2:10][CH2:9]2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCC1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1NCC1CC1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 4-bromo-N-(cyclopropylmethyl)-2-nitroaniline (Step A, 1.7 g, 6.2 mmol), iron (1.7 g, 31.2 mmol) and ammonium chloride (33 mg, 0.62 mmol) in ethanol (18 mL) and water (6 mL) was stirred under reflux for 4 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (40 mL) and the mixture was washed with water containing aqueous ammonia. The organic layer was separated, dried over sodium sulfate and concentrated to afford the title compound (1.48 g, 98%) as a brown oil.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@H:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]4[C:32]5[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=5)[N:26](S(C5C=CC(C)=CC=5)(=O)=O)[CH:25]=4)[N:18]=3)[CH2:11]2)=[O:8])[CH2:3]1.[Li+].[OH-].[Cl-].[NH4+]>C1COCC1>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@H:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]4[C:32]5[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=5)[NH:26][CH:25]=4)[N:18]=3)[CH2:11]2)=[O:8])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](OC(=O)N5CC[C@@H](F)C5)C4)n3)c3cc(F)cnc32)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1CCC[C@@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1)N1CC[C@H](F)C1
Temperature: 50 °C

Procedure:
To a solution of crude (R)-(1S,3R)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl 3-fluoropyrrolidine-1-carboxylate, 75d, (0.119 g, 0.019 mmol) in THF (2 mL) was added 5 mL 2N LiOH (10 mmol). The reaction mixture was heated at 50° C. for 2 hours. The mixture was diluted into aqueous saturated ammonium chloride (2 mL), and extracted with EtOAc (2×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified on the semi-prep HPLC, 10-70% CH3CN/H2O; Three runs; homogeneous fractions were combined and the solvent removed under a stream of nitrogen and then removed residual solvent on roto-evaporator to afford 74 mg of the desired product: LCMS RT=2.15 min (M+H) 461.51.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
(S)-3-(Aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.20 g, 0.49 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.49 mmol) were placed in a THF-DCM solution (1:1, 6 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.010 g, 49%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H), 7.02-6.98 (m, 2H), 5.25 (s, 1H), 4.96-4.95 (m, 1H), 4.55-4.52 (m, 1H), 4.30 (d, J=14.8 Hz, 1H), 4.21 (d, J=14.8 Hz, 1H), 2.01 (s, 3H), 1.51 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 444. Found: [M+H]+ 445.
Reaction SMILES: BrC1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:8]([OH:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C]=O.CC[O:51][C:52]([CH3:54])=[O:53]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([CH2:18][NH:17][C:15]([C:7]1[C:6](=[O:26])[C:5]2[CH:4]=[CH:3][C:54]([C:52]([OH:51])=[O:53])=[CH:11][C:10]=2[C:9]([CH3:12])([CH3:13])[C:8]=1[OH:14])=[O:16])([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(Br)ccc2C1=O
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC1(C)C(O)=C(C(=O)NCC(=O)O)C(=O)c2ccc(C(=O)O)cc21

Procedure:
Tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (253 mg, 596 μmol, Example 53A-E), trans-dichlorobis(triphenylphosphine)palladium (II) (21 mg, 30 μmol), and triphenylphosphine (16 mg, 60 μmol) were added to a vial, followed by water (32 μL, 1789 μmol) and n-tributylamine (1491 μL). The reaction mixture was placed under 4 atm of carbon monoxide at 90° C. for 18 hours. The reaction mixture was diluted with 50 mL of EtOAc, washed 3 times with 50 mL of 5 N NaOH (aqueous), and separated. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted 2 times with 50 mL of EtOAc, dried over sodium sulfate, and concentrated via rotovap to give the title compound. MS (ESI) m/z: Calculated; 333.3: Observed; 334.0.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(Br)cc1

Procedure:
The title compound was synthesized from methyl 4-(4-bromobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.0998 g, 0.3 mmol, 1 equiv) and lithium hydroxide (0.8 mL, 2 M aqueous, 1.6 mmol, 5.3 equiv), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (5 mL) was used. The resulting product was purified via preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 70% methanol and increasing to 100% over 7 minutes) afforded the title compound. 67.2 mg, with purity by HPLC of 100% (UV). LCMS m/e 318 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.02-2.16 (m, 1H), 2.49-2.67 (m, 3H), 2.74 (dd, J=9.77, 7.37 Hz, 2H), 3.19-3.29 (m, 1H), 6.29 (s, 1H), 7.11 (d, J=8.35 Hz, 2H), 7.41 (q, J=4.25 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[CH2:32][OH:33].C1(C=CC(O)=CC=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:32]1[O:33][C:26]2([CH2:27][CH2:28][CH:29]=[C:24]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25]2)[O:30][CH2:31]1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2=CCCC3(C2)OCCO3)c(OCc2ccccc2)c1

Procedure:
A solution of 500 mg. of 3-[2-benzyloxy-4-(1,1dimethylheptyl)phenyl]cyclohex-2-en-1-one, 7.8 g. of ethylene glycol, 375 mg. of hydroquinone and 50 mg. of p-toluenesulfonic acid monohydrate in 50 ml. of benzene is heated at reflux for 12 hours using a Dean-Stark condensor filled with 3A molecular sieves. The reaction is cooled, added to 500 ml. saturated sodium bicarbonate and the quenched mixture extracted with three 150 ml. portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid is purified via column chromatography on 50 g. of silica gel eluted with 50% ether-petroleum ether to yield the title product.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[S:16])[N:9]([CH3:17])[C:8](=[O:18])[CH:7]=1.Cl>O.C(O)C>[NH2:5][C:6]1[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[S:16])[N:9]([CH3:17])[C:8](=[O:18])[C:7]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: CC(C)Cn1c(N)cc(=O)n(C)c1=S
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(N)c(N=O)c(=O)n(C)c1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Sodium nitrite (0.34 g, 4.9 mmol) in water (1.5 mL) was added to a solution of the amine (1.00 g, 4.7 mmol) in ethanol (7.0 mL) at room temperature. 5M Hydrochloric acid (1.0 mL, 4.9 mmol) was added and the resulting dark red reaction mixture was stirred at room temperature for 2 h. Ethanol (20 mL) was added and the red crystals were filtered off and washed with diethyl ether. Drying of the crystals gave the title compound (0.68 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C@H:14]([O:16][CH3:17])[CH3:15])[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[O:19]1CCOCC1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C@H:14]([O:16][CH3:17])[CH3:15])[N:8]=[C:7]([CH:18]=[O:19])[CH:6]=[CH:5]2
Reactant: C1COCCO1
Reactant: CO[C@H](C)COc1cc2nc(C)ccc2cc1F
Solvent: O
Product: CO[C@H](C)COc1cc2nc(C=O)ccc2cc1F
Yield: 74 %

Procedure:
To a solution of (R)-6-fluoro-7-(2-methoxypropoxy)-2-methylquinoline (0.281 g, 1.13 mmol) in dioxane (4 mL) and water (0.04 mL) was added SeO2 (0.138 g, 1.24 mmol). The reaction mixture was heated at reflux for 3 hours. After cooling, the mixture was filtered through Celite®. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 4:1) to give (R)-6-fluoro-7-(2-methoxypropoxy)quinoline-2-carbaldehyde (0.219 g, 74%) as a solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[Cl:13])(=[O:3])[CH3:2].[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)c(C(C)=O)c2ccccc21
Reaction time: 8 h
Yield: 84.5 %

Procedure:
1 g of (75) was dissolved in 25 ml THF. 250 mg NaH was added, and then 1.87 g of (2-methyloxyethyl)oxymethylchlorid. The reaction was left with stirring overnight, another 100 mg NaH was added, and the reaction continued another 4 hours. The reaction mixture was added to a 2N K2CO3 solution and extracted with toluene. The organic phase was washed with water and brine, dried and evaporated. The resulting oil was extracted twice with boiling heptane, cooled, filtered, and evaporated giving 1.23 g of (80) as a yellow oil, 1H-NMR (ppm): 8.35(m, 1H); 7.44(m, 1H); 7.27(m, 2H); 5.62(s, 2H); 3.58(m, 2H); 3.47(m, 2H); 3.32(s, 3H); 2.65(s, 3H).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7].[Li]CCCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].CCCCCC>O1CCCC1>[F:7][C:6]([F:9])([F:8])[CH2:5][CH2:4][C:3]#[C:2][Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)(F)CCC=C(Br)Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CCCC(F)(F)F)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution the product from Step A (0.935 mg, 3.31 mmol) in 10 mL of tetrahydrofuran was added n-BuLi solution (2.65 mL, 6.63 mmol, 2.5 M hexanes) dropwise. The reaction was stirred at −78° C. for one hour, then allowed to warm to room temperature for one hour. The solution was cooled to 0° C., and tributyltin chloride (0.898 mL, 3.31 mmol) was added. After 10 minutes, the solution was poured into hexane, washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown liquid which was used without further purification.