Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:5]([O:19][CH3:20])[CH:4]=1.[CH2:21](O)[CH:22]=[CH2:23]>CO.C(Cl)(Cl)Cl>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[O:19][CH3:20])[CH:22]=[CH2:21]
Reactant: C=CCO
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OCCCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CCOC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Yield: 72 %

Procedure:
A mixture of compound 51 (7.00 g 24.50 mmol), allyl alcohol (80 mL) and p-tosic acid (742 mg, 3.90 mmol) was heated at reflux under a N2 atmosphere for 4 hOURS, at which time TLC (2% MeOH/CHCl3) indicated that reaction had gone to completion. Excess allyl alcohol was evaporated in vacuo to afford the crude compound (52), which was partitioned between NaHCO3 (50 mL) and EtOAc (50 mL). The organic layer was washed with water (3×50 mL), brine (3×50 mL) and then dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (CHCl3) yielded the product as an orange-brown solid (5.78 g, 72%). MP=73-75° C. 1H NMR (250 MHz, CDCl3) δ 7.70 (s, 1H), 7.16 (s, 1H), 6.00-5.84 (m, 1H), 5.36-5.21 (m, 2H), 4.94 (d, J=6.3 Hz), 4.62-4.59 (m, 2H), 4.13 (t, J=6.2 Hz, 2H), 3.97 (s, 3H), 2.67-2.56 (m, 3H), 2.20 (pent, J=6.7 Hz, 2H). 13C NMR 5173.1 (C12), 154.7 (Cquat.), 147.3 (Cquat.), 139.6 (Cquat.), 133.2 (Cquat.), 132.4 (C14), 118.7 (C15), 111.1 (C6), 109.9 (C3), 68.6 (C9), 65.6 (C13), 62.7 (C1), 56.7 (C8), 30.9 (C11), 24.6 (C10). IR (cm−1) 3329.4, 3100.0, 2972.1, 1734.5, 1647.9, 1577.4, 1508.1, 1281.5, 932.8, 884.0, 815.8, 758.2, 662.2. MS (M+ —OH) 308. Anal. Calcd for C16H19NO7: C, 55.38; H, 5.89; N, 4.31. Found: C, 52.41; H, 5.86; N, 4.67.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([NH2:13])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C(#N)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]#[N:13]
Reactant: NC(=O)c1sc2cnccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1sc2cnccc2c1Br
Temperature: 85 °C
Yield: 29.4 %

Procedure:
To a suspension of 3-bromothieno[2,3-c]pyridine-2-carboxamide (750 mg, 2.92 mmol) in acetonitrile (20 mL) was added phosphorus oxychloride (816 μL, 8.75 mmol) and the mixture was heated under N2 for 1 hour at 85° C. The same portion of phosphorus oxychloride was added every hour at 85° C. for a total of 6 h. The crude mixture was poured into saturated aqueous sodium carbonate on ice, to reach pH 7-8. DCM was added. The mixture was filtered to remove inorganic salts and the organic layer was separated. The DCM layer was washed with brine and dried over anhydrous Na2SO4. Purification by ISCO chromatography (100% DCM) afforded 205 mg (29%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 9.31-9.36 (m, 1 H), 8.71 (d, J=5.8 Hz, 1 H), 7.93 (dd, J=5.6, 1.0 Hz, 1 H); MS (ESI): 239.42, 241.35 [M+H]+; HPLC tR=1.04 min (HPLC: Analytical—2 min).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Product: COC(=O)[C@@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)C1

Procedure:
Using a method analogous to Method A, using (1R,3S)-methyl 3-aminocyclopentanecarboxylate and 2′,4′-difluorobiphenyl-4-sulphonyl chloride, the title compound was obtained as a pale yellow gum.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:37]C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=1>C(O)=O>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-n2cnnc2)cc1)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-n2cnnc2)cc1)C(C)C

Procedure:
0.543 g (0.89 mmol) of 1-[p-(1,2,4-triazol-4-yl)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane (Example 14f) is stirred in 20 ml of formic acid at RT for 4 h under nitrogen. The formic acid is removed, the residue is taken up in methylene chloride, and the organic phase is washed with a sat. solution of sodium bicarbonate. The title compound is isolated as a yellow foam, which is subjected to further processing without being purified.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:5]2=1.C1C(=O)N([Cl:40])C(=O)C1>>[Cl:40][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[CH:17]=1)=[CH:3][C:2]([CH3:1])=[N:11][CH:10]=3
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Cl)cc21
Yield: 45.6 %

Procedure:
(S)-tert-butyl (1-((2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.05 g, 0.114 mmol), prepared as described in Example 67, Part F, was subjected to chlorination using NCS (0.018 g, 0.137 mmol), using the procedure described in Example 20, Part A, to give (S)-tert-butyl (1-((9-chloro-2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.052 mmol, 45% yield) as colorless oil. LC/MS (ESI) m/e 474.7 [(M+H)+, calcd for C25H32ClN3O4 474.2]; LC/MS retention time (method H): tR=0.94 min.
Reaction SMILES: [OH:1][C@@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1>CCOC(C)=O.CCCCCC>[OH:1][C@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1
Reactant: O[C@@H]1C=C[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O[C@H]1C=C[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 77 %

Procedure:
Compound 37 was subjected to general procedure J. TLC: Rf=0.36 (10% EtOAc/Hexane). 1H NMR (400 MHz, DMSO): δ2.00 (m, 1H), 2.15 (m, 1H), 4.95 (m, 1H), 5.40 (m, 1H), 5.95 (m, 1H), 6.05 (m, 1H), 7.30-7.60 (m, 15H), 8.20 (d, 2H), 8.40 (d, 2H). Subsequent subjection of the product to general procedure E gave compound 65. Yield=77% (2 steps). TLC: Rf=0.32 (25% EtOAc/Hexane). 1H NMR (400 MHz, DMSO): δ1.55 (m, 1H), 1.80 (m, 1H), 4.70 (m, 1H), 4.80 (m, 1H), 5.10 (m, 1H), 5.80 (m, 1H), 7.40 (m, 3H), 7.45 (m, 6H), 7.55 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCOCC1.Cl.[NH:20]1[CH2:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:20]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: N#CC1(c2ccc(Cl)nc2)CC1
Reactant: C1CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: N#CC1(c2ccc(N3CCC3)nc2)CC1

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)cyclopropanecarbonitrile (200.0 mg, 0.001120 mol) in 1,4-dioxane (8.00 mL, 0.102 mol) at rt were added azetidine hydrochloride (128.3 mg, 0.001344 mol), palladium acetate (25.2 mg, 0.000112 mol), and sodium tert-butoxide (288 mg, 0.00291 mol). The reaction mixture was degassed and then microwave irradiated at 150° C. for 40 min. The reaction mixture was quenched with water and extracted with ethyl acetate and dichloromethane. The crude product was purified by combiflash. LCMS: m/z 200.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@:5]([CH3:10])([CH:7]=[N:8][OH:9])[CH2:4][O:3]1.[Cl:12]N1C(=O)CCC1=O>CN(C=O)C.O>[OH:9][N:8]=[C:7]([Cl:12])[C@:5]1([CH3:10])[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OC[C@@](C)(C=NO)O1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@](C)(C(Cl)=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
(R)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g, 30 mmol) was dissolved in DMF (100 mL) and 1-chloropyrrolidine-2,5-dione (4.0 g, 30 mmol) was added. The reaction was stirred at ambient temperature overnight, then poured in water (600 mL) with of stirring. After 15 minutes the cloudy suspension was extracted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to afford (S)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (5.5 g, 28 mmol, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7](Cl)=[O:8].[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[C:25]([NH2:34])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7]([NH:34][C:25]1[CH:26]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:28]=[C:29]2[C:24]=1[CH:23]=[N:22][N:21]2[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19])=[O:8]
Reactant: CCn1ncc(Cl)c1C(=O)Cl
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1ncc(Cl)c1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-1-ethyl-1H-pyrazole-5-carbonyl chloride (122 mg) in DCM (5 ml) was added over 5 min to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (250 mg) in DCM (10 ml) and pyridine (0.05 ml). The reaction was stirred at room temperature for 1.5 h. Saturated sodium bicarbonate (aq) (20 ml) was added and the reaction stirred vigorously before the DCM was passed through a hydrophobic frit and evaporated to dryness. The residue was passed through a silica cartridge, preconditioned with cyclohexane. The silica cartridge was washed with cyclohexane:diethyl ether (1:1, v/v), then diethyl ether. The product containing ether fraction was evaporated to dryness to give title compound, 303 mg.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=[N:7][C:5]=2[CH:6]=1.O.[CH3:12][N:13]([CH3:16])C=O>O1CCCC1>[CH2:1]1[CH2:2][CH2:3][CH:12]([N:13]=[C:16]=[N:7][CH:5]2[CH2:4][CH2:3][CH2:2][CH2:1][CH2:6]2)[CH2:5][CH2:6]1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The subtitled compound was prepared substantially in accordance with the procedure detailed in Example 33, using 0.41 g (0.12 mmol) of S-2-N(t-butoxycarbonyl)amino-3-naphth-2-ylthio propanoic acid, 0.47 g (0.12 mmol) of the subtitled intermediate of Preparation 3B and 0.16 g (0.12 mmol) of HOBT.H2O, and 0.24 g (0.12 mmol) of DCC in 8 mL of tetrahydrofuran and 0.5 mL of dimethylformamide to provide 0.86 g of crude material. This material was purified using flash chromatography (eluent of 10% methanol in methylene chloride) followed by flash chromatography (eluent of 3.5% methanol in methylene chloride) to provide 0.45 g of a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To 3-(6-Isopropyl-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (39, 35.0 mg, 0.086 mmol) in tetrahydrofuran (3.0 mL) was added tetra-n-butylammonium fluoride (29 mg, 0.11 mmol). The reaction was stirred at 20° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0019, 18.0 mg, 81.9%). MS (ESI) [M+H+]+=252.
Reaction SMILES: [Mg].BrCCCCOCC1C=CC=CC=1.[Cu](C#N)C#N.F[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH:32]([C:36]2[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=2)C2OC2)C2OC2)=[CH:23][CH:22]=1>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH2:27]([O:31][CH2:32][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: Fc1ccc(C(OC(c2ccc(F)cc2)C2CO2)C2CO2)cc1
Agent: N#C[Cu]C#N
Agent: BrCCCCOCc1ccccc1
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and flame dried. Dry THF, 25 ml, and 1 ml of dibromoethane were then added. 1-Bromo-4-benzyloxy-butane 41 (12 g, 49.4 mmol) dissolved in 50 ml of dry THF was added dropwise and the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture is cooled in an ice-water bath and 90 mg of copper cyanide is added. After 10 minutes in an ice-bath, 4-fluorophenyl-glycidyl ether (5 g, 29.6 mmol) dissolved in 30 ml of dry THF is added slowly. The reaction is monitored by TLC (ethyl acetate:hexane 3:7). After 15 minutes, the reaction is quenched with saturated aqueous ammonium chloride, concentrated and partitioned between water-ethyl acetate. The ethyl acetate layer is then washed with brine, dried over Na2SO4 and concentrated to give the desired benzyloxy-heptane 42. The structure was confirmed by 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([C:30]3([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:37]>>[ClH:1].[ClH:37].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([C:30]3([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)C2(O)CCCCC2)CC1
Agent: Cl
Product: OC1(C(CN2CCNCC2)c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)CCCCC1

Procedure:
In an analogous manner to Example 135, step 4, 1-[1-(3′,4′-dichloro-111′-biphenyl-4-yl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(3′,4′-dichloro-1,1′-biphenyl-4-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. MS (ESI) m/z 433 ([M+H]+); HRMS: calcd for C24H30Cl2N2O.2.00 HCl, 504.1269; found (ESI), 433.1793.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:24]=2)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c([N+](=O)[O-])c2)ccn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Solid anhydrous white powdered KHMDS (2 eq) was suspended in a solution of dimethylformamide. Red crystalline 4-amino-3-nitrophenol (1 eq) was charged to the rapidly stirring solution under an inert atmosphere and the heterogeneous solution was allowed to stir for 2 hours. Then a dimethylformamide solution of tert-butyl 4-chloropyridine-2-carboxylate (1 eq) was added dropwise. Anhydrous powdered potassium carbonate (1.2 eq) was charged to the reaction as an acid scavenger. The purple colored viscous mixture was heated to 80° C. for 12-15 hours until when it was determined to be complete by HPLC. The reaction was evaporated under reduced pressure and diluted with excess ethyl acetate and water. An extraction of the aqueous layer was made with ethyl acetate. The organic layers were combined and washed 4 times with water followed by brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was purified by flash silica gel chromatography using an eluent of 1:1 mixture of hexanes to ethyl acetate to give the desired product. MS: MH+=332.
Reaction SMILES: N[C:2]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18](=[O:26])[N:19](C(C)C)C(C)C)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:26]=[C:18]1[C:17]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:11]2=[CH:10][CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]2[NH:19]1
Reactant: COC(=O)c1cccc(-c2cnccc2C(=O)N(C(C)C)C(C)C)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1[nH]c(=O)c1ccncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-amino-3-(4-(diisopropylcarbamoyl)pyridin-3-yl)benzoate (1.0 eq, 244 mg, 0.686 mmol) was dissolved under nitrogen atmosphere in anhydrous THF (1.5 ml). A NaHMDS solution (1.0 M in THF, 2.0 eq, 1.4 ml, 1.4 mmol) was added dropwise through syringe. The resulting suspension was stirred at room temperature for 1 hour. The reaction was quenched by addition of a saturated aqueous solution of ammonium chloride. The solid that formed was filtered and dried. After trituration in methanol and filtration, methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-7-carboxylate was isolated as a grey fluffy solid (93 mg, 53% yield). LCMS (ES): >95% pure, m/z 255 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:26])[C:8]=2[NH:12][C:13](=[O:25])[CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:26][C:7]1[C:8]([NH:12][C:13](=[O:25])[CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCC(C(F)(F)F)CC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: C1CNCCN1
Product: O=C(CC1CCC(C(F)(F)F)CC1)Nc1c(Cl)ccc2nc(N3CCNCC3)ccc12
Yield: 24.5 %

Procedure:
Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-4 (trifluoromethyl)-cyclohexaneacetamide (Example 8 (c)) (200 mg) and piperazine (420 mg). Purification (SiO2, dichloromethane:methanol 95:5 as eluant) afforded the title compound as a solid (55 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=Cc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 101.2 %

Procedure:
A mixture of ethyl 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenyl]-2-propenoate (1.50 g, 3.5 mmol), 3N sodium hydroxide solution (3.5 mL) and methanol (100 mL) was heated on a steam bath. After 25 minutes the mixture was cooled, concentrated, diluted with water and made pH=1 with dilute hydrochloric acid solution. The mixture was extracted three times with CH2Cl2. The combined extracts were washed with saturated NaCl solution, dried over sodium sulfate and the solvent evaporated. The residual oil was chromatographed on a column of silica gel using a mixture of chloroform and methanol (9:1) as eluent to give 3-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenyl]-2-propenoic acid (1.40 g, 100%) as the hydrated hexane solvate after recrystallization from a mixture of hexanes and CH2Cl2 (3:1), mp 114°-115° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].[CH2:20]=[O:21].[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([Br:16])=[CH:11][C:12]([OH:15])=[C:13]([CH:14]=1)[CH:20]=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Oc1ccc(OCc2ccccc2)c(Br)c1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: CC#N
Product: O=Cc1cc(OCc2ccccc2)c(Br)cc1O
Temperature: 72 °C

Procedure:
To a chilled solution of phenol (Step 1) (4.7 g, 16.8 mmole) in ACN was added MgCl2 (1.92 g, 20 mmole) portion-wise while maintaining the temperature below 10° C., followed by paraformaldehyde (2.52 g, 84 mmole) and TEA (9.5 mL, 67 mmole) producing a 15° C. exotherm. The mixture was heated to 72° C. for 2 hrs. The reaction was cooled to room temperature and poured into saturated aqueous ammonium chloride (500 mL), extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with aqueous NaHCO3 solution (2×150 mL), aqueous 1N HCl solution (2×150 mL), and brine (2×150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was subjected to flash chromatography (Silica, 5% ethyl acetate/hexane). ESLRMS m/z 306.9 (M+H).
Reaction SMILES: [O:1]=[C:2]([C:14]1[O:18][C:17](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>C(O)C>[O:1]=[C:2]([C:14]1[O:18][C:17](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC(=O)c1ccc(/C=C/C(=O)OCC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCC(=O)c1ccc(/C=C/C(=O)O)o1
Temperature: 25 °C

Procedure:
A mixture of 5.0 g (0.014 mole) of ethyl (E)-3-[5-(1-oxododecyl)-2-furanyl]-2-propenoate and 108 ml of ethanol, is heated to reflux. To the mixture is added 50 ml of 1 N aqueous sodium hydroxide, the ethanol is distilled off being replaced with water, and the aqueous solution is cooled to room temperature acidified with 200 ml of 1 N hydrochloric acid. The solid is collected by filtration and dried. Recrystallization from methanol gives (E)-3-[5-(1-oxododecyl)-2-furanyl]-2-propenoic acid, mp 122°-127° C.