Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:34]2[S:35][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)s2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13i, and 5-chlorothiophene-2-sulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 1H), 7.79 (d, 2H), 7.43 (d, 1H), 7.34 (d, 1H), 7.24 (m, 3H), 7.13 (m, 1H), 6.94 (d, 1H), 6.76 (m, 1H), 6.68 (m, 2H), 4.41 (s, 2H), 4.35 (s, 2H), 4.30 (s, 2H), 1.48 (s, 9H); MS 591 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[C:4](=O)[NH:3]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:4]1[C:5]2[C:6](=[CH:9][N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: Cn1[nH]c(=O)c2cn(Cc3cccc4ccccc34)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1nc(Cl)c2cn(Cc3cccc4ccccc34)cc2c1=O

Procedure:
A suspension of 2,3-dihydro-2-methyl-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazine-1,4(6H)-dione (0.10 g) in phosphorus oxychloride (1 ml) was heated at reflux for 30 minutes and then allowed to cool. The solvent was evaporated, water (25 ml) was added and the mixture was extracted with ethyl acetate (2×25 ml). The organic extracts were dried, filtered and evaporated to give the sub-title compound (0.095 g).
Reaction SMILES: [OH-:1].[Na+:2].[C:3]([OH:12])(=[O:11])[C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5]>O>[C:8]([C@@H:6]([C@H:4]([C:3]([O-:12])=[O:11])[OH:5])[OH:7])([O-:10])=[O:9].[Na+:2].[Na+:2].[OH-:1].[Na+:2]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]

Procedure:
In a 1-liter reactor vessel, 606.04 g of NaOH solution (containing 50 wt % of NaOH and 50 wt % of water) were mixed with 414.40 g water and 96.70 g of L-tartaric acid. Upon mixing, a mixture comprising 11.2 wt % of disodium L-tartrate, 22.5 wt % of NaOH, and 66.3 wt % of water was obtained. The mixture was heated and was kept at atmospheric boiling conditions under reflux for 26 hours (Tboil˜110° C.), under continuous stirring. A clear solution was obtained. At regular intervals, a sample was taken from the liquid and analyzed by 1H-NMR for meso-tartaric acid, DL-tartaric acid, and acetate content (a distinction between the D and L-enantiomer cannot be made by 1H-NMR).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][CH2:10][OH:11].C(OI1(OC(=O)C)(OC(=O)C)C2C=CC=CC=2C(=O)O1)(=O)C>C(Cl)Cl>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:12])[C:2]=1[CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(C)c(CCO)c(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(C)c(CC=O)c(C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
2-Mesitylethanol (0.99 g, 6.0 mmol) was dissolved in DCM (10.0 mL, dry) and cooled to 0° C. 1,1,1-Tris(acetyloxy)-1λ5,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) in DCM (15 wt %, 2.80 g, 6.60 mmol) was added dropwise over a period of 20 mins. The ice bath was removed and the reaction mixture was stirred at rt for 4 h. NaOH (2N, 5 mL) was added to the mixture and it was diluted with water (5 mL). The layers were separated and the organic layer was washed with water, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel using heptane and EtOAc as eluant giving the title compound (0.69 g, 71%). 1H NMR (CDCl3, 400 MHz) δ 9.68-9.65 (m, 1H), 6.94-6.90 (m, 2H), 3.75-3.71 (m, 2H), 2.29 (s, 3H), 2.27 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.Br[C:29]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:29]2([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:26]=1
Reactant: COC(=O)C1(Br)CCCC1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-4-(β-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.46 g), 1-bromo-1-methoxycarbonylcyclopentane (0.87 g), potassium iodide (0.1 g) and potassium carbonate (0.5 g) in methanol (5 mL) is stirred at reflux for 16 h. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]=[CH:33][C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:35][CH:36]=1)[CH3:30]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CCc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a yellow solid. UPLC-MS (condition 1) tR=1.90 min, m/z=487.0 [M+H]+, m/z=485.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.58 Hz, 3H) 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.28 (m, 1H) 2.82 (q, J=7.58 Hz, 2H) 2.99 (dd, J=11.00, 6.60 Hz, 1H) 3.08-3.20 (m, 2H) 3.21-3.30 (m, 2H) 3.29-3.38 (m, 1H) 4.60 (br. s, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.38 (d, J=8.07 Hz, 1H) 7.75 (dd, J=7.82, 1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.02 (d, J=2.20 Hz, 1H) 8.55 (d, J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24].N1C=CN=C1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][Si:26]([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of compound 4 (10.9 mmol) in DMF (35 mL) were added TBDPSCl (24.0 mmol) and imidazole (32.7 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then diluted with DCM (140 mL) and washed sequentially with 1N HCl (140 mL) and H2O (140 mL). Organics were dried, concentrated, and purified by silica gel chromatography (PE/EtOAc) to yield compound 5 as a colourless oil in 65% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CN(C)C=O.C[Si]([C:18]#[CH:19])(C)C.CN(C)C(N(C)C)=N>Cl[Cu].Cl[Pd]Cl.O>[NH2:5][C:4]1[CH:3]=[C:2]([C:18]#[CH:19])[CH:8]=[CH:7][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cccc(Br)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cccc(N)c1
Temperature: 45 °C

Procedure:
A 250 ml round bottomed flask, fitted with refrigerator, under a nitrogen stream, is loaded with 3-bromoaniline (2 ml), dimethylformamide (10 ml), trimethylsilylacetylene (3.4 ml), 1,1,3,3-tetramethyl guanidine (2.5 ml), CuCl (3.6 mg), PdCl2 (9.7 mg) triphenyl phosphine (58 mg), in this order. The mixture is heated to 55°-57° C. keeping this temperature until completion of the reaction. H2O (50 ml) and ACOEt (50 ml) are added at a temperature of 35°-30° C. The organic phase is evaporated to dryness and the residue is dissolved in CH3OH (10 ml) and 50% HCl (10 ml) is heated to 40-50° C. for two hours. Methanol is evaporated off and the residual mixture is treated with NaOH, extracted with toluene. The organic phase is dried, and the solvent removed under vacuum affording 3-amino-phenyl acetylene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:28])[C:3]=1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:28])[C:3]=1[CH2:29][Br:51]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
To a mixture of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzene (8.10 g) in dichloromethane (81 ml) were added triphenylphosphine (5.66 g) and carbon tetrabromide (8.95 g) at 0° C. After 15 minutes, the reaction mixture was stirred at ambient temperature for 3 hours. To the mixture were added triphenylphosphine (1.42 g) and carbon tetrabromide (2.39 g) and stirred for another 2 hours. The reaction mixture was washed with saturated sodium hydrogen carbonate, water and brine. After dried over anhydrous magnesium sulfate, the mixture was evaporated in vacuo. The residue was purified by flash column chromatography followed by crystallizing from ethyl acetate to give 2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl bromide (6.40 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH:15]=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-2-oxazolyl] propanol (1.0 g) in dichloromethane (10 ml) were added dimethylsulfoxide (0.6 ml) and phosphoric anhydride (1.1 g) in that order. After stirring for 10 minutes at room temperature, the resultant was cooled to 0° C., to which triethylamine (2 ml) was added. The mixture was stirred for 40 minutes at room temperature, poured into 2N-HCl and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over MgSO4, and distilled to remove the solvent. The oily residue was subjected to a silica gel column chromatography. Crystals of 3-[4-(4-chlorophenyl)-2-oxazolyl]propanal (0.698 g, 70%) were obtained from the fraction eluted with ethyl acetate-hexane (1:3, V/V). Recrystallization from hexane gave colorless prism crystals of mp 41°-42° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.CCN(CC)CC>C(Cl)Cl>[CH:35]1([C:38]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:24][CH2:23]2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-ylmethyl-9H-purine (230 mg, 0.50 mmol), cyclopropyl carbonyl chloride (50 μL, 0.55 mmol) and NEt3 (140 μL, 1.00 mmol) in DCM (10 mL) was allowed to stir at r.t. for 5 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-5%) then further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 40-98%) affording 852 as a white solid (46 mg, 17%). LCMS (method I): RT 3.59 min, [M+H]+ 529.4. 1H NMR (DMSO, 400 MHz): δ 8.03-7.99 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 4.45-4.10 (6 H, m), 3.77-3.75 (6 H, m), 3.27-3.24 (3 H, m), 3.16-3.00 (1 H, m), 2.86 (2 H, d, J=7.07 Hz), 2.64-2.47 (1 H, m), 2.20-2.08 (1 H, m), 2.01-1.93 (1 H, m), 1.79-1.71 (2 H, m), 1.33 (3 H, t, J=7.43 Hz), 1.30-1.07 (2 H, m), 0.74-0.66 (4 H, m)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23].C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester (2.0 g, 5.6 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (1.78 g, 5.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol), and sodium bicarbonate (1.4 g, 16.8 mmol) were combined in DME (30 mL) and H2O (10 mL) and the mixture was purged with N2. The reaction was stirred at 80° C. overnight, and after aqueous workup the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: BrC1C=C(/C=C/C(OCC)=O)C=CC=1.[Br:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:20][CH:21]=1.[BH4-].[Na+]>CO.O.C(OCC)(=O)C.[Cu]Cl>[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:20][CH:21]=1
Reactant: CCOC(=O)/C=C\c1cncc(Br)c1
Agent: Cl[Cu]
Agent: CCOC(=O)/C=C/c1cccc(Br)c1
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cncc(Br)c1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl (2E)-3-(3-bromophenyl)prop-2-enoate and ethyl (2Z)-3-(5-bromopyridin-3-yl)prop-2-enoate (4:1 ratio of isomers, 332 mg, 1.30 mmol) in methanol (10 mL) and water (2.5 mL) was added copper (I) chloride (257 mg, 2.59 mmol) and sodium borohydride (98 mg, 2.59 mmol). After 15 minutes, the reaction was diluted with ethyl acetate and filtered through CELITE. The filtrate was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford ethyl 3-(5-bromopyridin-3-yl)propanoate. MS ESI calc'd. for C10H13BrNO2 [M+H]+ 258 and 260. found 258 and 260. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (d, J=2.2 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H).
Reaction SMILES: N1CCCC1.C1(NC(N2C3C(=CC(OC4C=CN=C(NC(=O)OC5C=CC=CC=5)C=4)=CC=3)C=C2)=O)CC1.[CH:38]1([NH:41][C:42]([N:44]2[C:52]3[C:47](=[CH:48][C:49]([O:53][C:54]4[CH:59]=[CH:58][N:57]=[C:56]([NH:60][C:61]([N:63]5[CH2:68][CH2:67][CH:66](N6CCCC6)[CH2:65]C5)=[O:62])[CH:55]=4)=[CH:50][CH:51]=3)[CH:46]=[CH:45]2)=[O:43])[CH2:40][CH2:39]1>CN(C)C=O>[CH:38]1([NH:41][C:42]([N:44]2[C:52]3[C:47](=[CH:48][C:49]([O:53][C:54]4[CH:59]=[CH:58][N:57]=[C:56]([NH:60][C:61]([N:63]5[CH2:68][CH2:67][CH2:66][CH2:65]5)=[O:62])[CH:55]=4)=[CH:50][CH:51]=3)[CH:46]=[CH:45]2)=[O:43])[CH2:40][CH2:39]1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Agent: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)Oc1ccccc1
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCCC1
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and pyrrolidine (0.35 ml, 4.2 mmol) were added to a mixture (470 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 68; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as white crystals (200 mg, 0.49 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1)([O-:9])=[O:8].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>O>[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C

Procedure:
Potassium carbonate (3.1 g, 23 mmol) is added to a solution of 4-nitrobenzylbromide (5 g, 23 mmol) and imidazole (1.6 g, 23 mmol) and the reaction mixture is stirred at RT. After the reaction has been completed according to HPLC-MS the suspension is poured into 800 mL water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated down. The residue is purified by chromatography on silica gel with dichloromethane/methanol. Yield: 2.1 g.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[O:30]=[C:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:22][CH2:21][CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC1CCNCC1)c1ccccc1
Reaction time: 3 h

Procedure:
TFA (1.0 mL) was added to a solution of 1-(tert-butoxycarbonyl)-4-(3-oxo-3-phenylpropyl)piperidine (50 mg, 0.16 mmol, from Step C) in CH2Cl2 (1.0 mL) at rt. After stirring for 3 h, the solution was concentrated at reduced pressure. Toluene was added and evaporated at reduced pressure, and this was repeated with two additional portions of toluene. Drying under vacuum yielded the title compound as colorless crystals.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Mg].Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:17][CH2:18][CH2:19][F:20])[CH:11]=[CH:10]2.BrC1C=C2C(=CC=1)C=C(O)C=C2.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:20][CH2:19][CH2:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:2]([CH3:4])[CH3:3])[CH:8]=2)[CH:13]=1
Reactant: FCCOc1ccc2cc(Br)ccc2c1
Reactant: CC(C)Br
Agent: Cl
Agent: Oc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)c1ccc2cc(OCCF)ccc2c1
Temperature: 50 °C
Yield: 49.4 %

Procedure:
A solution of 0.92 grams (0.0074 mole) of 2-bromopropane in 5 ml of dry tetrahydrofuran was added to a stirred mixture of 0.9 gram (0.04 mole) of magnesium turnings. This mixture was heated to initiate the reaction. A solution of 3.68 grams (0.0296 mole) of 2-bromopropane in 20 ml of dry tetrahydrofuran was added dropwise to the mixture. After complete addition the reaction mixture was stirred and heated at reflux for one hour. The reaction mixture was cooled, and the solution was decanted from the unreacted magnesium. The decanted liquid was added dropwise to a stirred slurry of 5.0 grams (0.037 mole) of zinc chloride in 15 ml of dry tetrahydrofuran. This mixture was stirred at room temperate for one hour. To this slurry was added 0.5 gram (0.004 mole) of tetrabis(triphenylphosphine)palladium and a solution of 2.5 grams (0.0093 mole) of 6-bromo-2-(2-fluoroethoxy)naphthalene (Compound 157, prepared by the method of Example 1 from 6-bromo- 2hydroxynaphthalene) in 20 ml of dry tetrahydrofuran. The reaction mixture was stirred and heated at 50° C. for approximately 18 hours. The mixture was hydrolyzed with 100 ml of a 1 N aqueous hydrochloric acid solution. This mixture was extracted with three 200 ml portions of diethyl ether. The extracts were combined and washed with water. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving an orange oil which solidified upon standing. This solid was purified by column chromatography on silica gel, eluting with n-hexane:diethyl ether (4:1) to yield 0.85 gram of 2-(2-fluoroethoxy)-6-(1-methylethyl)naphthalene as a solid, mp 46°-48° C.