Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=2[CH:30]=[CH:29]1)=[O:27].C(Cl)(=O)C.[NH2:42][C:43]1[CH:44]=[C:45]([S:49]([NH2:52])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([NH:42][C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([S:49](=[O:51])(=[O:50])[NH2:52])[CH:44]=3)[C:31]=2[CH:30]=[CH:29]1)=[O:27]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Cl)ncnc21
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CC(=O)Cl
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Nc3cccc(S(N)(=O)=O)c3)ncnc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 2, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-aminobenzenesulfonamide (43 mg, 0.25 mmol), and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together with n-butanol and concentrated. The residue is purified by preparative HPLC-MS to give 4-(3-sulfamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide (18.0 mg, yield 55%); 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 10.27 (s, 1H), 10.09 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=7.95 Hz, 1H), 7.95 (d, J=7.94, 2H), 7.87 (d, J=3.85 Hz, 1H), 7.54 (dd, J=7.61, 15.51 Hz, 2H), 7.52 (s, 1H), 7.45 (d, J=7.88 Hz, 2H), 7.37 (s, 2H), 7.25 (d, J=8.30 Hz, 1H), 7.11 (d, J=3.88 Hz, 1H), 3.69 (s, 2H), 3.54-3.3.17 (m, 2H), 3.01-2.93 (m, 6H), 2.75 (s, 3H), 2.41 (s, 3H); ESIMS m/z 654.20 (M++1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)(=[O:27])=[O:26])=[O:18])[C:13](O)=[O:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C1C[N:41]([P+](Br)(N2CCCC2)N2CCCC2)[CH2:40]C1.F[P-](F)(F)(F)(F)F.CN.C1COCC1>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)(=[O:26])=[O:27])=[O:18])[C:13](=[O:14])[NH:41][CH3:40])=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
To a room temperature solution of (S)-3-(4-isopropoxy-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid (319 mg, 0.588 mmol) (prepared according to the method described for the preparation of compound 17e), PyBroP (301 mg, 0.645 mmol), and methylene chloride (8 mL) was added methylamine (3.0 mL of a 2M THF solution) in one portion. The reaction mixture was shaken at room temperature in a sealed vessel for 2.5 h. The reaction mixture was then diluted with methylene chloride, washed with 0.5 N HCl and water successively, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate. Homogenous fractions with Rf=0.32 (silica gel, ethyl acetate) material were combined and concentrated to afford 197 mg (60%) of the title compound as a white foam. LC/MS: RT 3.38 min, Area % 100, m/e 556 (M+H). 1H NMR (400 MHz, d6-DMSO) δ8.01 d (J=8 Hz; Tyr NH), 7.99 brd (J=7.5 Hz; H-6 of ArSO2), 7.94 brs (H-2 of ArSO2), 7.84 q (J=4.5 Hz; CONHMe), 7.72 brd (J=8 Hz; H-4 of ArSO2), 7.59 dd (J=8, 7.5 Hz; H-5 of ArSO2), 7.11 m (2H, AA′-part of AA′MM′; H-2/H-6 of C6H4), 6.82 m (2H, MM′-part of AA′MM′; H-3/H-5 of C6H4), 4.56 brd (J=5 Hz; Pip H-2), 4.53 qq (J=6 Hz, 6; OiPr), 4.21 ddd (J=9, 8, 5.5 Hz; Tyr Ha), 3.65 dm (J=12.5; Pip H-6 eq), 3.17 ddd (J=13, 12.5, 3; Pip H-6ax), 2.84 dd (J=13.5, 5.5; Tyr Hb), 2.66 dd (J=13.5, 9; Tyr H′b), 2.53 d (3H, J=4.5; CONHMe), 1.95 brd (J=13.5; Pip H-3 eq), 1.49 dm (J=12.5 Hz; Pip H-Seq), 1.40 m (Pip H-4 eq), 1.36 m (Pip H-3ax), 1.21 d (3H, J=6 Hz; OiPr), 1.19 d (3H, J=6 Hz; OiPr), 1.16 m (Pip H-5ax), 1.06 m (Pip H-4ax).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([OH:14])=[N:9]2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[P:21](=[S:29])(Cl)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>C(#N)C>[P:21](=[S:29])([O:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[N:9]=1)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]
Reactant: Cc1nc(O)nn1-c1cccc(F)n1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1nc(C)n(-c2cccc(F)n2)n1
Temperature: 25 °C

Procedure:
A 3-neck, 500-ml flask was charged with 9 g (0.046 m) of 1-(6-fluoro-2-pyridinyl)-5-methyl-1H-1,2,-4-triazol-3-ol, 6.6 grams (0.048 m) of dry potassium carbonate and 150 ml of acetonitrile. The mixture was refluxed for 2 hours and then cooled to 25° C. To this mixture was added 8.67 g (0.46 m) of O,O-diethyl phosphorochloridothioate and the mixture was heated to 75° C. for 31/2 hours. The solid material which formed was removed by filtration and the acetonitrile was removed by evaporation under reduced pressure. The solid residue which remained was taken up in ethyl ether, washed with 2 percent sodium hydroxide and dried over sodium sulfate. The desired O,O-diethyl O-(1-(6-fluoro-2-pyridinyl)-5-methyl-1H-1,2,4-triazol-3-yl) phosphorothioate was crystallized from a 50:50 mixture of ethyl ether and hexane in a yield of 12.9 g (85 percent of theoretical). The product melted at 68°-70° C. and upon analysis was found to have carbon, hydrogen and nitrogen contents of 41.54, 4.66 and 16.05 percent, respectively, as compared to the theoretical contents of 41.62, 4.66 and 16.18 percent, respectively, as calculated for the above named compound. (Compound 2).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[F:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1>>[N:1]1([CH2:6][C:7]([N:17]2[CH2:18][C@H:14]([CH2:13][C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[F:10])[CH2:15][C@H:16]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid and (2S,4R)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 106, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.42-7.38 (m, 2H), 7.27-7.18 (m, 3H), 7.13-6.86 (m, 7H), 5.06 (d, 1H), 4.98 (d, 1H), 4.78 (d, 1H), 3.72-3.66 (m, 1H), 3.31 (t, 1H), 3.004-2.92 (m, 1H), 2.90-2.77 (m, 2H), 2.60 (dd, 1H), 1.81-1.72 (m, 1H), 1.45-1.38 (m, 1H). MS (EI) for C28H25F2N5O3 found 518 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>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.O1CCOCC1>[F:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH3:13])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc2cc(Br)cnc2c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cnc2cc(F)ccc2c1
Temperature: 90 °C
Yield: 74 %

Procedure:
3-bromo-7-fluoro-quinoline (Intermediate 30) (100 mg, 0.442 mmol) was combined with K2CO3 (153 mg, 1.10 mmol), anhydrous 1,4-dioxane (3 mL), and trimethylboroxine (0.092 mL, 0.663 mmol). Nitrogen was bubbled in to degas the reaction and Pd(PPh3)4 (50.9 mg, 0.044 mmol) was added. This was degassed again and then heated to 90° C. for 5 h. The reaction was cooled and partitioned between ethyl acetate and sat. aq. NaHCO3. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave 7-fluoro-3-methyl-quinoline (52.7 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=1.8 Hz, 1 H) 7.93 (s, 1 H) 7.65-7.79 (m, 2 H) 7.32 (td, J=8.6, 2.5 Hz, 1 H) 2.52 (s, 3 H); MS (M+1): 162.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:26][O:25][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[N:13]=[CH:12][N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]2=[O:24]
Reactant: C1CCNCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCCCC1
Yield: 83 %

Procedure:
A solution of 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.89 g, 6.78 mmol) in piperidine (10 ml) was heated at 100° C. for 1 hour. After cooling, the volatiles were removed under vacuum. The residue was dissolved in methylene chloride, and washed with saturated ammonium chloride and brine. The organic layer was dried (MgSO4) and the volatiles were removed by evaporation. The residue was dried under vacuum to give 6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.4 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C@H:24]([CH2:26][OH:27])[NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:25][C@H:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][OH:27])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-benzyloxybenzoic acid (22 g, 96 mmol) in toluene (200 ml) was added dropwise thionyl chloride (14.1 ml, 19 mmol). The reaction mixture was heated at 90° C. for 2 hours, cooled to ambient temperature and volatiles removed under reduced pressure to afford crude 3-benzyloxybenzoyl chloride (32 g, quant.). The crude 3-benzyloxybenzoyl chloride was dissolved in CH2Cl2 and added dropwise over 30 min., to a vigorously stirred solution of (R)-(-)-2-phenylglycinol (15.8 g, 115 mmol) and triethylamine (16 ml, 15 mmol) in CH2Cl2 (200 ml) cooled to 0° C. The reaction mixture was allowed to warm ambient temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1 L) and water (1 L). The aqueous layer was separated, extracted with ethyl acetate (2×500ml) and the combined organic phase washed with 1N HCl (500 ml), aqueous 4% NaHCO3 solution (500 ml) and brine (500 ml), dried over MgSO4 and concentrated under reduced pressure to give 2-(3-benzyloxybenzamido)-2(R)-phenylethan-1-ol (29 g, 88%) as pale yellow solids.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([S:14][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCBr
Reactant: Sc1cccc(CN2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCSc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h

Procedure:
A stirred suspension of 3-piperidinomethylthiophenol (0.36 g) in dry dimethylformamide (4 ml) was treated with anhydrous potassium carbonate (0.5 g) and stirred for 30 minutes. 4-Bromobutyronitrile (0.18 ml) was then added to the reaction mixture with dimethylformamide (1 ml) and the resultant suspension stirred at room temperature for 48 hours. The resulting product was poured into 5 volumes of water and extracted with ethyl acetate; the extracts were washed with water, dried and evaporated to give 4-(3-piperidinomethylphenylthio)butyronitrile as an orange-red oil.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:27]2[CH:30]=[CH:31][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(OCc3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 12.0 g of 4-benzyloxybenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 165°-166° C.). 'H NMR (CDCl3) δ2.91 (dd, 2H), 3.56 (dd, 2H), 5.09 (s, 2H), 5.65 (dd, 1H), 6.98-7.04 (m, 2H), 7.30-7.44 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[CH3:16]>Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[CH3:16]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1C
Agent: Cl
Product: COc1ccc(CCCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 97.5 %

Procedure:
Zinc dust (40.0 g) was washed with HCl 10% and shaken for 2 min, and the water was decanted. HgCl2 (6.0 g) was then added, followed by water (60 mL) and concentrated HCl (2 mL). The mixture was shaken for 5 min, the water was decanted, and covered with water (30 mL) and concentrated HCl (70 mL). Toluene (20 mL) was added, followed by 4-(4-methoxy-3-methylphenyl)-4-oxobutyric acid (Compound 2, 11.7 g, 52.7 mmol). The resulting solution was refluxed vigorously for 24 h with addition of concentrated HCl (3×20 mL every 3 h). After being cooled down to room temperature, the two layers were separated, and the aqueous layer was washed three times with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 10.7 g (98%) of the title compound as a light yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1CCN2C(=NCCC2)CC1.[O:21]1CCOC[CH2:22]1>>[O:21]=[C:22]1[O:1][N:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:9]1
Reactant: C1COCCO1
Reactant: CCOC(=O)C(=N)NO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1noc(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(hydroxyamino)-2-iminoacetate (2 g, 15.14 mmol) in dioxane (15.00 mL) is added CDl (2.7 g, 16.65 mmol) and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring for 1 hour at 80° C., the reaction is quenched with 1N HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g). HPLC retention time=0.72 minutes (condition B); MS 159.1 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.CS([Cl:26])(=O)=O>ClCCl>[Cl:26][CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)C)ccc(CO)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc(CCl)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (2.81 g, 13.5 mmol) and pyridine (1.31 ml, 16.2 mmol) were dissolved in dichloromethane (5 ml) and cooled to 0° C. The solution was stirred while methanesulfonyl chloride (1.25 ml, 16.2 mmol) was added thereto. After stirred at 0° C. for 2 hours, the reaction solution was slowly brought back to room temperature. After 2 hours, the reaction solution was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate, water and 2N HCl, then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (1:1)] to give 1.38 g of 7-chloromethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (yield: 45%) as a pale yellow oil. This oil was solidified when allowed to stand at room temperature.
Reaction SMILES: F[B-](F)(F)F.[C:6](=[NH:11])([O:8][CH2:9][CH3:10])[NH2:7].[CH2:12]([CH:19]([C:25](=O)[CH3:26])[C:20](OCC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[CH2:12]([C:19]1[C:20](=[O:21])[NH:11][C:6]([O:8][CH2:9][CH3:10])=[N:7][C:25]=1[CH3:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: CCOC(=N)N
Agent: C[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reaction time: 12 h
Yield: 24.3 %

Procedure:
To a solution of ethyl imidocarbamate tetrafluoroborate (2.4 g) and ethyl 2-benzyl-3-oxobutanoate (1 g) in methanol (20 mL) was added sodium methoxide (28% methanol solution, 5.25 mL), and the mixture was stirred for 12 hr. The reaction mixture was concentrated, and the residue was dissolved in water. The solution was weakly acidified with acetic acid, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (0.27 g, 24%) as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:20][CH2:21][C:22]1[CH:27]=[C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3cccc(CO)c3)cc2)c1

Procedure:
3-(3′-Hydroxymethyl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3-(hydroxymethyl)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=335.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]#[C:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:33]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CN(c1ccccc1C#Cc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(C#Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.208 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in an analogous manner to Example 2d. Product isolated as a tan foam (0.055 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.54 (d, J=7.7 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.37 (t, J=7.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.15 (s, 1H), 6.91-6.85 (m, 2H), 6.62 (d, J=8.0 Hz, 1H), 3.61 (s, 3H), 3.31-3.26 (m, 4H), 3.22 (s, 3H), 2.62-2.57 (m, 4H), 2.37 (s, 3H). MS=516 (MH)+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](O)(=[O:14])/[CH:11]=[CH:12]/[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:7][CH:6]([O:8][C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: C/C=C/C(=O)O
Reactant: CC(C)=CCCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)CCC=C(C)C
Temperature: 121.5 °C

Procedure:
6-Methyl-hept-5-en-2-ol (256 g, commercially available at IFF), crotonic acid (193 g), PTSA (2.5 g), and toluene (250 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 110-133° C. Water was removed azeotropically. The reaction was aged at reflux for about 6 hours until no more water evolved. The reaction mixture was cooled to under 60° C. and quenched with water (300 mL). The aqueous and organic layers were split. The organic layer was subsequently washed with sodium carbonate (2%, 300 mL) and further fractional distilled to provide but-2-enoic acid 1,5-dimethyl-hex-4-enyl ester (204 g) with a boiling point of 98° C. at 4 mmHg.