Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH2:22]>C(OCC)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: C=COC(C)(C)C
Reactant: C=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C=Cc1ccc(OC(C)OC(C)(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
12.02 g (100 mmol) of 4-hydroxystyrene, 0.09 g of p-toluenesulfonic acid and 100 ml of diethyl ether are introduced under a nitrogen atmosphere into a 250 ml three-neck flask. The mixture is cooled to between 0° and 5° C., and 11.02 g (110 mmol) of tert-butyl vinyl ether are added dropwise at this temperature over the course of 15 minutes. The mixture is then stirred at 10° C. for 2 hours. The reaction mixture is washed three times with 150 ml of 1N NaOH and three times with demineralized water. Stripping off of the solvent gives 16 g (72% of theory) of the desired product in the form of a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]3(O)[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:26]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[CH:36][CH:35]=4)(O)[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:46]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[C:37]2[CH:36]=[CH:35][C:34]([C:26]3[C:25]4[C:20]([C:19]([C:16]5[CH:15]=[CH:14][C:13]([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=6[C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:18][CH:17]=5)=[C:32]5[C:27]=3[CH:28]=[CH:29][CH:30]=[CH:31]5)=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:39][CH:38]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: OC1(c2ccc(-c3ccccc3-c3ccccc3)cc2)c2ccccc2C(O)(c2ccc(-c3ccccc3-c3ccccc3)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2ccccc2-c2ccc(-c3c4ccccc4c(-c4ccc(-c5ccccc5-c5ccccc5)cc4)c4ccccc34)cc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
9,10-bis(4-(2-Phenylphenyl)phenyl)-9,10-dihydroxy-9,10-dihydro-anthracene (4.9 g, 7.3 mmole) was suspended in acetic acid (70 ml). To the resultant suspension, a 57% hydroiodic acid (10 ml, 77 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (50 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a light yellow solid (4.6 g, 88%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[O:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CC(O)=O.N1CCCCC1>C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:11](/[C:12](=[CH:6]/[C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:9][CH:8]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)/C(=C\c1ccc(Cl)nc1)C(=O)c1ccccc1
Yield: 90.5 %

Procedure:
A mixture of 6-chloronicotinaldehyde (1 g), ethyl 3-oxo-3-phenylpropanoate (1.36 g), AcOH (0.04 ml), piperidine (0.028 ml) in benzene (15 ml) was refluxed for 1.5 hours. After cooling, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:2) to give ethyl (2Z)-2-benzoyl-3-(6-chloro-3-pyridyl)acrylate (2.018 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[N:9]=2)=[N:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)(C)C>[CH3:15][C:10]1[N:9]=[C:8]([NH:7][C:5]2[S:6][C:2]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[CH:3][N:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: Cc1cc(Nc2ncc(Br)s2)nc(C)n1
Reactant: OB(O)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Nc2ncc(-c3ccncc3)s2)nc(C)n1

Procedure:
To a round bottomed flask were added (5-bromo-thiazol-2-yl)-(2,6-dimethyl-pyrimidin-4-yl)-amine (23-3) (100 mg, 0.35 mmol), 4-pyridineboronicacid (47 mg, 0.39 mmol), and isopropanol. After 0.5 hour palladium acetate (0.1 mg 0.0035 mmol), triphenylphosphine (2.75 mg, 0.0105 mmol), sodiumcarbonate (45 mg, 0.42 mmol) and water were added. The reaction was heated under reflux for 1.0 hour. The reaction was cooled, solvents removed and the residue dissolved into methanol (4.0 mL). Trifluoroacetic acid (0.5 mL) was added and the mixture purified by reverse phase preparative HPLC (C18) giving the above compound as a TFA salt. 1H-NMR (400 MHz, CD3OD) 8.71 (2H, br-s), 8.48 (1H, s), 8.18 (2H, br-s), 6.99 (1H, s), 2.82 (3H, s), 2.57 (3H, s). MS(M+1)=284.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([F:21])=[CH:4][C:3]=1[C:22]#[N:23].[F:24][C:25]1[CH:26]=[C:27]2[C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:28]2=[N:29][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([C:3]1[CH:4]=[C:5]([F:21])[C:6]([NH:8][CH:9]([C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]=1[C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([F:24])[CH:26]=2)[N:31]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)(=[O:44])=[O:45])[CH:32]=1)#[N:23]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CCOC(=O)CC(Nc1nc(Cl)c(C#N)cc1F)C(C)(C)CC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)c(C#N)cc1F)C(C)(C)CC
Temperature: 125 °C

Procedure:
A solution of ethyl 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate, 158a, (0.21 g, 0.600 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.30 g, 0.72 mmol) and K3PO4 (0.51 g, 2.40 mmol) in 2-methyl THF (20.5 mL) and H2O (2.7 mL) was degassed for 45 minutes and treated with X-phos (0.03 g, 0.07 mmol) and Pd2(dba)3 (0.01 g, 0.02 mmol). The reaction vessel was sealed and heated to 125° C. for 90 minutes. After cooling to room temperature, the aqueous phase was removed and the organic phase was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to provide 270 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.51 (dd, J=9.1, 2.7 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.41 (d, J=10.3 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 5.28-5.22 (m, 1H), 4.92 (td, J=10.4, 3.2 Hz, 1H), 4.03-3.91 (m, 2H), 2.75 (dd, J=14.9, 3.5 Hz, 1H), 2.45 (dd, J=12.6, 8.2 Hz, 1H), 2.40 (s, J=4.7 Hz, 3H), 1.36 (q, J=7.4 Hz, 2H), 1.01 (t, J=7.1 Hz, 3H), 0.92 (d, J=8.8 Hz, 6H), 0.88 (t, J=7.5 Hz, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.86 minutes (M+H) 596.02.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:11])[C:4]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(C(C)C)C(C)C)C.O>CS(C)=O>[CH3:11][N:3]1[C:4]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]=[C:2]1[N:22]1[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]1
Reactant: Cn1c(Cl)nc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cccnc21

Procedure:
A solution of 3.83 g (0.011 mol)-2-chloro-3-methyl-3H-imidazo[4,5]pyridine, 2.2 g (0.012 mol) of 1-Boc-piperazine and 5 ml (0.029 mol) of ethyl-diisopropylamine in 15 ml of DMSO is stirred for 12 hours at 130° C. Water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: dichloromethane/acetone=20:1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([CH2:7][N:8]1[CH:12]=[C:11](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][C:19]\2=[O:20])[N:10]=[N:9]1)=[O:6]>O1CCCC1>[CH3:3][O:4][C:5]([CH2:7][N:8]1[CH:12]=[C:11](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18][CH:19]\2[OH:20])[N:10]=[N:9]1)=[O:6]
Reactant: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)nn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
Sodium borohydride (508 mg) was added to a solution of (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (6.61 g) obtained in Example 160-(c) in tetrahydrofuran (150 ml) at 0° C. After being stirred at 0° C. for 6 hours, the mixture was filtered and the filtrate was diluted with ethyl acetate, then the reaction was quenched by addition of a saturated aqueous ammonium chloride solution. Products were extracted with ethyl acetate, and the separated organic layer was washed with a saturated aqueous sodium chloride solution. Concentration under reduced pressure gave a solid, which was collected by filtration and washed with a mixed solvent of hexane-ethyl acetate-dichloromethane (1:1:1) to afford the title compound (4.7 g, yield: 71%) as a pale yellow amorphous solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH2:29][OH:30])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:31]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH2:29][OH:30])[N:23]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 5 h
Yield: 104.3 %

Procedure:
A solution of 0.12 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylic acid (prepared as described in Example 4) in 2 ml of a 4N solution of hydrogen chloride in dioxane was allowed to stand at room temperature for 5 hours and then the solvent was removed by distillation under reduced pressure. The resulting residue was triturated in ethyl acetate, to give 0.11 g of the title compound in the form of its hydrochloride, melting at 130°-140° C. (with softening).
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.N[C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].NC1C=CC=CC=1>CC#N>[CH2:3]([C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:1]=[CH2:2]
Reactant: CCOC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)ON=O
Solvent: C=CCBr
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=CCc1cc(C(=O)OCC)cc([N+](=O)[O-])c1
Temperature: 11 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), ethyl 3-amino-5-nitrobenzoate (631 mg, 3.0 mmol) was added during 20 minutes while maintaining the temperature of the reaction mixture at 10-12° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 47:3) gave 470 mg (67%) of ethyl 3-allyl-5-nitrobenzoate as a light yellow oil, which crystallized upon standing overnight in the refrigerator. 1H NMR (CDCl3, 400 MHz) δ 8.70, (m, 1H), 8.24, (m, 1H), 8.20, (m, 1H), 6.03-5.91, (m, 1H), 5.24-5.13, (m, 2H), 4.44, (q, 2H, J=7.1 Hz), 3.56, (d, 2H, J=6.5 Hz), 1.44, (t, 3H, J=7.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 165.0, 148.8, 143.1, 135.9, 135.5, 132.6, 127.7, 122.9, 118.4, 62.3, 39.9, 14.7; Anal HRMS Calcd. for C12H13NO4 (M): 235.0845. Found: 235.0846.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH2:36][CH3:37])([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:35])[CH:21]=3)[CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH:10]=1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH2:36][CH3:37])([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:35])[CH:21]=3)[CH2:18][CH3:19])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: [H][H]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(CCC2(O)CCCCC2)c(C)c1
Yield: 66.8 %

Procedure:
10% palladium carbon (13.0 mg) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 147-(1); 29.7 mg, 0.058 mmol) in methanol (0.3 mL), and the mixture was stirred in a hydrogen atmosphere for 19 hours. The reaction solution was filtered and concentrated under reduced pressure to give the title compound (19.9 mg, 66%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11]2[C:6](=[C:7]([CH2:14][CH2:15]O)[C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH:4]1[CH3:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C1C(=O)N([Br:49])C(=O)C1>>[Br:49][CH2:15][CH2:14][C:7]1[C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=[C:11]2[C:6]=1[CH2:5][CH:4]([CH3:17])[CH:3]2[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1c2cc(C)c(C)c(CCO)c2CC1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1c2cc(C)c(C)c(CCBr)c2CC1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 36.66 g (156.44 mmol) of 2-(1-methoxy-2,5,6-trimethyl-2,3-dihydro-1H-inden-4-yl)ethanol and 41 g (156.44 mmol) PPh3 in 650 ml of THF 27.85 g (156.44 mmol) of NBS was added at vigorous stirring for 5 min at 0° C. This mixture was stirred for 2 h at room temperature and then evaporated to dryness. A solution of the residue in 500 ml of hexanes was filtered through glass frit (G3), and the precipitate was additionally washed by 3×300 ml hexanes. The combined organic extract was evaporated to dryness. The product was isolated from the residue using flash chromatography on Silica Gel 60 (40-63 um, d 80 mm, 1250 mm; eluent: hexanes/ether=20/1, vol.). Yield 31.38 g (67%) of ca. 1 to 2 mixture of diastereomers.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([O:13]C(OCC2C=CC=CC=2)=O)=[CH:9][CH:8]=1)[CH2:3][CH3:4].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][CH:2]([O:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCC(C)OC(=O)c1ccc(OC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)c1ccc(O)cc1
Yield: 92.7 %

Procedure:
A solution of 10 m moles (3.1 g) of the above 4-carbobenzoxyoxybenzoic acid 1-methylpropyl ester and 0.5 g of palladium carbon (5% catalyst) in 40 ml of ethyl acetate was reacted for four hours in an atmosphere of hydrogen gas. After the reaction, palladium carbon was filtered out using a membrane filter, and the filtrate was concentrated, then purified by column chromatography to obtain 1.7 g of 4-hydroxybenzoic acid 1-methylpropyl ester. (yield: 86%)
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:15]=2)=[CH:7][C:6]=1[N+:29]([O-])=[O:30].O.O.Cl[Sn]Cl.O>CCOC(C)=O>[OH:30][N:29]1[C:6]2[C:5](=[N:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]4)[CH:15]=3)[CH:7]=2)[CH:4]=[CH:3]1
Reactant: CN(C)/C=C/c1ncc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Yield: 54 %

Procedure:
tert-butyl 4-(4-{6-[(E)-2-(dimethylamino)ethenyl]-5-nitropyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (366 mg, 0.81 mmol) and SnCl2.2H2O (966 mg, 4.26 mmol, 5.0 eq) in 3 ml of EtOAc were stirred at r.t. for 2 hours. EtOAc and water were added and layers were separated. The aqueous layer was extracted with EtOAc, washed with sat. NH4Cl and brine. After evaporation, the crude product was chromatographed (Mesh/DCM 1:20) to give a yellow solid, 170 mg, in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([Cl:28])=[CH:4][N:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([Cl:28])=[CH:4][N:3]=1
Reactant: CI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3Cl)ccc21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of Example 441 (520 mg, 1.23 mmol) in DMF (15 mL) at 0° C. was added portionwise NaH (95 mg, 2.45 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (0.31 mL, 4.90 mmol) was added. After 18 h of agitation at rt, the excess NaH was quenched by the slow addition of NH4Cl (10% solution in water) [H2 evolution]. The resulting mixture was concentrated under reduced pressure, brought to basic pH using a saturated solution of NaHCO3, and the product was extracted with EtOAc. The combined organic layers were washed with water and brine, after which they were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (442 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H), 1.75-1.82 (m, 1H), 2.12-2.20 (m, 2H), 2.30-2.45 (m, 2H), 2.70 (dd, 1H), 2.72-2.90 (m, 2H), 3.30 (s, 3H), 3.44-3.54 (m, 1H), 3.84 (t, 2H), 3.95 (t, 2H), 4.16 (q, 2H), 6.65 (d, 1H), 6.75 (s, 1H), 7.05 (d, 1H), 8.15 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[NH2:48][CH:49]([C:51]1[C:52](=[O:68])[NH:53][C:54]([CH2:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:61]=[CH:60][CH:59]=2)=[N:55][N:56]=1)[CH3:50]>>[OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([NH:48][CH:49]([C:51]1[C:52](=[O:68])[NH:53][C:54]([CH2:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:61]=[CH:60][CH:59]=2)=[N:55][N:56]=1)[CH3:50])=[O:7])[CH3:3]
Reactant: CC(N)c1nnc(Cc2cccc3ccccc23)[nH]c1=O
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C(CCCc1ccccc1)C(C)O)c1nnc(Cc2cccc3ccccc23)[nH]c1=O

Procedure:
526 mg (2.37 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid are reacted analogously to Example 39A with 320 mg (2.37 mmol) of 1-hydroxy-1H-benzotriazole, 408 mg (3.16 mmol) of N-ethyldiisopropylamine, 454 mg (6.350 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 500 mg (1.58 mmol) of 6-(1-aminoethyl)-3-(1-naphthylmethyl)-1,2,4-triazin-5(4H)-one to give 2-(1-hydroxyethyl)-N-{1-[3-(1-naphthylmethyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].CCN(CC)CC.[Br:24][CH2:25][C:26](Br)=[O:27]>ClCCCl.O>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[NH:15][C:26](=[O:27])[CH2:25][Br:24]
Reactant: O=C(Br)CBr
Reactant: Cc1ccccc1C(N)c1ccccc1C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccccc1C(NC(=O)CBr)c1ccccc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 117.8 %

Procedure:
The compound of Example 554F (100 mg, 0.47 mmol) was dissolved in 2 mL of 1,2-dichloroethane. To this solution at −78° C. was added Et3N (0.05 mL) and then dropwise bromoacetyl bromide (40 mL, 0.47 mmol in 1 mL of 1,2-dichloroethane). The reaction mixture was stirred at −78° C. for 10 min, then at r.t. for 2 h., diluted with water (10 mL), and extracted with 1,2-dichloroethane (2×25 mL). The combined organic layers were concentrated to give the bromoacetamide as a white solid (184 mg, 96%) suitable for further use without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>C1(C)C=CC=CC=1.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20]([CH:24]=[CH2:25])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc3ccc(Br)cn23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ncc(C3CCN(C(=O)OC(C)(C)C)CC3)n2c1
Temperature: 25 °C
Yield: 110 %

Procedure:
To a solution of 95 mg of 1-(t-butoxycarbonyl)-4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-piperidine (from Example 274, Step A), and 158 mg of tributyl(vinyl)tin in 6 mL toluene was added 5.3 mg of dichlorobis (triphenyl phosphine)-palladium(II). The mixture was refluxed for 2 hours. The reaction was cooled down to r.t. and partitioned between CH2Cl2and water. Aqueous layer was extracted with CH2Cl2 (3×). The combined organic phase was washed with brine and dried over MgSO4. After concentration, the residue was purified by prep TLC (100% EtOAc) to give 90 mg of the title compound as a viscous oil, which was used in next step without further purification.