Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22]1
Reactant: O[C@@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](O)C3)s2)noc1C(F)(F)F
Yield: 45 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (R)-(+)-3-hydroxypiperidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine (containing and additional 1.1 eq. to neutralize the piperdinyl hydrochloride salt) and piperdine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude product was then chromatographed on silica gel with EtOAc/hexanes (50 then 75 then 100%) as eluant to afford product as a colorless solid (41 mg, 45%). 1H NMR (CDCl3) 1.56-1.62 (m, 1 H), 1.62-1.80 (m, 1 H), 1.83-2.10 (m, 2 H), 2.36 (d, J=1.3, 3 H), 2.86 (br, 1 H), 3.50-3.76 (m, 4 H), 3.82-3.98 (m, 2 H), 7.39 (br d, J=4.0, 1 H), 7.44 (d, J=4.0, 1 H). 13C NMR 7.9, 22.6, 32.5, ˜48 (br), ˜52 (br), 66.2, 114.7, 118.7 (q, J=271), 128.0, 129.6, 131.3, 140.1, 155.2 (q, J=40), 157.9, 163.5. 19F NMR −63.2. LC/MS 5.65 min, [M+1]+ 361.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.C([Li])CCC.[I:24]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([I:24])=[CH:10][C:3]=12
Reactant: II
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(I)cc2c(Cl)ccnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (235 mg, 0.831 mmol) was dissolved in tetrahydrofuran (3 mL) under nitrogen atmosphere. After cooling to −78° C., n-butyllithium (0.675 mL, 1.080 mmol, 1.6 M hexane solution) was slowly added dropwise. The resulting mixture was stirred for 1 hour. After adding a solution of iodine (253 mg, 0.997 mmol) in tetrahydrofuran (2 mL), the mixture was slowly heated to room temperature. One hour later, the mixture was extracted with dichloromethane and water and the organic layer was washed with sodium chloride aqueous solution. The organic layer was dried with magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1) to give the target compound as a yellow oil (339 mg, 0.83 mmol, 97% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH2:16]([O:23][C:24](=[O:36])[CH2:25][N:26]([C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30](Cl)[N:29]=1)[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:16]([O:23][C:24](=[O:36])[CH2:25][N:26]([C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:29]=1)[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(N(C)CC(=O)OCc2ccccc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nc(C)cc(N(C)CC(=O)OCc3ccccc3)n2)ccc1-n1cnc(C)c1
Yield: 56 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and [(2-chloro-6-methyl-pyrimidin-4-yl)-methyl-amino]acetic acid benzyl ester, using potassium carbonate as a base. The title compound was isolated as a colorless solid in a yield of 56%. MS ISP (m/e): 473.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.58 (s, 1H), 7.54 (s broad, 1H), 7.35-7.20 (m, 4H), 7.10-6.95 (m, 2H), 6.89 (s broad, 1H), 6.82 (s, 1H), 5.95 (s, 1H), 5.16 (s, 2H), 4.39 (s broad, 2H), 3.80 (s, 3H), 3.14 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:26])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:26][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCCC1
Reactant: O=c1c(Cc2ccccc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(OCCN4CCCCC4)cc13)Sc1ccc(Br)cc1-2
Yield: 60.2 %

Procedure:
According to Example 34, the compound (200 mg) produced in Example 70 was reacted with 1-(2-chloroethyl)piperidine (158 mg) to obtain the title compound (151 mg; 60%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([OH:14])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[H-].[Na+].I[CH3:18].O>O1CCCC1>[CH3:18][O:14][C:4]1([CH2:3][O:2][CH3:1])[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][CH2:5]1
Reactant: CI
Reactant: COCC1(O)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1(OC)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.40 g (16.8 mmol) of the compound from Example 8A were dissolved in 170 ml of tetrahydrofuran, 1.01 g (25.2 mmol) of sodium hydride (60% in paraffin oil) were added and the mixture was stirred at room temperature for 0.5 hour. 3.58 g (25.2 mmol) of iodomethane were then added, and the reaction mixture was stirred at room temperature for two hours. 3.58 g (25.2 mmol) of iodomethane were then added, and the reaction mixture was stirred at room temperature for two hours. Water was added, the mixture was extracted repeatedly with ethyl acetate and the combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 3.35 g (92% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>>[CH2:1]([C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][S:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=2)(=[O:32])=[O:31])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Product: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 56.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.505 g, 1.29 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.612 g, 2.58 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 15% EtOAc/hexane gave 0.432 g (57%) of the title compound a pale yellow solid, mp 70-77° C. 1H NMR (DMSO-d6) δ 1.29-1.34 (m, 2H), 1.51-1.57 (m, 2H), 1.62-1.77 (m,4H), 1.79 (s, 3H), 2.25 (s, 3H), 2.99 (quintet, 1H), 3.84 (s, 2H), 6.98 (d, 2H), 7.12-7.25 (m, 4H), 7.39 (d, 2H), 7.52 (dd, 1H), 7.57 (d, 1H), 7.99 (d, 1H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm−1. mass spectrum (+ESI) m/z 591 (M+H). Anal. Calcd. for C32H30O7S2.0.5H2O: C, 64.09; H, 5.21; N, 0.00. Found: C, 63.96; H, 5.30; N, 0.04.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[S:23][C:24]([C:30]4[C:35]([F:36])=[CH:34][C:33]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:32][C:31]=4[F:41])=[CH:25][C:26]=3[C:27]([NH2:29])=[O:28])[N:16]=2)[CH:13]=1)(C)(C)C.Cl.O1CCOCC1>CCOC(C)=O>[NH2:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[N:16]=[C:17]([NH:21][C:22]3[S:23][C:24]([C:30]4[C:31]([F:41])=[CH:32][C:33]([C:37]([OH:40])([CH3:38])[CH3:39])=[CH:34][C:35]=4[F:36])=[CH:25][C:26]=3[C:27]([NH2:29])=[O:28])[CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cn4cc(CN)nn4)n3)s2)c(F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of tert-butyl[(1-{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]carbamate (90 mg, 0.15 mmol) in EtOAc (7.0 mL) at ° C. was added 4 M HCl in dioxane (1.88 mL, 7.50 mmol). The reaction was stirred at 0° C. for 4 h. The yellow suspension was quenched with saturated NaHCO3 and extracted with 5:1 CH2Cl2:MeOH (2×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by reverse phase HPLC (15-75% MeCN/water w/0.025% TFA). Product fractions were neutralized with saturated NaHCO3, extracted with 5:1 CH2Cl2:MeOH (2×), dried (MgSO4), filtered, and evaporated to give the title compound as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][O:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCCC1CCCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCCO1

Procedure:
Prepared similarly to Intermediate 213 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[N:16][CH:17]=3)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(-c4ccc(F)cc4)c3)cnc21
Temperature: 100 °C
Yield: 67 %

Procedure:
6-(5-Bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (50 mg, 0.15 mmol), 4-fluorophenylboronic acid (42 mg, 0.30 mmol) and 2.0 M Na2CO3 aqueous solution (0.15 mL, 0.30 mmol) are dissolved in 2.0 mL of 1,4-dioxane. The Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (7.7 mg, 0.011 mmol) is added. The mixture is heated at 100° C. for 2 hrs before it is cooled down to room temperature. Then 30 mL of DCM and 20 mL of water are added. The organic layer is separated and the aqueous layer is extracted with DCM (2×20 mL). All the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography followed by washing with EtOAc (2×1 mL) affords 35 mg of the titled product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30]([CH3:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1>>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH2:31][N:30]([CH3:47])[CH3:29])=[CH:33][CH:34]=4)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]4[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=3[CH:6]=[N:7]2)[CH2:13][CH2:12]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C1CC1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c1cnn2C1CC1

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-1-cyclopropyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.075 g, 0.169 mmol) and N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.060 g, 0.203 mmol). The title compound was collected as a white solid (59 mg, 69%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3H), 1.12-1.21 (m, 4H), 1.45-1.58 (m, 2H), 2.13 (s, 3H), 2.18 (s, 6H), 3.45 (s, 2H), 3.88 (quin, J=5.37 Hz, 1H), 4.41 (d, J=5.05 Hz, 2H), 5.91 (s, 1H), 7.43 (m, J=8.34 Hz, 2H), 7.80 (m, J=8.08 Hz, 2H), 7.89 (d, J=1.26 Hz, 1H), 8.04 (s, 1H), 8.32 (s, 1H), 8.68 (t, J=4.93 Hz, 1H), 11.54 (s, 1H); LC-MS (ES) m/z=498.4 [M+H].
Reaction SMILES: O[CH:2]([CH3:14])[CH:3](C)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.NN.[C:17]([O-:20])([O-])=O.[K+].[K+]>C(O)COCCO>[CH2:5]([C:7]1[CH:12]=[CH:11][C:17]([OH:20])=[C:9]([CH3:10])[CH:8]=1)[CH2:4][CH2:3][CH2:2][CH3:14]
Reactant: CC(O)C(C)CC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Product: CCCCCc1ccc(O)c(C)c1
Temperature: 135 °C
Yield: 85.3 %

Procedure:
153.6 g (0.8 moles) of 4-hydroxy-3-methyl-pentanophenone are added to 500 ml of diethylene glycol, 120 g (3.8 moles) of hydrazine and 196 g (3.5 moles) of potash. The solution is refluxed at 135° C. in the mass for 2 hours and then the excess hydrozine and water are distilled until the temperature of the mass is 230° C. The solution is allowed to cool and then poured into 2.5 l of deionized water. It is then acidified with concentrated hydrochloric acid to pH1. The product precipitates. It is extracted with ether. The ethereal extract is washed with deionized water and then dried on magnesium sulphate. The ether is distilled and the product is purified by distillation. It distills at 97.5° C. at 0.4 mm of mercury. 121.6 g of pure compound is obtained, namely a yield of 85%.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[C:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([OH:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:29]4[CH:30]=[CH:31][C:26]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)cc1
Temperature: 80 °C

Procedure:
150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 71.3 mg (0.43 mmol) of 4-carboxyphenylboronic acid are introduced into 1.5 ml of DMF. Addition of 0.64 ml of 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf) is followed by heating at 80° C. for 18 h. After cooling, the reaction mixture is filtered through kieselguhr, and the filtrate is concentrated and partitioned between water and ethyl acetate. The aqueous phase is washed with ethyl acetate and then concentrated. The crude product is purified by preparative HPLC. The product fractions are combined and concentrated and, after addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, again concentrated. The crude product is stirred with acetonitrile. The precipitate is filtered off with suction and dried under high vacuum to result in 37 mg (20% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:40])=[C:4]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C:5]([I:34])=[C:6]([C:32]=1[I:33])[C:7]([N:9]([CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][O:24]C(=O)C)[CH2:10][CH:11]([O:17]C(=O)C)[CH2:12][O:13]C(=O)C)=[O:8].[C:41]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][Cl:52])[C:46](Cl)=[O:47])(=[O:43])[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:41]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][Cl:52])[C:46]([NH:1][C:2]1[C:3]([I:40])=[C:4]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C:5]([I:34])=[C:6]([C:32]=1[I:33])[C:7]([N:9]([CH2:21][CH:22]([OH:28])[CH2:23][OH:24])[CH2:10][CH:11]([OH:17])[CH2:12][OH:13])=[O:8])=[O:47])(=[O:43])[CH3:42]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(CC(COC(C)=O)OC(C)=O)CC(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OC(CCCCl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(CCCCl)OC(C)=O)c(I)c(C(=O)N(CC(O)CO)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Amino-3-acetoxymethyl-N,N-bis-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide g, 6.85 mmol) was dissolved in dry N,N-dimethylacetamide (10 ml) and the mixture was cooled in an ice-bath. 2-Acetoxy-5-chloropentanoyl chloride (4.36g, mmol) was then added dropwise. The mixture was stirred at room temperature for 24 h, and then added slowly to aqueous sodium hydrogen carbonate (5%, 600 ml) with efficient stirring. A precepitate was formed and filtered off, redissolved in methylene chloride (250 ml) which was washed with water (6×70 ml), dried (Na2SO4) and concentrate in vacuo. The residue was chromatographed on a column of silica gel using heptane/ethyl acetate (3/7) as the eluent Yield: 7.30 g (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:67]1[C:72](=[O:73])[CH2:71][NH:70][CH2:69][C:68]1=[O:74]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:32])([F:31])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:70]4[CH2:71][C:72](=[O:73])[NH:67][C:68](=[O:74])[CH2:69]4)=[O:22])=[C:19]([C:26]([F:28])([F:29])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CNCC(=O)N1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (70 mg, 0.14 mmol, 1.00 equiv), N,N-dimethylformamide (3 mL), HATU (105 mg, 0.28 mmol, 2.00 equiv), DIEA (36 mg, 0.28 mmol, 1.96 equiv), piperazine-2,6-dione (32 mg, 0.28 mmol, 1.99 equiv). The resulting solution was stirred for 1 h at 25° C. The reaction was then quenched by the addition of 10 ml of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (1/1). This resulted in 70 mg (76%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]piperazine-2,6-dione as colorless oil.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.C1C(C(OO)=[O:18])=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]2[O:18][CH:9]2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(OO)c1ccccc1
Reactant: ClC=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClC=CCC1=CC=CC2OC12
Reaction time: 8 h
Yield: 33 %

Procedure:
(a) To 6.1 g of m-chloroallylbenzene was added 85 ml of chloroform solution containing perbenzoic acid and the mixture was allowed to stand at room temperature overnight. This solution was washed with sodium hydroxide solution, 20% Mohr's salt solution and then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 2.2 g (yield 33%) of m-chloroallylbenzene oxide having a boiling point of 117° C/7 mmHg.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH:40]1([N:46]=C=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([NH:46][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C=NC1CCCCC1
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)NC1CCCCC1
Yield: 6 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and cyclohexyl isocyanate as described in Example 16 in a 6% yield; ESMS, (M+1)+452.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]1[C@H:16]2[N:12]([CH2:13][CH2:14][CH2:15]2)[C:11](=O)[CH:10]=[C:9]1N1CCCC1.[OH-].[Na+].C([OH:27])C>O1CCCC1>[CH3:7][CH:8]1[C@H:16]2[N:12]([CH2:13][CH2:14][CH2:15]2)[CH2:11][CH2:10][C:9]1=[O:27]
Reactant: CCO
Reactant: CC1C(N2CCCC2)=CC(=O)N2CCC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1C(=O)CCN2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
1.79 g (47.1 mmol) of lithium aluminum hydride were added in several portions to a stirred, ice-cooled solution of 3.67 g (15.7 mmol) of (8aS)-8-methyl-7-(1-pyrrolidinyl)-1,2,3,5,8,8a-hexahydroindolizin-5-one [obtained as described in Preparative Example 9(iv)′ above] in 50 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature overnight. At the end of this time, 7.22 ml of a 1N aqueous solution of sodium hydroxide were added followed by the addition of ethanol, and any insoluble material was then filtered off. The filtrate thus obtained was concentrated by evaporation under reduced pressure, and the resulting residue was purified by chromatography on an alumina column using ethyl acetate as the eluant to afford 1.69 g (yield: 70%) of the title compound as a pale yellow oil.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][N:14]([CH3:25])[N:13]=1.O.NN>CO>[NH2:3][C:12]1[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:15][N:14]([CH3:25])[N:13]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CO
Product: Cn1cc(NC(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl (3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (1.8 g) in methanol (26 mL) was added hydrazine monohydrate (0.38 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.1 g).