Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12](Br)[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[C:22]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:1]([N:8]1[CH:13]=[C:12]([C:35]2[CH:36]=[CH:37][C:32]([C:22]3[C:23]4[O:24][C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[C:27]=4[CH:19]=[CH:20][CH:21]=3)=[CH:33][CH:34]=2)[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: O=c1c([N+](=O)[O-])cc(Br)cn1Cc1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c([N+](=O)[O-])cc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cn1Cc1ccccc1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A solution of 1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one (1.0 g, 3.24 mmol), 4-dibenzofuran-4-yl-phenyl-boronic acid (932 mg, 3.24 mmol), K2CO3 (1.34 g, 3 equiv., 9.7 mmol) in toluene (15 mL), ethanol (10 mL) and water (5 mL) was treated with treated with Pd(PPh3)4 (125 mg). After heating to 80° C. overnight, the solution was cooled to room temperature and the resulting solids were filtered and washed with ether (2×6 mL) to give 1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-3-nitro-1H-pyridin-2-one as a yellow solid (1.53 g, 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl.CCN(CC)CC>[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:33])[CH3:32]
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml DCM, 0.3 ml NEt3 and 11 mg acetic acid anhydride were added at RT and stirred over night. After removal of the solvent under reduced pressure the residue was directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:18]([CH3:19])=[N:17][C:10]2[N:11]=[C:12](SC)[N:13]=[CH:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].C(O)(=O)C.[O-]Cl.[Na+].[CH3:29][NH2:30].C1COCC1>CN(C)C=O>[F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:18]([CH3:19])=[N:17][C:10]2[N:11]=[C:12]([NH:30][CH3:29])[N:13]=[CH:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: CSc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Reactant: CN
Agent: [Na+]
Agent: [O-]Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Temperature: 47.5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Heat a mixture 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (28.6 g, 84 mmol), dimethylformamide (74 mL) and glacial acetic acid (9.61 mL, 169 mmol) to 45° C. and then add 6.15% aqueous NaOCl (bleach, 612 g, 506 mmol) dropwise over 2 h. Heat at 45-50° C. for 2 h, cool to RT, collect the solids by filtration and wash with water (300 mL). Add DCM (200 mL) to the solids, cool the suspension in an ice-water bath and treat with a solution of 2.0 M N-methylamine in THF (126 mL, 253 mmol). Allow the mixture to slowly warm to RT and stir for 2 h. Remove the solvent under reduced pressure, treat with methanol (MeOH) (50 mL) and stir at RT for 30 min. Collect the solid by filtration and wash with MeOH. Treat the solid with EtOAc (30 mL) and stir at RT for 30 min. Collect the solid by filtration and wash with EtOAc to obtain the title compound (19.82 g, 73% yield). MS (m/z): 323.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].CC[N:17](C(C)C)[CH:18]([CH3:20])[CH3:19].C(N)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:14][C:7]1[CH:8]=[C:9]([C:11]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:13])[NH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C(=O)NC(C)C)cc1C
Yield: 5.3 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added isopropylamine (0.017 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 3-methyl-5-{[(1-methylethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.010 g, 47%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.58 (br. s., 1H) 8.07 (s, 1H) 6.60 (s, 1H) 4.26 (q, 2H) 3.97-4.12 (m, 1H) 2.24 (s, 3H) 1.30 (t, 3H) 1.14 (d, 6H). MS: m/z 239.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][Br:18])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1ncn2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Yield: 60 %

Procedure:
To a stirred solution of 4-methyl-benzimidazole-1-carboxylic acid tert-butyl ester (800 mg, 3.4 mmol) in CCl4 (7 mL) was added N-bromosuccinimide (730 mg, 4.1 mmol) and 2,2′-azobis(2-methylpropionitrile) (84 mg, 0.51 mmol). The resultant mixture was heated at reflux for 18 h after which it was filtered and concentrated to a yellow/orange syrup and crystals (1.4 g). Purification by column chromatography on silica gel (200:15—Hexanes:EtOAc) gave the desired title compound as a yellow syrup (635 mg, 60%). 1H NMR (300 MHz, CDCl3) δ8.48 (s, 1H), 7.95 (dd, 1H, J=7.8, 1.5 Hz), 7.42-7.34 (m, 2H), 4.96 (s, 2H), 1.71 (s, 9H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)CC(C)C>[OH:4][CH2:1][C@H:11]1[CH2:10][N:9]2[CH2:13][CH2:8][N:9]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH2:10][C@@H:8]2[CH2:13][CH2:12]1
Reactant: Brc1ccccn1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@@H]1CC[C@H]2CN(c3ccccn3)CCN2C1

Procedure:
A mixture consisting of title product of Preparation 5 (9.10 g; 53.4 mmol), sodium carbonate (14.1 g; 0.13 mol), and 2-bromopyridine (25.5 ml; 42.3 g; 0.27 mol) in isoamylalcohol (25 ml) was refluxed for 72 hours. The reaction was filtered while hot, and the filter cake washed with 50 ml of methylene chloride. The filtrate was concentrated in vacuo to an oil, which was taken up in 100 ml ethyl acetate. An equal volume of water was added, and the pH of the well-stirred mixture was adjusted to 11.5 (saturated sodium carbonate). The organic phase was separated, treated with activated carbon, dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil. Flash chromatography of the entire sample (125 g silica gel, 32-63 mesh; elution with methylene chloride/methanol=97:3 by volume) with TLC monitoring of fractions [product Rf =0.26 (methylene chloride:methanol 9:1 in volume), detection by U.V. and Dmgendorf's spray] afforded 7.50 g (56.6% yield) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:10]1([C:16]([NH:2][C@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[OH:9])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O[C@@H]1CCCC[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of cis-2-aminocyclohexanol hydrochloride (4.88 g; 32 mmol) (William S. Johnson and Elliot N. Schubert, J.A.C.S., Vol. 72, pp. 2187-2190 (1950), triphenylmethylchloride (10.7 g; 38.4 mmol) and triethylamine (16 ml; 115 mmol) in 250 ml methylene chloride are refluxed for 3 hrs. then stirred at room temperature overnight. The mixture is poured into H2O and extracted with CH2Cl2 (200 ml), dried (Na2SO4) concentrated in vacuo and flash chromatographed using 9:1 7:1; hexane:EtOAc to obtain cis-2-triphenylmethylaminocyclohexanol which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:40](=[O:41])[CH2:39][Cl:38])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)CCl)cc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Part A: To a stirred, cooled (0° C.) solution of 9.26 g (20 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 45 mL of THF and 10 mL of DMF was added 3.90 mL (28 mmol) of triethylamine followed by 1.99 mL (25 mmol) of chloroacetyl chloride over 5 min. The solution was stirred 30 min. at 0° C. and quenched by addition of 150 mL of 0.1 N aq. HCl. The resulting solid was collected by filtration, washed with water then 1:1 ether-hexanes, and air-dried to afford 10.2 g (95%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid. 1H NMR (300 MHz, DMSO) δ 12.49(s, 1H); 9.74(s, 1H); 7.97(s, 2H); 7.46(d, 2H, J=8.0 Hz); 7.20(d, 2H, J=8.8 Hz); 4.19(s, 2H); 3.80(s, 2H); 3.20-3.33(m, 1H); 1.28(d, 6H, J=6.9 Hz).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:17]([CH2:25][CH2:26][N:27]=4)[C:18]([NH2:24])=[N:19][C:20]=3[C:21]=2[O:22][CH3:23])[CH2:4][CH2:3]1.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][N:31]=1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([NH:24][C:18]2[N:17]3[CH2:25][CH2:26][N:27]=[C:16]3[C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][S:2](=[O:1])(=[O:28])[CH2:3][CH2:4]4)=[C:21]([O:22][CH3:23])[C:20]=3[N:19]=2)=[O:37])=[CH:32][N:31]=1
Reactant: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ncc(C(=O)O)cn1
Product: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 8-[3-(1,1-dioxidothiomorpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 19, Step 1) and 2-aminopyrimidine-5-carboxylic acid. High vacuum drying at 60° C. gave the title compound (272 mg, 79%): HPLC MS RT=1.45 min, MH+=529.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.25-2.30 (2H, m), 3.44-3.49 (2H, m), 3.61-3.63 (4H, m), 3.83 (4H, bs), 3.99 (3H, s), 4.18-4.25 (2H, m), 4.33 (2H, t), 4.48-4.55 (2H, m), 7.43 (1H, d), 8.02 (1H, d), 9.04 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:11]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:32][CH:33]=4)=[CH:25][CH:24]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58](O)=[O:59])=[O:52])([CH3:49])([CH3:48])[CH3:47].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>CS(C)=O>[C:42]([O:41][C:39]([N:35]1[CH2:36][CH2:37][CH2:38][C@H:34]1[C:31]1[NH:32][CH:33]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:11]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:15][CH:14]=4)[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:58]([C@H:54]5[CH2:55][CH2:56][CH2:57][N:53]5[C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])=[O:59])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[CH:24][CH:25]=2)[N:30]=1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(C2CCC(c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)N2c2ccc(C(C)(C)C)cc2)cc1
Yield: 58.6 %

Procedure:
The product from Example 40D (1.3 g, 2.146 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.386 g, 6.44 mmol), HATU (1.305 g, 3.43 mmol) and Hunig's base (1.124 mL, 6.44 mmol) in DMSO (20 mL) was reacted according to the procedure in Example 39H to provide the title compound (1.01 g, 59%) as a mixture of stereoisomers.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=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: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 14 h
Yield: 87.4 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (1.5 g, 3.88 mmol), phenylboronic acid (0.710 g, 5.82 mmol), Pd(Ph3P)4 (0.449 g, 0.388 mmol) and aqueous Na2CO3 (3.88 mL, 7.77 mmol) in toluene (25 mL) is allowed to stir at 95° C. under nitrogen for 14 hours. The reaction mixture is cooled to room temperature and quenched with brine. The mixture is extracted twice with ethylacetate, and the combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (1.30 g); HPLC retention time=1.61 minutes (condition B); MS (ES+)=328.0 (m-tBu+2); 284.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3 H) 2.48 (A of ABX, Jab=16.1 Hz, Jax=5.9 Hz, 1 H) 2.53 (B of ABX, Jab=16.0 Hz, Jbx=5.3 Hz, 1 H) 2.83-3.00 (m, 2 H) 4.14-4.19 (m, 3 H) 5.06 (br s) 7.26-7.27 (m, 2 H) 7.31-7.35 (m, 2 H) 7.43 (t, J=7.6 Hz, 2 H) 7.52-7.58 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:31]5[S:32][CH:33]=[CH:34][N:35]=5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(-c5nccs5)cc43)CC2)cc1
Yield: 3 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.56 g) and 2-tributylstannylthiazole (2.778 g) synthesized in accordance with the method described in Synthesis, 757 (1986). were treated as in Production Example 13-2 to give the title compound (0.017 g) as pale yellow crystals (yield: 3.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH:29]([N:32]([CH2:36][CH2:37]Cl)[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:37][CH2:36][N:32]([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN(C(C)C)C(C)C)cc2)cc1
Temperature: 100 °C

Procedure:
The title compound was prepared by reacting the compound of Preparation 4a supra, 2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with 2-(N,N-diisopropylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06 g, 80.2 mmol). The mixture was heated to 100° C. and was maintained at that temperature for about two hours. The reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12]([CH:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])COS(C)(=O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O.[CH:38]1C=CC=CC=1>>[CH3:38][CH:30]([CH:29]([CH:7]([CH:5]([CH2:4][OH:3])[OH:6])[OH:8])[CH2:28][CH2:27][CH2:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: c1ccccc1
Reactant: CCCCCCCCCCC(CCCCCCCC)COS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCC(C(C)CCCCCC)C(O)C(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
(R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (8.3 ml, 66.59 mmol), powdered potassium hydroxide (12 grams) and methanesulfonic acid-2-octyl-dodecyl ester (22.77 grams, 60.50 mmol) were stirred in benzene (250 ml) and refluxed for 5 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 150 ml. The reaction mixture was cooled to room temperature and stirred at room temperature overnight. 200 ml water was added, and the mixture was extracted with diethyl ether (3×200 ml). The combined organic phase was washed with water (200 ml) and the solvent was removed under reduced pressure. The obtained residue was dissolved in 105 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 30 minutes. After cooling to room temperature, water (100 ml) was added. The product was extracted with chloroform (3×100 ml), and washed consecutively with water (100 ml), saturated aqueous solution of sodium carbonate (100 ml) and again with water (100 ml). The solvent was removed under reduced pressure, and the crude product was purified by chromatography on a silica gel (400 grams) column. 17 grams of pure 1-(2-octyl)dodecyl-glycerol was eluted by chloroform followed by a mixtures of chloroform and 10%-30% ethyl acetate as a colorless oil. The yield was 75.5%.
Reaction SMILES: CN(OC)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl.CCCCCC>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:11])=[CH:5][N:6]=1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1ccc(C=O)cn1
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
6-Methylnicotinic acid N,O-dimethylhydroxylamide (737 mg, 4.09 mmol) was dissolved in dichloromethane. To this, diisobutylaluminum hydride (a 0.98 mol/L solution in hexane, 4.60 mL, 4.50 mmol) was added dropwise under a nitrogen atmosphere at −10° C. and the mixture was stirred at the same temperature for 10 minutes. To this, water (4.60 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give a 3:1 mixture (405 mg) of 2-methyl-5-formylpyridine and 6-methylnicotinic acid N,O-dimethylhydroxylamide. The mixture was dissolved in tetrahydrofuran (8.0 mL). To this, (trifluoromethyl)trimethylsilane (593 μL, 4.01 mmol) and tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 340 μL, 0.340 mmol) were added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a 1N aqueous hydrogen chloride solution (6.0 mL) was added and the mixture was further stirred for 10 minutes. Then, the reaction mixture was neutralized with a saturated sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 2-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CK) (387 mg, yield: 50%).
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:9][C:10]1[C:11]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[CH3:22])=[N:12][NH:13][CH:14]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:13]1[CH:14]=[C:10]([CH3:9])[C:11]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[CH3:22])=[N:12]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:23]
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1ccc(C)c(-c2n[nH]cc2C)c1
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2cc(C)ccc2C)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 4-methyl-3-(2,5-dimethylphenyl)pyrazole for 4-methyl-3-phenylpyrazole there is obtained α-ethyl-N,N,4-trimethyl-3-(2,5-dimethylphenyl)pyrazole-1-acetamide isolated as an oil.