Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([NH2:32])[CH2:27][CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([NH:32][C:20]1[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=1)[CH2:27][CH2:26]2
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1CCc2cc(F)ccc21
Product: O=[N+]([O-])c1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Yield: 75.6 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (1.22 g, 3.76 mmol; HPLC: 4.446 min) and rac-5-fluoro-indan-1-ylamine (CAS 148960-33-2) (568 mg, 3.76 mmol; HPLC 0.4 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (0.93 g, 90%), MS (ISP) m/e=328.2 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].Cl[CH2:11][CH:12]=O>CCO>[Br:1][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=CCCl
Reactant: Nc1nnc(Cl)cc1Br
Solvent: CCO
Product: Clc1cc(Br)c2nccn2n1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (D-2) (16 g, 77.3 mmol, 1.0 eq) in EtOH (200 mL), 2-chloroacetaldehyde (45% in water, 67.4 g, 386.6 mmol, 5.0 eq) is added and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo to remove EtOH. The residue is slurried in acetone. The solid is collected by filtration and washed with acetone. The solid is suspended in water, neutralized with aqueous ammonia to adjust the pH to 8 at 0-5° C. and then extracted with ethyl acetate (2×150 mL). The combined layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (D-3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:47]=[CH:46][C:20]([CH2:21][CH:22]([C:30]([NH:32][S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])=[O:31])[C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH2:28]([N:25]([CH2:26][CH3:27])[C:23](=[O:24])[CH:22]([CH2:21][C:20]1[CH:46]=[CH:47][C:17]([NH:16][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:18][CH:19]=1)[C:30]([NH:32][S:33]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)(=[O:34])=[O:35])=[O:31])[CH3:29]
Reactant: CCN(CC)C(=O)C(Cc1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)C(Cc1ccc(NC(=O)C2CCNCC2)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 16 h

Procedure:
To a solution of the compound (250 mg) obtained in Example 17 in methylene chloride (10 mL) was added trifluoroacetic acid (3 mL) at room temperature, and the mixture was stirred for 16 hr. After concentration under reduced pressure, an ether/chloroform mixture was added, and the precipitate was collected by filtration to give the title compound (247 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[O:17][CH3:18]
Reactant: COCOc1cc(OC)c(OC)c(OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCOc1cc(OC)c(OC)c(OC)c1OC
Temperature: 45 °C

Procedure:
11.5 g of 2-methoxymethyloxy-4,5,6-trimethoxyphenol prepared in Referential Example 12 and 23.0 g of potassium carbonate were suspended in 100 ml of DMF. The suspension was heated at 45° C. while stirring, and 5.2 ml of iodomethane was dropwise added thereto. After the completion of the dropwise addition, the mixture was heated for 30 min, cooled and separated by filtration. 1 l of water was added to the mother liquor, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; n-hexane : ethyl acetate=85 : 15) to prepare 6.2 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][CH2:18][C:19]#[CH:20])[NH:8]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH2:8]
Reactant: C#CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#COC[C@H](N)C(=O)NCC(=O)OC
Yield: 65.5 %

Procedure:
N-tert-butoxycarbonyl-O-propargyl L-seryl glycine methyl ester (6.17 g, 19.6 mmol) was treated with a 50% (v/v) solution of TFA in CH2Cl2 (50 mL). The reaction mixture was stirred for 1 h 20 min before the solvent and bulk of excess TFA was evaporated. The residue was dissolved in H2O (50 mL) and the solution washed with Et2O (3×25 mL). The pH was regulated to pH 10-11 and the solution extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated affording a yellowish liquid (2.75 g, 65%); δH (300 MHz; d6-DMSO) 8.33 (1H, t/dd, J difficult to measure, NH), 4.14 (2H, d, J 2, CH2CCH), 3.87 (1H, s, CαHH(Gly)), 3.85 (1H, s, CαHH(Gly)), 3.63 (3H, s, OCH3), 3.58 (1H, dd, J 9 and 5, CHH), 3.49 (1H, dd, J 9 and 6, CHH), 3.41 (1H, dd, J 6 and 5, CαH(propSer)), 3.30 (1H, t, J 2, CCH), 1.86 (2H, br s, NH2); δC (75 MHz; d6-DMSO) 173.1, 170.2, 80.1, 77.1, 72.1, 57.6, 54.8, 54.3, 51.6, 40.5
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:49])[F:50])=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 84.4 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (2-methoxy-5-(trifluoromethyl)phenyl)boronic acid (89 mg, 0.40 mmol), sodium carbonate (43 mg, 0.40 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-ethyl acetate) to give 99 mg (85% yield) of the title compound. Purity 100%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]3[NH:27][CH2:26][CH2:25][S:24]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30]>CC(C)=O>[CH3:28][S:29]([NH:32][C:33]([N:27]1[CH2:26][CH2:25][S:24][CH:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10]1)=[O:34])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)N=C=O
Reactant: Fc1cccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
1.94 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine are dissolved in anhydrous acetone, and 0.73 g of methanesulfonyl isocyanate is added thereto at room temperature. After the mixture is stirred for 30 minutes, the mixture is concentrated under reduced pressure to remove solvent. The residue is collected by filtration, and washed with water and ether, successively. The crude product thus obtained is recrystallized from a mixture of acetone and ether. 1.56 g of N-methanesulfonyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazollidine-3-carboxamide are obtained.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:1][NH:2][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)c1ccc2ccnc(Cl)c2c1
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2ccnc(NC)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of methylamine in tetrahydrofuran (30 mL, 60 mmol, 2 M) was added to ethyl 1-chloroisoquinoline-7-carboxylate (formed in Step 3 of Intermediate 27) (705 mg, 2.99 mmol) in a sealed tube. The reaction was heated to 60° C. and stirred overnight. LCMS indicated the reaction was not complete. Additional methylamine (10 mL, 20 mmol, 2 M in THF) was added and the reaction was heated to 60° C. for another 18 hours. The reaction was cooled to room temperature and concentrated. The residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulphate, filtered, and concentrated. Purification by flash column chromatography (25-65% ethyl acetate/heptanes) gave the title compound (584 mg, 85%) as a yellow oil that solidified upon standing. +ESI (M+H) 231.1; 1H NMR (400 MHz, DMSO-d6, δ): 8.83-8.94 (m, 1H), 8.07 (dd, J=8.58, 1.56 Hz, 1H), 7.99 (d, J=5.85 Hz, 1H), 7.89 (d, J=4.49 Hz, 1H), 7.77 (d, J=8.58 Hz, 1H), 6.92 (d, J=5.07 Hz, 1H), 4.38 (q, J=7.02 Hz, 2H), 2.97 (d, J=4.49 Hz, 3H), 1.38 (t, J=7.12 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:23]([C:27]1[CH:31]=[C:30]([NH2:32])[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(OCc3ccccc3)cc2)on1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
(4-Benzyloxy-phenyl)-acetic acid (50 mg, 0.2 mmol, 1 eq) was stirred with 1 mL of thionyl chloride at 80° C. for approximately three hours. The completion of the reaction was checked by TLC. Excess thionyl chloride was removed in vacuo, the residue was dissolved in dichloromethane and added to a mixture of 3-tert-butyl-isoxazol-5-ylamine (28 mg, 0.2 mmol, 1 eq) and DIEA (35 μL, 0.2 mmol, 1 eq). The reaction was stirred overnight at 45° C. The solvent was removed and the product purified by HPLC. Yield: 42 mg (57%), LC/MS [MH+] 365.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24])(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C1COCC1>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:16])([F:15])[F:17])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[C:7]2=[O:24])[CH3:2]
Reactant: CC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 72.8 %

Procedure:
A solution of N-(6-acetyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (12.1 g, 33.1 mmol) in THF (150 mL)/MeOH (150 mL) under nitrogen was treated with sodium borohydride (25.0 g, 660 mmol) portionwise over 18 h at r.t. The suspension was then poured into a mixture of ice/concentrated EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 60, DCM/MeOH 9:1) affording colorless crystals, which were recrystallized in EtOAc to provide N-[6-(1-hydroxy-ethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (8.85 g, 24.1 mmol, 73%) as a white powder, m.p. 263-268° C., 1H-NMR (DMSO-d6, 400 MHz) 8.41 (s, 1H), 7.49 (s, 1H), 5.66 (m, 1H), 5.03 (br s, 1H), 3.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].I[C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1>>[C:3]1([C:1]#[C:2][C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:18][C@H:17]3[C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(I)cc1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(C#Cc2ccccc2)cc1

Procedure:
The title compound was prepared from ethynylbenzene (0.05 mL, 0.46 mmol) and trans-2-(4-iodophenyl)cyclopropanecarboxylic acid (100 mg, 0.35 mmol) according to the general procedure IC to give 47 mg (53%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:2→1:0): Rt=12.54 min (HPLC method I); 1H NMR (CDCl3) δ 7.53-7.51 (m, 2H), 7.47-7.44 (m, 2H), 7.36-7.31 (m, 3H), 7.09-7.07 (m, 2H), 2.63-2.58 (m, 1H), 1.95-1.90 (m, 1H), 1.72-1.67 (m, 1H), 1.44-1.39 (m, 1H); 13C NMR (CDCl3) δ 179.5, 140.0, 131.9, 131.7, 128.5, 128.4, 126.4, 123.4, 121.8, 89.7, 89.2, 27.1, 24.3, 17.8; ESI-MS calcd for C18H14O2 (M+Na+) 285.0887. found 285.0894.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12](#[N:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:13][C:12]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC#N
Reactant: COc1ccc(C=O)cc1Br
Product: COc1ccc(C(O)CC#N)cc1Br

Procedure:
Addition of 3-bromo-4-methoxybenzaldehyde to acetonitrile gave 3-(3-bromo-4-methoxyphenyl)-3-hydroxypropanenitrile as a pale orange oil. Yield (10.32 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.93 (d, J=4.4 Hz, 1H), 4.85-4.81 (m, 1H). 3.81 (s, 3H), 2.86 (ABd, J=16.4, 4.8 Hz, 1H), 2.79 (ABd, J=16.8, 6.8 Hz, 1H).
Reaction SMILES: NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(OC)=O)=CC=2)=CC=1.ClC1SC2C=CC=CC=2N=1.[S:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56](=[O:65])[CH2:57][C:58]([CH3:64])([CH3:63])[C:59]([O:61]C)=[O:60])=[CH:52][CH:51]=2)=[CH:46][CH:45]=1.[OH-].[Na+].Cl>C(O)CCC>[S:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56](=[O:65])[CH2:57][C:58]([CH3:63])([CH3:64])[C:59]([OH:61])=[O:60])=[CH:52][CH:51]=2)=[CH:48][CH:49]=1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1
Agent: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: Clc1nc2ccccc2s1
Solvent: CCCCO
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
In a 8-mL screw-cap vial, a mixture of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (60 mg, 0.19 mmol) and 2-chloro-1,3-benzothiazole (40 mg, 0.23 mmol) in 3 mL n-butanol were heated at 90° C. overnight. The formation of methyl 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate was monitored by LC-MS. The solvent was removed under reduced pressure. The residue was dissolved in 2 mL tetrahydrofuran/dioxane (1:1), and 3 equivalents of 1 N aqueous sodium hydroxide was added to the solution. The mixture was shaken at rt overnight and then at 50° C. for 2 h. The progress of the hydrolysis reaction was monitored by LC-MS. A solution of 1N aqueous HCl (3.1 equivalents) was then added to the mixture, and the solvent was removed under reduced pressure. The residue was redissolved in 2 mL methanol and a minimum amount of DMF, and the product was isolated and purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to give 40 mg of 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid (Yield: 45%). 1H NMR (400 MHz, DMSO-d6) δ 11.90 (bs, 1 H), 10.65 (s, 1 H), 8.00 (d, 2 H), 7.90 (d, 2 H), 7.80 (m, 5 H), 7.60 (d, 1 H), 7.35 (t, 1 H), 7.20 (t, 1 H), 3.30 (s, 2 H), 1.10 (s, 6 H); LC-MS m/z 431.2 (MH+), ret. time 3.40 min.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:51]([O:55][C:56]([N:58]([CH2:66][C:67]1[CH:68]=[C:69]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH:70]=[CH:71][CH:72]=1)[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O>[C:62]([O:61][C:59]([N:58]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]2[CH2:74][CH2:75][N:76]([C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:10]=3)=[O:17])[CH2:77][CH2:78]2)[CH:68]=1)[C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:57])=[O:60])([CH3:63])([CH3:64])[CH3:65]
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.25 g, 1.1 mmol) in anhydrous dimethylformamide (5 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.42 g, 1.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol). This mixture was stirred 15 minutes at ambient temperature and then treated with a solution of 4-{3-[N,N-Bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidine (0.39 g, 1.0 mmol) in dimethylformamide (5 ml). After stirring at ambient temperature for 18 hours the reaction mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (15 ml). The organic layer was dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of dichloromethane and methanol (49:1, v/v) to give N,N-bis-(tert-butoxycarbonyl)-3-[1-(5-phenylethynyl -pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine as a yellow oil (0.25 g). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.82 (s, 1H), 8.62 (s, 1H), 8.02 (s, 1H), 7.61 (m, 2H), 7.45 (m, 3H), 7.30 (m, 1H), 7.20 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 4.68 (s, 2H), 4.62 (br m, 1H), 3.60 (br m, 1H), 3.23 (br m, 1H), 2.85 (m, 2H), 1.83 (br m, 1H), 1.65 (m, 3H), 1.39 (s, 18H). MS(EI): 596(M++H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+:29]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O-:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+:29]
Reactant: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)[O-])c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
(1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (1 gm.) is treated with sodium bicarbonate (0.25 gm.) in water (10 ml.) and the mixture stirred and heated to effect solution. The solution is diluted with water to a volume of 50 ml. and sterilized by autoclaving at 120° C. for one hour.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.[CH3:35][N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[CH2:41][CH2:42][NH2:43]>O.CN(C=O)C.C(N(CC)CC)C>[CH3:35][N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[CH2:41][CH2:42][NH:43][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=1[CH3:20])=[O:23]
Reactant: CN1CCCC1CCN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCC1CCCN1C
Temperature: 0 °C
Yield: 50.2 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were sequentially added to DMF (500 mL) with stirring at about 0° C., and stirred for 1.5 hrs, then (1-methylpyrrolidin-2-yl)ethylamine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 139.1 g (502 mmol) of N-[(1-methylpyrrolidin-2-yl)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 50.2%, m.p. 143-149° C.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([C:18](=[O:20])[CH3:19])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(Cl)Cl>[C:18]([C:9]1[CH:10]=[C:11]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:12]2[O:13][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:8]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(N)c(O)c(C(C)(C)C)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCC(=O)N2
Temperature: 70 °C
Reaction time: 7 h
Yield: 28.4 %

Procedure:
Chloroacetyl chloride (0.14 ml, 1.76 mmol) was added at room temperature to a solution of the 1-[3-amino-5-(tert-butyl)-4-hydroxyphenyl]-1-ethanone (300 mg, 1.45 mmol) in a methylene chloride (3 ml)-saturated aqueous sodium hydrogencarbonate (3 ml) mixed solvent, and the resultant mixture was stirred for 30 minutes. After adding ethyl acetate to the reaction mixture for separation, the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (6 ml), potassium carbonate (401 mg, 2.90 mmol) was added and the mixture was stirred at 70° C. for 7 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and then ethyl acetate was added to the residue and the mixture was washed with water and brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,7 g), and the fraction containing the target compound was obtained from the ethyl acetate-toluene (1:9˜1:6) fractions and crystallized from diethyl ether-diisopropyl ether to yield the title compound (102 mg, 28.5% yield) as yellow ochre crystals.