Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[NH:15]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>CN1C(=O)CCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:15][C:11]3[N:12]=[CH:13][S:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncsc1C#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Fc1ccc(-c2cc3scnc3[nH]2)cc1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
238 mg (0.75 mmol) of tert-butyl N-{5-[2-(4-fluorophenyl)ethynyl]-1,3-thiazol-4-yl}carbamate are dissolved in 4.5 ml of NMP in a microwave vessel, and 143 mg (1.27 mmol) of KOtBu are added. The reaction vessel is sealed under nitrogen and heated at 90° C. for 20 min in the microwave while cooling in a stream of nitrogen. The mixture is diluted with 50 ml of diethyl ether and washed with 50 ml of sat. NaCl solution. The aqueous phase is again extracted with diethyl ether. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/1), giving 109 mg (0.49 mmol, 66%) of 5-(4-fluorophenyl)-4H-pyrrolo[2,3-d]-1,3-thiazole as white crystals; m.p. 244-245;
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:34][C@@H:31]([CH2:32][OH:33])[CH2:30][NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: NC[C@@H](O)CO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (R)-3-aminopropane-1,2-diol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=449.3 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1)#[N:2]>CO.N.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1
Reactant: COc1ccccc1N1CCN(CCCC#N)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccccc1N1CCN(CCCCN)CC1
Yield: 88.6 %

Procedure:
1-N(3-cyanopropyl)-4-N(2-methoxyphenyl)piperazine (5 g) was dissolved in a mixture of MeOH and aqueous ammonia (28%) in 1/1 ratio (20 mL) and the mixture is shook in a Parr apparatus in presence of Raney/Ni (500 mg) at 60 psi for 18 h. The catalyst is removed by filtration and the filtrate concentrated in vacuo. The residue is taken in AcOEt, the organic layer is washed three times with H2O, dried over Na2SO4 and concentrated. The oily residue is dissolved in EtOH and aqueous HCl (37%, 15 mL) is added. The obtained hydrochloride salt is crystallized in Et2O to give the title compound B2 (4.5 g, 81%) as crystals. 1H NMR (200 MHz, CDCl3) δ 1.48-1.64 (m, 4H), 2.16 (s, 2H), 2.36-2.43 (m, 2H), 2.57-2.62 (m, 4H), 2.69-2.76 (m, 2H), 3.18-3.23 (m, 4H), 3.79 (s, 3H), 6.40-6.56 (m, 3H), 7.20 (t, 1H). 13C NMR (50 MHz, CDCl3) δ 24.2, 31.6, 42.0, 49.0, 53.1, 55.1, 58.4, 102.4, 104.3, 108.8, 129.7, 152.6, 160.5.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]#[N:17])=[CH:3][CH:2]=1.Cl.C([OH:21])C>[OH-].[Na+]>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([NH2:17])=[O:21])=[CH:3][CH:2]=1
Reactant: N#Cc1cccc2c1CCCc1ccccc1-2
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-carbonitrile (1.0 gram, 0.0045 mole) in ethanol (20 ml) and 10% aqueous sodium hydroxide (20 ml) was heated at reflux for two days. The mixture was cooled and poured into dilute hydrochloric acid (150 ml). The resulting mixture was extracted with five 100 ml portions of methylene chloride and the extracts combined. The combined extracts were washed with two 100 ml portions of water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filtrate by distillation under reduced pressure to leave 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-carboxamide as a white solid (1.1 grams, mp>250°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14]C)[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[CH3:18][Sn](C)(C)C.[F-].[K+].Cl>C1(C)C=CC=CC=1.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH3:18])=[C:9]([OH:14])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd+]
Agent: Cl
Agent: [CH2-]c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C

Procedure:
8-Chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.50 g) was suspended in toluene (12 mL) and trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (50 mg) and tetramethyltin (0.30 mL) were added. The mixture was allowed to reflux for 17 hours, was cooled to room temperature, and 10% (w/w) aqueous potassium fluoride (3 mL) was added, followed by 3N hydrochloric acid (10 mL). The resulting mixture was warmed to 50 ° C. for 6 hours. The reaction mixture was filtered, and the crude product was washed (water, hexane). Crystallization, twice, from dimethylformamide and water gave the title compound as an off-white solid (110 mg); mp 277°-279 ° C.; NMR: 11.72 (s,1), 10.28 (s,1), 7.95 (d,1, J=8.7), 7.48 (t,1, J=2.0), 7.31 (dd,1, J=8.7, 2.0), 2.07 (s,1). Analysis for C11H8ClNO3 ·0.10 H2 0: Calculated: C, 55.18; H, 3.45; N, 5.85; Found: C, 55.23; H, 3.47; N, 5.83.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1Cl
Yield: 57.8 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (500 mg, 2.23 mmol), the [3-chloro-4-(methyloxy)phenyl]boronic acid (831 mg, 4.46 mmol), copper (II) acetate (608 mg, 3.345 mmol), powdered molecular sieves (400 mg) and pyridine (0.36 mL, 4.46 mmol) in DCM (75 mL) were stirred at room temperature in the presence of air. After 5 days the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (1.06 g) was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of EtOAc (0 to 20%) in hexane to afford 470 mg of title compound (D33) containing an impurity.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH:5]=O.O.[NH2:16]N>C(O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:3]=[N:2][NH:16][CH:5]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C=O)c1ccc(F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2cn[nH]c2)cc1

Procedure:
To a solution of 3-(dimethylamino)-2-(4-fluorophenyl)acrylaldehyde (3.0 g) in ethanol (30 mL) was added hydrazine monohydrate (0.90 mL), followed by heating and refluxing for 3 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure until the amount of the reaction liquid was reduced to about a half. Water (20 mL) was added thereto, and the resulting solid was collected by filtration and dried under reduced pressure to obtain 4-(4-fluorophenyl)-1H-pyrazole (2.44 g) as a yellow solid.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCn1nncc1/C=C1\CNCCC1SC(C)=O
Temperature: 0 °C
Yield: 61 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidine (4.27 g) in dichloromethane (100 ml) was added trifluoroacetic acid (1.2 ml) with stirring at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography using dichloromethane and methanol (10:1) as the eluent to afford the title compound (2.0 mg, yield: 61%) as a yellow amorphous solid.
Reaction SMILES: [OH-].[K+].[CH2:3](O)[CH3:4].C#C.[CH3:8][C@:9]12[CH2:26][CH:25]=[C:24]3[C@@H:14]([CH2:15][CH2:16][C:17]4[C@:22]3([CH3:23])[CH:21]=[CH:20][C:19](=[O:27])[CH:18]=4)[C@@H:13]1[CH2:12][CH2:11][C:10]2=[O:28]>O1CCCC1.O>[C:3]([C@:10]1([OH:28])[CH2:11][CH2:12][C@H:13]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:8])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH:20]=[CH:21]1)[CH2:16][CH2:15]3)#[CH:4]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCO
Agent: C#C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 3 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
In a three-necked flask, 95 percent potassium hydroxide (200 g), tetrahydrofuran (1000 ml) and ethanol (120 ml) were stirred at 50° C. for 1 hour under a nitrogen atmosphere and then cooled to 3° C. Into the mixture prepared as above, pure dry acetylene was passed at 3° C. for 2 hours. A solution of 1,4,9(11)-androstatriene-3,17-dione (100 g) in 200 ml of dry tetrahydrofuran was added and stirred for 2 hours. The mixture was acidified with 10 percent aqueous Hcl solution, stirred under reflux for half an hour, and diluted with water. The resulting precipitated product was collected by filtration, washed with water, and dried to give 17α-ethynyl-17β-hydroxyandrosta-1,4-dien-3-one (110.3 g, purity 92.9 percent, yield 96.6 percent).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][C@@H:4]([OH:8])[C:5]#[C:6][CH3:7].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](O)=[O:22])([O-:17])=[O:16].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:8][C@H:4]([CH2:3][C@H:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]#[C:6][CH3:7])=[O:22])([O-:17])=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC#C[C@H](O)C[C@H](C)CCCC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC#C[C@@H](C[C@H](C)CCCC(C)C)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
This compound was prepared similar to the method described in Example 44 from 4.22 g (21.6 mmol) of 6(R),10-dimethyl-undecan-2-yn-4(R)-ol, 4.58 g (21.6 mmol) of 3,5-dinitrobenzoic acid and 8.25 g (43.2 mmol) of p-toluenesulfonyl chloride in dry pyridine (total 55 ml) at 4° C. for 31/2 hr. It was worked up as described in Example 44 to give after recrystallization once from methanol 6.73 g (84.2%) of pure 6(R),10-dimethyl-undecan-2-yn-4(R)-ol 3,5-dinitrobenzoate, m.p. 90°-91°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C[Si]([C:14]([F:17])([F:16])[F:15])(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:14]([F:17])([F:16])[F:15]
Reactant: O=Cc1ccccc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.4 %

Procedure:
To a solution of 2-bromobenzaldehyde (27.0 g, 146.5 mmol) and trimethylsilyl-trifluoromethane (25.0 g, 175.8 mmol) in tetrahydrofuran (300 ml) was added drop-wise tetrabutylammonium fluoride (1 M in tetrahydrofuran, 5 ml, 5 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 2 hours. Further tetrabutylammonium fluoride hydrate (49.0 g, 175.8 mmol) was added and the mixture was stirred for 30 minutes. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (200 ml) and washed with hydrochloric acid (2N aqueous solution) (4×100 ml). The organic layer was separated, washed with Na2CO3 (10% aqueous solution) (50 ml), dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to afford the crude title compound as a yellow oil (45.0 g, ˜100%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:13]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccccc2C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 74.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 2-methylbenzoyl chloride (1.546 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 7 hours. The reaction mixture was treated in the same manner as described in Example 120 to obtain 1.679 g of the title compound (yield: 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([Cl:28])=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.OCC[N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[Cl:28][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12](/[CH:16]=[C:17]3/[C:18](=[O:27])[N:19]([CH2:23][CH2:24][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20](=[O:22])[S:21]/3)[CH:11]=2)[N:7]([CH2:6][C:5]2[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]=2[C:31]([F:34])([F:32])[F:33])[N:8]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O
Reactant: OCCN1CCCC1
Product: O=C1S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1CCN1CCCC1

Procedure:
(5Z)-5-({3-Chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({3-chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 287) and 1-(2-hydroxyethyl)pyrrolidine following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([OH:22])=O.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36]([NH2:38])=[O:37])[CH2:31]1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH2:31][CH:32]1[C:36]([NH2:38])=[O:37])=[O:22]
Reactant: COc1cc(OC2CCN(C(C)=O)CC2)ccc1CC(=O)O
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Methoxy-4-(1-acetyl-4-piperidyloxy)phenylacetic acid (35 mg, 0.11 mmol), 4-(2-methylphenyl)piperazine-2-carboxamide (25 mg, 0.11 mmol), EDC (28 mg, 0.15 mmol), and HBT (17 mg, 0.13 mmol) were combined in DMF (4 ml) under nitrogen. The mixture was rendered basic by addition of triethylamine (0.043 ml) and stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluted with 2% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo and the residue was rechromatographed on silica gel eluted with 96:4:0.4 methylene chloride:methanol:concentrated ammonia. The combined product fractions were evaporated to dryness in vacuo and the residue was concentrated from methanol and ether to give 1-(2-methoxy-4-(1-acetyl-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)-piperazine-2-carboxamide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>CN(C=O)C.O>[CH2:19]([O:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2cccc(I)c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1cccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step A (1.18 g, 4.37 mmol) in 20 mL of DMF was added cesium carbonate (2.48 g, 8.74 mmol) and benzyl bromide (0.52 mL, 4.37 mmol). After stirring overnight at room temperature, the reaction was poured into EtOAc and water, washed with 5% NaOH solution, water, 10% NaHSO3 solution and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% EtOAc/hexane) to yield the desired product as a pink solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:21])=O>C(OCC)(=O)C>[Cl:21][C:3]1[N:2]([CH3:1])[C:6]2[C:7]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(CCC)c1cccc2[nH]c(=O)n(C)c12
Solvent: CCOC(C)=O
Product: CCCC(CCC)c1cccc2nc(Cl)n(C)c12
Temperature: 100 °C
Yield: 86 %

Procedure:
The crude 1-methyl-7-(1-propylbutyl)-1,3-dihydrobenzimidazol-2-one (710 mg, 2.88 mmol) was dissolved in 10 mL of phosphorous oxychloride and heated at 100° C. overnight. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue thus obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give 655 mg (86%) of the title compound, which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][O:10][C:9]1([CH3:14])[CH3:13])(C)(C)C.[ClH:16]>CO>[ClH:16].[CH3:13][C:9]1([CH3:14])[CH:8]([NH2:7])[CH2:12][CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)NC1CCOC1(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)OCCC1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2,2-Dimethyl-tetrahydro-furan-3-yl)-carbamic acid tert-butyl ester (266 mg, 1.10 mmol) was dissolved in a solution of HCl in MeOH (pre-generated from MeOH (8 mL) and acetyl chloride (2 mL)) and stirred at room temperature overnight. The reaction mixture was concentrated to afford 193 mg of 2,2-dimethyl-tetrahydrofuran-3-ylamine hydrochloride as a hydroscopic white solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30].C([O-])(O)=O.[Na+]>C1COCC1>[C:14]([C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:2]([O:1][S:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=2)(=[O:31])=[O:30])=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=1)(=[O:15])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Reaction time: 3.5 h
Yield: 20.5 %

Procedure:
At ambient temperature, to a stirred solution of (2'-hydroxy-[1,1';3',1"]terphenyl-5'-yl)-phenyl-methanone (2.02 g, 5.77 mmol) in THF (55 mL) was added portionwise 4-chlorosulphonyl-2-hydroxybenzoic acid (2.70 g, 11.4 mmol, RN 98273-15-5) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After the addition was complete the reaction was stirred for 3.5 h. To the reaction was added 4-chlorosulphonyl-2-hydroxybenzoic acid (2.70 g, 11.4 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5 M aq. NaHCO3. After the addition was complete the reaction was stirred for 18 h. To the reaction was added 4-chlorosulphonyl-2-hydroxybenzoic acid (2.05 g, 8.66 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After 2h, the reaction was quenched with 2N HCl (25 mL), extracted with EtOAc and concentrated. Purification by preparative HPLC (C18, eluting with 75% CH3CN/H2O containing 0.1% TFA) and crystallization from EtOAc/hexane gave 0.65 g (20%) of the title compound as a yellow solid, mp 217° C.; 1H NMR (DMSO-d6) δ 6.60 (d, 1H), 6.74 (dd, 1H), 7.30-7.35 (m, 6H), 7.46-7.49 (m, 4H), 7.57-7.61 (m, 3H), 7.68-7.72 (m, 3H), 7.83-7.85 (m, 2H). mass spectrum (EI) ml/z 550 (M+). Anal. Calcd. for C32H22O7S 0.4H2O: C,68.91; H,4.12; N,0.00. Found: C,68.87; H,4.10; N,0.16.