Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([O:20]C)=[O:19])=[O:10])=[C:7]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[Li+].[OH-]>O1CCCC1>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([OH:20])=[O:19])=[O:10])=[C:7]([O:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnccc1NC(=O)c1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccncc2C(=O)O)CC1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a stirring solution of methyl 4-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoylamino]pyridine-3-carboxylate (0.192 g, 0.376 mmol) in tetrahydrofuran (4 mL) was added water (1 mL), followed by a 1 M solution of LiOH in water (0.4 mL, 0.4 mmol). After stirring overnight, the solution was partially concentrated in vacuo and then diluted with water and washed with diethyl ether. The pH of the aq phase was then adjusted to 4-5 by the addition of citric acid. The resulting precipitate was dried in vacuo to give the title compound (0.15 g, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][OH:25])[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.S(Cl)(Cl)=O.[Cl-].[CH3:34][O-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][O:25][CH3:34])[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: C[O-]
Reactant: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COCc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 282) (196 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of Example 288. Obtained as an off-white solid (72 mg, 35%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:7]([C:11]1[S:12][C:13]2[CH:19]=[C:18]([S:20][C:21]3[N:25]4[N:26]=[C:27]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH:28]=[CH:29][C:24]4=[N:23][N:22]=3)[CH:17]=[CH:16][C:14]=2[N:15]=1)C(=O)[O-])(C)C.[CH3:37][O:38]CCCl.C1(C)C=CC=CC=1>CN(C)C=O.CO>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]3[N:25]([C:21]([S:20][C:18]4[CH:17]=[CH:16][C:14]5[N:15]=[C:11]([NH:7][CH2:4][CH2:3][O:38][CH3:37])[S:12][C:13]=5[CH:19]=4)=[N:22][N:23]=3)[N:26]=2)=[CH:31][CH:32]=1
Reactant: COCCCl
Reactant: CC(C)(C)N(C(=O)[O-])c1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: COCCNc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
45 mg of sodium hydride at 60% in oil are added to a mixture of 263 mg of 1,1-dimethylethyl(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate and 0.10 cm3 of 2-chloroethyl methyl ether in 3 cm3 of N,N-dimethylformamide at 20° C. The suspension is heated in a bath at 90° C. overnight. The cooled reaction mixture is coevaporated to dryness several times with toluene. The residue obtained is taken up in methanol. After paste formation for 15 min, the brownish-yellow suspension is spin-filter-dried. The insoluble material is washed several times with methanol. This solid is treated with 0.4 cm3 of trifluoroacetic acid in 3 cm3 of dichloromethane at 20° C. for 2 h. The resulting reaction mixture is concentrated to dryness under vacuum, to give 116 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-N-(2-methoxyethyl)-1,3-benzothiazol-2-amine in the form of a yellowy-beige powder, the characteristics of which are as follows:
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:8]2[C:13]3[N:14]4[CH2:20][CH2:19][CH2:18][N:17]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])[C:15]4=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[OH:7])[CH2:5][CH2:4]1.[CH3:29]I>CN(C)C=O.O>[CH:3]1([CH:6]([O:7][CH3:29])[C:8]2[C:13]3[N:14]4[CH2:20][CH2:19][CH2:18][N:17]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])[C:15]4=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4]1
Reactant: CI
Reactant: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Sodium hydride (60% in oil, 45.3 mg, 1.13 mmol) was added to a stirred solution of cyclopropyl[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (400 mg, 1.03 mmol) in N,N-dimethylformamide (3.0 mL) at 0° C. After stirring 5 min, methyl iodide (219 mg, 1.55 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (265 mg, 0.659 mmol, 64%).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][C:7]2[N:11]([C:12]3[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=3[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[O:15])[CH:10]=[N:9][N:8]=2)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.[Cl:33]N1C(=O)C2=CC=CC=C2C1=O>>[Cl:33][C:10]1[N:11]([C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[O:15])[C:7]([CH2:6][N:5]2[C:4](=[O:27])[C:3]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]3[C:1]2=[O:32])=[N:8][N:9]=1
Reactant: O=C(c1ccccc1Cl)c1ccccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1Cl
Product: O=C(c1ccccc1Cl)c1ccccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 2, 2-(3-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone is reacted with N-chlorophthalimide to form 2-(3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.O.[NH2:17][NH2:18]>>[NH:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:18]
Reactant: NN
Reactant: COc1ccc(-c2ccc(Cl)nc2)cc1
Solvent: O
Product: COc1ccc(-c2ccc(NN)nc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A round-bottom flask was charged with 2-chloro-5-(4-methoxyphenyl)pyridine (260 mg, 1.19 mmol) and hydrazine hydrate (4 mL) at room temperature. The reaction mixture was heated at 100° C. for 48 h. It was cooled to room temperature, then was kept in a refrigerator for 3 h. The precipitate was filtered, washed with cold water, and dried to give the title compound as gray solids (200 mg, 78.0% yield). MS: m/z 216.1 [M+H+].
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4].[CH2:34]([CH2:36][NH2:37])[OH:35]>CO>[OH:35][CH2:34][CH2:36][NH:37][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4]
Reactant: NCCO
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Solvent: CO
Product: Cc1cc(Nc2cc(C(=O)NCCO)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 88 °C
Yield: 51.6 %

Procedure:
A mixture of 6-methoxycarbonyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}pyrimidine (Example 45) (49.5 mg, 0.11 mmol) and ethanolamine (2.0 ml, 33.7 mmol) in methanol (4 ml) was heated at 88° C. for 2 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2) the fractions containing product were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral impurities, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue triturated with diethylether and the resulting solid collected by filtration to give the title compound (27 mg, 57%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.C(Cl)(=O)[C:11]([Cl:13])=O.[N+](=C)=[N-].Cl>>[Cl:13][CH2:11][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(CCl)Cc1ccsc1
Yield: 100 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting thiophene-3-acetic acid (5.32 g, 37.4 mmol) with oxalyl chloride (3.6 mL, 5.2 g, 41 mmol, then ethereal diazomethane, then dry HCl gas. Work-up gave pure product, a brown oil which solidified upon refrigeration to a golden-brown, waxy solid (6.52 g, 100% yield): 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 2H) 4.13 (s, 2H) 6.99 (d, J=5.1 Hz, 1H) 7.16 (dd, J=1.5, 0.8 Hz, 1H) 7.33 (dd, J=4.9, 2.9 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:14]2[S:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].C(N(CC)CC)C>ClCCl.CN(C)C=O.O>[CH3:25][O:24][N:23]([CH3:22])[C:18]([C:16]1[S:15][C:14]2[C:9]([O:8][CH3:7])=[CH:10][CH:11]=[CH:12][C:13]=2[CH:17]=1)=[O:20]
Reactant: CNOC
Reactant: COc1cccc2cc(C(=O)O)sc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2cc(C(=O)N(C)OC)sc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65.4 %

Procedure:
Oxalyl chloride (1 ml) was added dropwise under nitrogen at 0° C. to a stirred suspension of 7-methoxybenzo[b]thiophene-2-carboxylic acid (1.9 g) in dichloromethane (25 ml), then dimethylformamide (2 drops) was added and the mixture was stirred at ambient temperature for 4.5 hours. N,O-Dimethylhydroxylamine hydrochloride (1 g), triethylamine (3.2 ml) and dichloromethane (5 ml) were added, the mixture was stirred at ambient temperature for 19 hours, then it was poured into water (60 ml). The product was extracted into dichloromethane (2×30 ml), the combined extracts were dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvent removed in vacuo to give N,7-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (1.5 g) as a gum which was used without further purification.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH2+:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(CC)CC.[C:39](Cl)(=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43]>ClCCCl>[C:2]([O:6][C:7](=[O:8])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][N:23]([C:39](=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC[NH2+]CCc2ccccc2)nc2ccccc21
Reactant: CCCCC(=O)Cl
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)CCc1ccccc1
Reaction time: 2 h

Procedure:
[3-(1-tert-Butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-propyl]-phenethyl-ammonium chloride (Precursor U-01b, 11.6 mg, 0.025 mmol) and Et3N (12.2 mg, 17.2 μl, 0.1 mmol) are dissolved in 1,2-dichloroethane (0.2 ml). To this solution is added valerylchloride (9 mg, 8.95 μl, 0.075 mmol) and the stirring is continued for 2 h. Then 1,2-dichloroethane (0.4 ml) and tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 22 mg, 0.075 mmol) are added. After 30 min of shaking the resin is filtered off. Then methylisocyanate polystyrene (2.5 mmol/g, 30 mg, 0.075 mmol) is added as well as 1,2-dichloroethane (0.5 ml) and the resulting suspension is stirred for 2 h. It is filtered and the organic filtrate is washed with an aqueous KH2PO4 solution (pH=4) and water. Finally the organic phase is dried over Na2SO4 and evaporated to dryness yielding the title compound: tR=2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+; 1H-NMR (DMSO-d6 at 100° C.): δ (ppm) 0.80 (t, 3H, CH2CH3), 1.19 (m, 2H, CH2CH3), 1.37 (m, 2H, CH2CH2CH3), 1.40 (s, 9H, tBu), 1.91 (m, 2H, CH2CH2N), 2.08 (m, 1H, COCHa), 2.24 (m, 1H, COCHb), 2.71-2.83 (m, 2H, CH2Ph), 3.30 (m, 2H), 3.32-3.43 (m, 4H), 4.98 (m, 2H, CH2CO2), 7.12-7.26 (m, 7 Harm), 7.50 (m, 2Harom).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([Li])CCC.CN([CH:26]=[O:27])C>C1COCC1>[Si:9]([O:8][CH2:7][C:6]1[CH:16]=[C:2]([CH:3]=[CH:4][C:5]=1[Cl:17])[CH:26]=[O:27])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of [(5-bromo-2-chlorobenzyl)oxy](tert-butyl)dimethylsilane from the previous step (1 eq.) in THF (0.08 M) was added, at −78° C., n-butyl lithium (2.5 M hexane solution, 1.1 eq) dropwise over 15 min. The reaction mixture was stirred at −78° C. for a further 30 min before DMF (2 eq.) was slowly added. The resulting solution was allowed to warm to RT over 3 h and then quenched with H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [N:1]([CH:4]([C:10]1[N:14]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:13]=[CH:12][CH:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[N+]=[N-]>[Pd]>[CH2:8]([CH:5]([CH2:6][CH3:7])[CH:4]([NH2:1])[C:10]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[N:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCC(CC)C(N=[N+]=[N-])c1ccnn1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Product: CCC(CC)C(N)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Reaction time: 15 h
Yield: 86.1 %

Procedure:
A mixture of 5-(1-azido-2-ethylbutyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (0.260 g) and 5% Pd/C (16 mg) was stirred under an atm pressure of H2 for 15 h. The mixture was filtered through a plug of Celite and the solvent was removed in vacuo to give 0.207 g of (2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butyl)amine with an impurity present. This compound was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccc(Cl)cc1
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 40.3 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.029 g (40%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=O.[C:9](=[S:11])=[S:10]>>[SH:11][C:9]1[S:10][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:1]=1
Reactant: O=Nc1ccccc1
Reactant: S=C=S
Product: Sc1nc2ccccc2s1

Procedure:
It must be considered surprising, that nitrosobenzene can be transformed substantially quantitatively to 2-mercaptobenzothiazole with hydrogen sulfide and carbon disulfide. The reaction may be represented by a summation formula, as follows: ##STR1## However, the reaction is in fact much more complicated and is composed of a great number of individual reactions partly taking place concurrently and partly taking place sequentially. At any rate, it can be stated with certainty that an initial quantitative reduction of the nitrosobenzene by hydrogen sulfide to aniline, which then reacts with carbon disulfide to 2-mercaptobenzothiazole in the known manner, is not possible. The main reaction product of nitrosobenzene and hydrogen sulfide is indeed aniline, which is formed with a yield of about 75%, but at least ten more reaction products with aromatic nitrogen groupings are also formed thereby. When this mixture of products is subsequently reacted with carbon disulfide, one nevertheless obtains an almost quantitative--based on the charged nitrosobenzene--yield of 2-mercaptobenzothiazole, thus a much higher yield than would correspond to the aniline content of the reaction mixture. It follows therefore, that, surprisingly, the other reaction products are also transformed into 2-mercaptobenzothiazole. Therefore, when the nitrosobenzene is being reacted with hydrogen sulfide and carbon disulfide at the same time, in keeping with the invention, the reaction will produce the desired 2-mercaptobenzothiazole with high selectivity and yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:23][C:22](=[O:24])[C:21]3[C:16](=[C:17]([CH3:28])[CH:18]=[C:19]4[CH:27]=[N:26][NH:25][C:20]4=3)[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C(#N)C.O>[CH:29]([NH:32][C:22]([C:21]1[C:16]([NH:15][C:14]([C:4]2[N:5]([C:7]3[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]([Br:1])[CH:3]=2)=[O:23])=[C:17]([CH3:28])[CH:18]=[C:19]2[C:20]=1[NH:25][N:26]=[CH:27]2)=[O:24])([CH3:31])[CH3:30]
Reactant: CC(C)N
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a suspension of 600 mg of the above 7-[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v) is added 1.11 mL (13.1 mmol) of isopropylamine. The reaction mixture is stirred for 9 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 1:2) affords 110 mg (16% over two steps) of the product as a white solid; LC/MS:518/520 (M+H)+, m.p.: 163-166° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:18])[CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:18][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CN=[N+]=[N-])C1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CN=[N+]=[N-])Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
(S)-3-((S)-2-Azido-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.3 g, 5.0 mmol, 1.0 eq.) was combined with DMF (18 mL). Washed and dried NaH (362 mg, 15.1 mmol, 3.0 eq.) was carefully added in 3 separate portions. The resulting mixture was stirred at room temperature for 15 minutes under nitrogen. 4-Fluorobenzotrifluoride (1.9 mL, 15.1 mmol, 3.0 eq.) was added and the mixture was stirred at 100° C. for 3 hours. The mixture was then concentrated under reduced pressure. The resulting material was dissolved in EtOAc (15 mL) and washed with water (1×15 mL). The organic layer was concentrated and purified by flash chromatography (0-100% EtOAc/hexanes) to yield (S)-3-[(S)-2-azido-1-(4-trifluoromethylphenoxy)ethyl]-pyrrolidine-1-carboxylic acid t-butyl ester (1.4 g).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].I[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[O:18][C:17]2=[O:24].C#C.[C:27]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[O:44][C:43]2=[O:50])#[C:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[O:33][C:32]2=[O:39]>>[C:27]([C:21]1[CH:22]=[CH:14][CH:15]=[C:16]2[C:20]=1[C:19](=[O:23])[O:18][C:17]2=[O:24])#[C:28][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[C:28]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[O:33][C:32]2=[O:39])#[C:27][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[O:44][C:43]2=[O:50]
Reactant: O=C1OC(=O)c2c(I)cccc21
Reactant: O=C1OC(=O)c2cc(I)ccc21
Agent: C#C
Agent: O=C1OC(=O)c2cc(C#Cc3ccc4c(c3)C(=O)OC4=O)ccc21
Product: O=C1OC(=O)c2c(C#Cc3cccc4c3C(=O)OC4=O)cccc21

Procedure:
The present inventors have found that (ethyne-1,2-diyl)bis(isobenzofuran-1,3-diones), such as 5,5′-(ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione), may be obtained in a high yield in a one-step procedure by employing a Sonogashira coupling to react a chloro-, bromo-, or iodoisobenzofuran-1,3-dione, such as 5-chloro-, 5-bromo-, or 5-iodoisobenzofuran-1,3-dione, with acetylene, i.e. ethyne. By employing a one step procedure and by avoiding aqueous work-up, causing hydrolysis of the anhydride moieties, a (ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione), such as 5,5′-(ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione), may be obtained in significantly higher yield and shorter process time compared to known processes.