Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([O:28]C)[CH:27]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([NH:14][C:15]2[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23]O)[CH:18]=[CH:19][CH:20]=2)[N:8]=1.C(Cl)Cl.B(Br)(Br)[Br:34].C([O-])(O)=O.[Na+]>C(=O)=O>[Br:1][C:2]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:4]([CH2:5][NH:6][C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][Br:34])[CH:16]=3)[N:8]=2)[CH:3]=1
Reactant: COc1cc(Br)cc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(Br)cc(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Into a reaction flask was added 3-[3-({4-[(3-bromo-5-methoxybenzyl)amino]-5-chloropyrimidin-2-yl}amino)phenyl]propan-1-ol (2.70 g, 5.65 mmol), methylene chloride (30 mL), and a solution of boron tribromide in methylene chloride (17.0 mL, 17.0 mmol, 1.0 M). The mixture was stirred at rt overnight. The resultant mixture was cooled in dry ice when NaHCO3 (saturated aqueous solution) was added. After removal of the organic solvent, the aqueous layer was extracted with methylene chloride twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product (2.97 g, 100%). LCMS for C20H19Br2ClN4O (M+H)+: m/z=526.9, 528.8.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][C:8]1[C:16]2[NH:15][C:14]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][CH3:28])=[O:26])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:28][O:27][C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:14]1[NH:15][C:16]2[C:8]([CH2:7][C:6]([OH:29])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=2[N:13]=1)=[O:26]
Reactant: COC(=O)c1ccccc1CSc1nc2cccc(CC(=O)OC(C)(C)C)c2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1CSc1nc2cccc(CC(=O)O)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To 2-(2-((2-(methoxycarbonyl)phenyl)methylthio)benzimidazolyl)acetic acid t-butyl ester (1290 mg, 3.13 mmol), trifluoroacetic acid (15 ml) was added, and stirred at room temperature overnight. After the solvent was evaporated, it was dried under reduced pressure to obtain 2-(2-((2-(methoxycarbonyl)phenyl)methylthio)benzimidazolyl)acetic acid (715 mg, yield 64%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)=[O:9].Cl.[NH2:20][CH2:21][C:22]#[N:23]>O1CCCC1.CN(C)C=O>[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([CH:22]([NH2:23])[C:21]#[N:20])=[O:15])=[CH:12][CH:11]=1)=[O:9]
Reactant: N#CCN
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC(N)C(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
First,12.2 g (0.12 mol) of triethylamine and then, dropwise with stirring, a solution of 10.1 g (0.06 mol) of 4-formylbenzoyl chloride in 10 ml of tetrahydrofuran are added at 0° C. to 5.6 g (0.06 mol) of 2-aminoacetonitrile hydrochloride in 50 ml of dimethylformamide at a rate such that the internal temperature does not exceed 10° C. When the addition is complete, the batch is stirred for a further 15 minutes at room temperature, poured into 400 ml of ice water and filtered, and the product thus obtained is dried. Extraction of the filtrate with 5 times 100 ml of ethyl acetate, washing the combined organic phases, drying over sodium sulphate and concentrating in vacuo yields a further fraction. In total, 8.9 g (79% of theory) of 2-(4-formylbenzoyl)-aminoacetonitrile of melting point 122°-125° C. are obtained.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C[CH2:25][N:26](C(C)C)C(C)C.N#CBr>CN(C=O)C.O>[C:25]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)#[N:26]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C#N)C4)cc2)C(=O)O1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (0.2 g, 0.57 mmol) in DMF (5 mL) were added DIPEA (0.3 mL, 1.7 mmol) and cyanogen bromide (0.18 g, 1.1 mmol) at r.t. The reaction mixture was stirred at 100° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound (0.05 g, 26%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:19][CH2:20][CH2:21]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:19][CH2:20][CH2:21][O:18][N:17]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: ON=C(Cc1ccc(F)cc1)c1ccc(F)cc1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(CC(=NOCCBr)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of the above oxime (5.0 g, 20 mmol), 1,2-dibromoethane (18 ml) and N,N,N,N-tetrabutylammonium bromide (0.61 g, 3 mmol) was carefully added 12N sodium hydroxide (19 ml) while the temperature was kept below 35° C. After stirring at ambient temperature for 17 h, water (50 ml) was added and the resulting mixture was extracted with dichloromethane (2×100 ml). Water (100 ml) was added to the combined organic phases and pH in the aqueous phase was adjusted to 5 with 10% citric acid. The organic phase was washed with water (50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue purified by column chromatography on silica gel (100 g, gradient n-heptane to n-heptane/ethyl acetate 20/1) to give 4.7 g of 1,2-bis(4-fluorophenyl)ethanone O-(2-bromoethyl)oxime.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2].[SH:21][CH2:22][C:23]([OH:25])=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[C:5]([CH:13]([S:21][CH2:22][C:23]([OH:25])=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)CS
Reactant: CC(C)c1cc2c(cc1C(O)c1ccccc1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)c1cc2c(cc1C(SCC(=O)O)c1ccccc1)OCO2
Yield: 92.9 %

Procedure:
1.2 g of α-(6-isopropyl-1,3-benzodioxol-5-yl)benzyl alcohol was dissolved in 10 ml of benzene, followed by the addition of 490 mg of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate. The obtained mixture was heated under reflux for one hour and cooled, followed by the addition of benzene. The mixture was washed with water, followed by the addition of a 1N aqueous solution of sodium hydroxide. The alkaline layer was separated, acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/chloroform=3:7) to obtain 1.42 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C1(C)C(C)=CC=CC=1.[C:17]([CH2:25][C:26](S)=[S:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1>O>[C:18]1([C:17]2[CH2:25][C:26](=[S:27])[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CC(=S)S)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1C
Product: S=C1CC(c2ccccc2)=Nc2ccccc2N1

Procedure:
A mixture of 1.08 g of o-phenylendiamine, 10 ml of xylene and 1.96 g of benzoyldithioacetic acid (Thuillier et al - Bull. Soc. Chim. Fr. 1938 (1959) is refluxed for 1 hour under a stream of nitrogen. The reaction may also be carried out in water, alcohol or dioxane. After cooling, the precipitate is filtered, washed with ethyl ether, and crystallized from ethyl acetate. Yield 2 g, m.p. 228°-230°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([Br:16])=[N:11][NH:10][C:9]2=[O:17])=[O:5])[CH3:2].[H-].[Na+].Br[CH:21]([CH3:24])[CH2:22]O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([Br:16])=[N:11][N:10]([CH:21]([CH3:24])[CH3:22])[C:9]2=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(Br)n[nH]c(=O)c2c1
Reactant: CC(Br)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Bromo-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid ethyl ester (6 g, 0.02 mol) was dissolved in DMF (60 ml). To this was added NaH (60%, 0.97 g, 0.024 mol) as a DMF suspension (5 ml). The mixture was stirred at RT for 30 min then 2-bromo-propanol (3.7 g, 0.03 mol) was added in one portion as a solution in DMF (5 ml). The reaction mixture was stirred for 48 hours whereupon LC-MS showed complete consumption of starting material. The DMF was removed under vacuum and the resulting residue was partitioned between DCM (100 ml) and water (100 ml), the organic layer was dried (MgSO4), filtered and concentrated under vacuum. The resulting yellow oil was recrystallised from MeOH to give the title compound (2.3 g, 34% yield) as a white solid. MS (ESI+)=(M+H)+ 339 & 341
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12](OC)[C:13]([O:15]C)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:21][NH2:22].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:15])[NH:21][N:22]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COC(=O)C(CC(=O)c1cc(Cl)c(C)c(Cl)c1)OC
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 70.6 %

Procedure:
A mixture of 3.05 g (0.01 mole) of methyl 4-(3,5-dichloro-4-methylphenyl)-2-methoxy-4-oxobutyrate, 0.6 g (0.012 mole) of hydrazine monohydrate and 30 ml of methanol was heated under reflux for 3.5 hours. 1.1 ml of concentrated hydrochloric acid was then added to the mixture, after which it was again heated under reflux for a further 6 hours. At the end of this time, the solvent was distilled off and the residue was washed, in turn, with water and with a small amount of diethyl ether, after which it was dried to give 1.80 g of the desired product. The washings were extracted with ethyl acetate and the extract was dried over anhydrous sodium sulphate, after which the organic solvent was distilled off. The residue was washed in turn with benzene and with diethyl ether, to give a further 0.11 g of the desired product. The total yield of 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone was 1.91 g (74.9%) and the properties of the product were identical with those of the products of Examples 1(d), 2 and 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4C(C)=CC=C4C)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.NO.Cl.C(N(CC)CC)C>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=3[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C

Procedure:
To the mixture of 1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indole (70 mg) in ethanol/H2O (3 mL/1 mL) was added NH2OH—HCl (178 mg) and triethylamine (87 mg) and the reaction mixture was refluxed for 18 h in an oil bath, cooled to room temperature, concentrated, and extracted with ethyl acetate (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (20-40% ethyl acetate in hexane) to afford the title compound as a brown solid. LC/MS m/z=329.1 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)(O)[O-:12].[Na+].[N+]1([O-])C=CC=CC=1>C1(C)C=CC=CC=1>[O:12]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C([O-])O
Reactant: CCOC(=O)CCCCBr
Agent: [Na+]
Agent: [O-][n+]1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCC=O
Reaction time: 9 h
Yield: 48.7 %

Procedure:
Ethyl 5-bromopentanoate (42 g), sodium bicarbonate (34 g) and pyridine N-oxide (38 g) in toluene (250 ml) are heated together under reflux in an atmosphere of nitrogen with vigorous stirring for 9 hours. After cooling, the product is partitioned with water (400 ml). The toluene layer is separated and the aqueous layer is extracted with a further amount of toluene (100 ml). The combined toluene extracts are dried over magnesium sulphate and the toluene removed by fractional distillation. The residue is distilled under vacuum to give ethyl 5-oxopentanoate as a colourless oil (14.1 g), m.s. M+ 144.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:17]=[CH:16][S:15][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1C(=O)N([Br:29])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:17]=[C:16]([Br:29])[S:15][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2c3sccc3CC2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC2c3sc(Br)cc3CC2C1

Procedure:
A solution of the product from step h) (722 mg, 2.88 mmol) in AcOH (7.2 ml) and CHCl3 (7.2 ml) was treated with NBS (529 mg, 2.97 mmol) at 22° C. for 30 minutes. Next, the reaction was carefully quenched with sat. NaHCO3 (10 ml), extracted with EtOAc (2×75 ml) and the combined organic extracts were dried (MgSO4) and solvent evaporated in vacuo leaving the crude product that was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (10% to 50% ethyl acetate) to give the subtitle compound. MS calculated for C15H20BrNO2S+H 358, observed M-tBu 302, 304.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21](=[O:22])[C:20]([C:23](O)=[O:24])=[C:19]([CH2:26][CH3:27])[N:18]=[C:17]2[CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:26]([C:19]1[N:18]=[C:17]([CH2:28][CH2:29][CH3:30])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)[C:21](=[O:22])[C:20]=1[C:23]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:24])[CH3:27]
Reactant: CCCc1nc(CC)c(C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(CC)c(C(=O)N2CCOCC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To a solution of 1-[(2′-cyanobiphenyl-4-yl)methyl]-4-ethyl-6-oxo-2-propyl-1,6-dihydropyrimidine-5-carboxylic acid (0.21 g), morpholine (0.07 g) and triethylamine (0.22 mL) in N,N-dimethylformamide were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 g) and 1-hydroxybenzotriazole monohydrate (0.12 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.22 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2C(OC(C)(C)C)=O.[Cl:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.O>O1CCOCC1.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:18][C:19]1[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1n[nH]c2ccc(Br)cc12
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ncccc1-c1ccc2[nH]ncc2c1
Temperature: 100 °C
Yield: 48.7 %

Procedure:
A single necked round bottom flask (250 mL) equipped with a magnetic stir bar was charged with tert-butyl 5-bromo-1H-indazole-carboxylate (4.0 g, 13.4 mmol) dissolved in 1,4-dioxane (130 mL), 2-chloro-3-pyridine boronic acid pinacol ester (4 g, 16.7 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol) and 2M aq.Na2CO3 (20 mL, 40 mmol) under nitrogen atmosphere. The rubber septum was replaced with reflux condenser containing three-way stopcock equipped with argon filled balloon. The reaction contents were stirred and air was removed from the closed reaction system by vacuum and back filled with argon. Following three cycles of degassing, the reaction mixture was heated at 100° C. (oil-bath) under argon. Inflated argon balloon was emptied, refilled with argon and remounted in the course of reaction. The initial pale yellow heterogeneous reaction mixture turned to clear biphasic off-brown solution. After 18 h with no additional change in the proportion of the product (62%) as analyzed by LC/MS, the reaction mixture was cooled to room temperature. Upon concentration of the reaction mixture, EtOAc/water (200 mL/75 mL) was transferred to the concentrate and stirred for 30 min. The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL×2). MgSO4 (20g) and Celite® (20g) were added to combined organic layers and the contents suction filtered after stirring for 1 h. The filter cake was washed with EtOAc (300 mL) and the combined filtrates concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in 1% MeOH/CH2Cl2 and absorbed on silica gel (20g) by evaporating the solvent followed by drying. Subsequent purification by flash silica gel column purification of the dry powder (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent) provided 5-(2-chloropyridin-3-yl)-1H-indazole (1.5 g, 47%) as a white crystalline solid after concentration of the desired product fractions. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 8.13 (s, 1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5 Hz). LCMS: 95%, MS (m/e) 230 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cccc(Br)c1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1cccc(N(c2ccccc2)c2ccccc2)c1
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
Diphenylamine (9 g, 53.3 mmol), and 1,3-dibromobenzene (25 g, 106.8 mmol) were mixed in toluene (500 mL). The solution was bubbled nitrogen while stirring for 15 min. Pd(OAc)2 (0.18 g, 0.8 mmol), triphenylphosphine (0.84 g, 3.2 mmol) and tBuONa (7.7 g, 80.2 mmol) were added in sequence. The mixture was heated to reflux overnight under nitrogen. After cooling, the reaction mixture was filtered through Celite®/silica pad and the solvent was then evaporated. The residue was purified by column using hexane as eluent to obtain 13.5 g (60%) of 3-bromo-N,N-diphenylaniline.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB(/[CH:26]=[CH:27]/[CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1/[CH:26]=[CH:27]/[CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(C/C=C/B2OC(C)(C)C(C)(C)O2)C1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1/C=C/CN1CCCC(NC(=O)OC(C)(C)C)C1
Yield: 46 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (530 mg, 1.7 mmol) was reacted with (E)-tert-Butyl 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidin-3-ylcarbamate (320 mg, 0.88 mmol) to afford the desired product (190 mg, 47%) as a light brown solid: ESI MS m/z 456 [C24H29N3O4S+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH:4]=[CH:3]1.[CH2:9]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C.CCOCC>[OH:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[CH:3]=[CH:4]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@H]1C=C[C@@H](O)CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1C=CC(O)CC1)OCc1ccccc1
Yield: 55.5 %

Procedure:
A solution of 4.64 g of cis-4-amino-2-cyclohexen-1-ol, 10.2 g of N-(benzyloxycarbonyloxy)succinimide and 5.7 ml of triethylamine in DMF is diluted with ether after stirring, washed with saturated sodium chloride solution, dried and concentrated. Chromatography of the residue on silica gel (ethyl acetate/hexane 2:1) gives 5.62 g of benzyl (1RS,4SR)-4-hydroxy-2-cyclohexene-1-carbamate. MS: 156 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([NH:13][CH2:14][C:15]1[S:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:19]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=O>>[CH2:23]([O:22][C:20]([C:17]1[S:16][C:15]2=[CH:14][N:13]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:19]2[CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C(=O)NCc1ncc(C(=O)OCC)s1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cn2c(C(=O)OCC)ncc2s1
Yield: 71.6 %

Procedure:
A 20 ml potion of phosphorus oxychloride was added to 3.53 g of 2-(ethoxalylamino)methyl-5-ethoxycarbonylthiazole under ice-cooling, and the solution was then heated under reflux for 15 hours. After cooled, the reaction solution was concentrated to dryness under reduced pressure, and 20 ml of water and 20 ml of dichloromethane were then added so as to dissolve it. Under ice-cooling, potassium carbonate was added until the solution was alkalified. The solution was extracted with dichloromethane (10 ml×4). The combined organic layer was dried over anhydrous magnesium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by a silica gel column chromatograph to obtain 2.37 g of 2,5-diethoxycarbonylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9](O)[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.[ClH:13]>>[Cl:13][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][CH3:11]
Reactant: Cl
Reactant: CCC(O)c1cccc(OC)c1
Product: CCC(Cl)c1cccc(OC)c1

Procedure:
The preparation was effected in analogy to example 1(b) from 1-(3'-methoxyphenyl)-propan-1-ol and HCl gas.