Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][NH:10][CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21].C(N(C(C)C)CC)(C)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>CN(C=O)C.C1COCC1>[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][N:10]([C:34](=[O:35])[CH2:33][Cl:32])[CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CNC3
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CN(C(=O)CCl)C3
Temperature: 25 °C

Procedure:
To 50 mg (0.158 mmol) of 3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide hydrochloride in 3.0 ml of DMF was added dropwise 0.32 ml of 1.0 M solution containing diisopropylethylamine (DIPEA) in THF and (0.16 mmol) of 2-chloroacetyl chloride in 1.0 ml of DMF, according to standard procedures. The resulting mixture was continuously stirred at room temperature for several hours, and the progress of the reaction was monitored by TLC. The solvent was removed under vacuum, and the residue was recrystallized from a polar solvent. Similar procedures were used for 3-amino-6-[2-(4-benzyl-cyclohexylamino)-acetyl]-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (103) and 3-amino-6-(6-morpholin-4-yl-pyridine-3-carbonyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (105). In some cases, if the product was not recrystallized from methanol or ethanol, the reaction mixture was purified by flash column chromatography or preparative HPLC. All products were verified by NMR spectroscopy.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Yield: 81 %

Procedure:
As described for example 84f, 6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (67 mg, 0.21 mmol) was converted, instead of [643-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (59 mg, 81%) which was obtained as an off white solid. MS: m/e=338.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C=O.[BH3-][C:21]#N.[Na+].CC(O)=O>CO>[CH3:7][C:4]1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[N:13]([CH3:21])[CH2:14][CH2:15][N:10]3[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCNC2C
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C)n1-c1cc2n(n1)CCN(C)C2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287g (1.54 g, 1.0 eq., 6.70 mmol), formaldehyde (37% in water) (1.09 g, 2.0 eq., 13.4 mmol), NaBH3CN (2.11 g, 5.0 eq., 33.5 mmol), HOAc (3 mL), and methanol (30 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and dichloromethane (50 mL). The water phase was extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated under reduced pressure to afford crude 287h, which was used in the next step without further purification. MS-ESI: [M+H]+ 245.0
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1>ClCCl.O>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (52 mg, 0.17 mmol) in dichloromethane (10 mL) was treated with O—(1H-benzotriazolo-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (72 mg, 0.19 mmol), diisopropyl-ethylamine (0.09 mL, 0.52 mmol) and 2-aminothiazole (26 mg, 0.25 mmol). The resulting brownish-orange solution was then stirred 16 h at 25° C. The reaction was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine (1×10 mL), then were dried over sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to furnish rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (45 mg, 70% yield) as a white foam: EI-HRMS m/e calcd for C16H16Cl2O2N2S (M+) 370.0309, found 370.0309.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C2C=NNC(=O)C2c2ccc(F)cc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
The dihydropyridazinone product from Example 18 (47 mg, 0.136 mmol) was dissolved in acetic acid (25 mL). Bromine (0.025 mL, 0.16 mmol) was added to the solution and the reaction mixture was stirred at 95° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to provide a solid which was eluted through a short pad of silica gel with ethyl acetate. The title compound was crystallized from ethyl acetate/hexanes (yield: 35 mg, 75%). mp 255–256° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.16–7.23 (m, 2H), 7.35 (d, J=9 Hz, 2H), 7.86 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 345 (M+H)+ and m/z 362 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CI.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:12])[N:4]([CH3:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1nc2ccccc2cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)c(Br)cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
To a solution of 3-bromo-2-hydroxyquinoline (50 mg, 0.223 mmol) in DMF (1 mL) was added methyl iodide (0.017 mL, 0.268 mmol) and potassium carbonate (46.3 mg, 0.335 mmol.) at room temperature. The reaction mixture was stirred for 16 hours at room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with water then aqueous saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=/1) to give 3-bromo-1-methylquinolin-2(1H)-one (52 mg, MS: 238.1 [M+H+].)
Reaction SMILES: [C:1]([C:4]1[N:5]=[N:6][N:7]([C:9]2[CH:10]=[C:11]([CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30])[CH:26]=2)[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:8]=1)(=[O:3])[CH3:2].C([Li])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH2:43]1COCC1>CCOCC>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:28][CH2:29][CH3:30])[CH:26]=[C:9]([N:7]3[CH:8]=[C:4]([C:1]([OH:3])([CH3:43])[CH2:2][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:5]=[N:6]3)[CH:10]=2)[CH3:16])=[CH:22][CH:21]=1
Reactant: [Li]Cc1ccccc1
Reactant: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)=O)nn2)c1)S(C)(=O)=O
Reactant: C1CCOC1
Solvent: CCOCC
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)(O)Cc3ccccc3)nn2)c1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of 0.013 g (0.027 mmol) 3-(4-acetyl-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 1 mL THF at 0° C. was added 0.3 mL (approx. 0.06 mmol) benzyllithium in ether. After 30 min, another 0.3 mL benzyllithium was added and after a further 30 min the reaction mixture was quenched with 10 mL saturated NH4Cl, extracted w. 20 mL EtOAc, washed with 10 mL brine, dried over MgSO4, filtered, and concentrated. Purification by preparative HPLC (5->95% CH3CN/H2O over 30 min, 0.1% added TFA, C18 PRO YMC 20×150 nm) afforded 2 mg N-[(1R)-1-(4-fluorophenyl)ethyl]-3-[4-(1-hydroxy-1-methyl-2-phenylethyl)-1H-1,2,3-triazol-1-yl]-5-[(methylsulfonyl)(propyl)amino]benzamide as a white solid. NMR 1H NMR (CDCl3) δ 8.06 (s, 1H), 7.82 (m, 3H), 7.39 (m, 2H) 7.30 (m, 1H), 7.24 (m, 2H), 7.06 (m, 4H), 6.59 (br d, J=7.14 Hz, 1H), 5.30 (m, 1H), 3.71 (t, J=7.14 Hz, 2H), 3.34 (br d, J=13 Hz, 1H), 3.15 (m, 1H), 2.93 (s, 3H), 1.65 (m, 6H), 1.52 (m, 2H), 0.92 (t, J=7.33 Hz, 3H). High resolution mass spec (FT/ICR) calc M+H=580.2389 found 580.2400.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[C:36](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:37][C:38]([CH3:42])([CH3:41])[C:39]=1[CH3:40])#[N:34].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=[CH:40][C:39]2[C:38]([CH3:41])([CH3:42])[O:37][C:36](=[C:43]([C:44]#[N:45])[C:46]#[N:47])[C:35]=2[C:33]#[N:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
In 10 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 300 mg (0.67 mmol) of 5-[2-(2-benzyloxy-4-dibutylaminophenyl)vinyl]thiophene-2-carboaldehyde and 147 mg (0.74 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 52 mg of ammonium acetate, and the mixture was stirred at room temperature for 18 hours and further stirred with heating at 50° C. for 7 hours. The solvent was evaporated off and the residue was washed with ethanol to give 246 mg of a dark brown crystal (yield: 58.4%; mp: 218-219° C.)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]2)=[C:20](Br)[CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]2)=[CH:22][CH:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2-c2ccccc2)S(=O)(=O)N1
Temperature: 100 °C
Yield: 35.8 %

Procedure:
To a solution of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoate (52.0 mg, 0.0990 mmol) in toluene (1.0 mL) and 1,4-dioxane (1.0 mL) was added phenylboronic acid (14.5 mg, 0.119 mmol), 2 M sodium carbonate in water (0.30 mL) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) under an atmosphere of nitrogen. The resulting mixture was heated at 100° C. overnight. The reaction solution was filtered, and purified by preparative LCMS to afford product as a white solid (18 mg, 38%). 1H NMR (400 MHz, CD3OD): δ 7.28 (m, 13H), 5.03 (m, 1H), 4.47 (m, 1H), 3.26 (m, 3H), 3.00 (m, 1H). LCMS found for C26H25N2O7S (M+H)+: m/z=509.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:26][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccc(Cl)cc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccc(Cl)cc3)c2c1

Procedure:
A mixed solution of 6 g of the above-mentioned 2-tert-butyl-9-(4-chlorophenyl)anthracene, 3.5 g of N-bromosuccinimide and 55 g of dimethylformamide was stirred under nitrogen gas stream at room temperature for 3 hours. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-(4-chlorophenyl)anthracene.
Reaction SMILES: C([N:4]1[CH2:25][CH2:24][C:7]2[N:8]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:7]3[CH2:24][CH2:25][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(C)ccc3n2C=Cc2ccncc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2C=Cc2ccncc2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
2-Allyl-8-methyl-5-(2-(pyridin-4-yl)vinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (50 mg, 0.151 mmol) was dissolved in DCM (2 mL), which was degassed with nitrogen for 15 min. To this was added Pd(PPh3)4 (4 mg, 0.002 mmol) followed by 1,3-dimethyl barbituric acid (71 mg, 0.454 mmol). The reaction mixture was again degassed by nitrogen for 15 min. The resultant mixture was stirred at RT for 1 h. DCM was evaporated in vacuo. EtOAc (20 mL) was added to reaction mixture and was washed with saturated potassium carbonate solution (3×1 mL). The organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo and purified by reverse phase HPLC to obtain 2 mg of 8-methyl-5-(2-(pyridin-4-yl)vinyl)-2,3,4,5-tetrahydro-1H-pyrido[4, 3-b]indole. 1H NMR (CD3OD, Free base): δ (ppm): 8.45 (d, 2H), 8.0 (d, 1H), 7.7 (d, 1H), 7.58 (d, 2H), 7.3 (s, 1H), 7.19 (d, 1H), 6.8 (d, 1H), 4.29 (s, 2H), 3.42 (m, 2H), 3.2 (m, 2H), 2.4 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C=O>[N:3]1([CH:13]([CH2:12][CH2:11][CH2:10][CH3:9])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCCCCBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(C(=O)OCc1ccccc1)n1ccnc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a suspension of 9.74 g of 57% sodium hydride in 100 ml of dimethylformamide was added a solution of 15.0 g of imidazole in 500 ml of dimethylformamide at a temperature of 15°-25° C. The resulting mixture was heated to 60° C. for 1 hour, was cooled to room temperature and 62.8 g of benzyl 6-bromohexanoate was added. The mixture was heated to 60° C. for two hours, allowed to stand overnight at room temperature, and was evaporated. The residue was taken up in aqueous hydrochloric acid, washed with ether, made basic with sodium hydroxide and extracted with dichloromethane. The combined organic layers were dried, evaporated and distilled to yield 45.1 g (75%) of benzyl (1H-imidazol-yl)hexanoate.
Reaction SMILES: [OH:1][C@:2]1([CH3:25])[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:24])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:23])[CH2:16]2)[C@:19]2([CH3:22])[C@H:4]([CH2:3][C@@:2]([OH:1])([CH3:25])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: O
Solvent: CO
Product: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C1

Procedure:
A stirred solution of 3α-hydroxy-3β-methyl-5α-pregnane-11,20-dione (17) (5.0 g., 15.0 mmole) in methanol (300 ml.) was treated with a solution of bromine (1.0 ml.) in methanol (30 ml.) at 0° and at such a rate that the yellow colour of the solution disappeared before further addition of the bromine solution took place. The mixture was then poured into water; the precipitated title compound (2.8 g.) was collected by filtration and dried over P2O5 in vacuo.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].S(Cl)([Cl:27])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([Cl:27])=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: C=CCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
A mixture of 1.3 g of 4-(7-octenyloxy)biphenyl4'-carboxylic acid and an excessive amount of thionyl chloride was refluxed for 6 hours, and then unaltered thionyl chloride was evaporated to leave 4-(7-octenyloxy)-biphenyl-4'-carbonyl chloride.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-].ClCCl>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([Cl:1])=[C:15]([OH:20])[CH:14]=[CH:13]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc2cc(Br)ccc2c1Cl
Temperature: 0 °C
Reaction time: 10 h
Yield: 95.4 %

Procedure:
The synthesis of (S1-2) was carried out following the method described in Synlett, No. 18, 2837 (2005), wherein 29.9 g of N-chlorosuccinimide and 600 ml of dichloromethane were added to a reactor in nitrogen atmosphere and cooled to 0° C., 2.6 g of zirconium (IV) chloride was added, and then 50 g of 6-bromo-2-naphthol (S1-1) was added slowly. The reaction solution was heated to room temperature and stirred for 10 hours, then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and distilled under a reduced pressure to remove the solvent. Recrystallization was carried out using a mixed solvent of toluene/heptane=1/1 (volumetric ratio) to obtain 55 g of 6-bromo-1-chloro-2-naphthol (S1-2).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:34]=[C:35]([O:41][CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=2)=[O:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: COc1cc(CNC2CC2)cc(OC)c1
Product: COc1cc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc(OC)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3,5-dimethoxy-benzyl)-amine
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=[O:4].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=C2.Cl.[OH-].[Na+]>CN(C)C=O.O>[CH2:6]([O:5][C:3]([C:2]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([Br:14])[CH:16]=2)[NH:20][CH:19]=1)=[O:4])[CH3:7]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic anhydride (8.5 ml) was added to a solution of 5-bromoindole (10.0 g) in N,N-dimethylformamide (50 ml) at 0° C., and stirred at the same temperature for three hours. After completion of the reaction, water was added to the reaction solution and the precipitated crystalline was collected by filtration. Water (250 ml) and sodium hydroxide (50 g) were added to a solution of the resulting residue in ethanol (50 ml) and the mixture was stirred at 120° C. for eight hours. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated hydrochloric acid was added and the precipitated solid was collected by filtration. To a solution of the resulting residue in ethanol (250 ml), was added concentrated sulfuric acid (5.0 ml) and the mixture was stirred at 90° C. for three hours. Concentrated sulfuric acid (5.0 ml) was further added and stirred at the same temperature for four hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 4N aqueous solution of sodium hydroxide was added until the solution becomes pH 7. Ethanol was evaporated, the precipitated solid was collected and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-bromo-1H-indole-3-carboxylic acid ethyl ester (5.40 g) as a white solid.