Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@@H:18]([S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[N:17]([S:26]([O-:29])(=[O:28])=[O:27])[C:16]2=[O:30])=[O:13])[N:10]=1)=O.[Na+:34].CSC(=S)N.[Na]>CO>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@@H:18]([S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[N:17]([S:26]([O-:29])(=[O:28])=[O:27])[C:16]2=[O:30])=[O:13])[N:10]=1.[Na+:34]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1Sc1nnnn1C)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1Sc1nnnn1C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.4 %

Procedure:
To a solution of 0.260 g of the above sodium (3R,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-5-yl)thio-2-oxoazetidine-1-sulfonate in 20 ml of 50% methanol is added under ice-cooling 0.0597 g of sodium monomethyldithiocarbamate, and the mixture is stirred at room temperature for 5 hours. The same procedure as Example 3B yields 0.093 g of sodium (3R,4R)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-5-yl)thio-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][N:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]COC)=[CH:22][CH:21]=3)[N:17]=[C:16]3[N:30](C4CCCCO4)[N:31]=[C:32]([CH3:33])[C:15]=23)[CH2:7][C:6]1([CH3:41])[CH3:40].Cl>>[CH3:1][O:2][C:3](=[O:42])[CH2:4][N:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:17]=[C:16]3[NH:30][N:31]=[C:32]([CH3:33])[C:15]=23)[CH2:7][C:6]1([CH3:41])[CH3:40]
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CC(=O)OC)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: Cl
Product: COC(=O)CN1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3)nc3[nH]nc(C)c23)CC1(C)C

Procedure:
78 mg of {4-[6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-acetic acid methyl ester were reacted with hydrochloric acid (4M in dioxane) and the volatiles were removed after 5 h. After purification by preparative HPLC 14 mg (21%) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][N:7]3[CH2:8][C:9]4([CH2:13][CH2:12][CH2:11]4)[O:10][C:5]([C:6]=23)=[C:4]([F:24])[C:3]=1[F:25].[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[CH2:8][C:9]4([CH2:13][CH2:12][CH2:11]4)[O:10][C:5]([C:6]=23)=[C:4]([F:24])[C:3]=1[F:25]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OC1(CCC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3CC1(CCC1)O2
Yield: 95.1 %

Procedure:
A solution of ethyl 8′-amino-9′,10′-difluoro-7′-oxospiro[cyclobutane-1,2′(3′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (247 mg, 0.705 mmol) and 1M NaOH aq. (3.5 mL) in EtOH (3.5 mL) was stirred at room 50° C. for 1.5 hours. The solvent was removed and the residue was dissolved in water. The solution was acidified to pH 7 with 2M HCl and the resulting precipitate was removed by filtration, washed with water and dried to yield the title compound (216 mg, 95%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.73-1.97 (2H, m), 2.04-2.27 (4H, m), 4.50 (2H, s), 7.25 (2H, brs), 8.76 (1H, s), 14.67 (1H, s). ESIMS (+): 322[M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[CH:6]=[CH:5]2.[Li]CCCC.Cl[Ge:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[CH3:19][C:14]1[CH:13]=[C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Ge:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=3)[N:8]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Cc1cc(C)cc(-c2ccc3cc(Br)ccc3n2)c1
Reactant: C[Ge](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2ccc3cc([Ge](C)(C)C)ccc3n2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
6-Bromo-2-(3,5-dimethylphenyl)quinoline (6.0 g, 19.2 mmol) and 150 mL anhydrous THF were added in a dry 2-necked round bottom flask and cooled down to −78° C. 8.46 mL BuLi (2.5 M in hexane) was added dropwise. The solution was stirred for 45 minutes at −78° C. and 2.83 mL (23.06 mmol) of chlorotrimethylgermane was slowly added with a syringe. The solution was stirred for overnight. The reaction mixture was purified by column 5% ethyl acetate in hexane and distillation. ˜4.1 g white slide was obtained after recrystallization from hexane. GC-MS confirmed the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:25])([F:24])[C:14](=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH2:16]([C:15]1[C:14]([C:13]([F:12])([F:25])[F:24])=[N:1][C:2]2[C:3]([C:4]=1[OH:6])=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCc1ccccc1)C(F)(F)F
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Oc1c(Cc2ccccc2)c(C(F)(F)F)nc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (2.53 g, 11.7 mmol), 1,1,1-trifluoro-4-phenylbutan-2-one (2.83 g, 14.0 mmol, see reference Yang, D; Wong, M; Yan, Z. J. Org. Chem. 2000, 65, 4179-4184), and Eaton's reagent (8.8 mL) in a sealed pressure tube was heated at 100° C. for 4 hours. The mixture was then cooled down to room temperature, ice-water was added slowly, and the mixture was stirred vigorously for about 15 minutes. The precipitated solid was filtered, washed with water, and air dried over night to afford the title compound as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:5][C:4]=1[OH:16].C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[CH3:15][C:13]1[N:14]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:16][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:5]=2)[S:11][CH:12]=1
Reactant: COc1ccc(Nc2nc(C)cs2)cc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(C)cs2)cc1OCC=C(C)C
Yield: 54 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of 2-methoxy-5-(4-methylthiazol-2-ylamino)phenol (30 mg, 0.10 mmol) and K2CO3 (15 mg, 0.11 mmol) in acetone (1.0 mL) was treated with 4-bromo-2-methyl-2-butene (0.014 mL, 0.12 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 54% yield (16 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:63]>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)=[C:19](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[CH2:20][CH2:21][Cl:63])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: ClCC/C(=C(/c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1

Procedure:
4-[4-(2-benzyloxyethoxy)-phenyl]-4-(4-benzyloxyphenyl)-3-phenylbut-3-en-1-ol (1.9 g, 3.45 mmol), triphenyl phosphine (1.8 g, 6.9 mmol), carbon tetrachloride (2.6 g, 17.25 mmol) and acetonitrile (10 ml) were stirred at room temperature for an hour. The product was separated by the same method as Z-1-[4-(2-benzyloxyethoxy)-phenyl]-4-chloro-1,2-diphenyl-but-1-ene described in example 2 and purified by flash chromatography (toluene: methanol, 9.75:0.25). Yield 1.2 g.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[ClH:12].[H][H]>C(O)(C)C.[Pd]>[ClH:12].[F:11][C:2]([F:1])([F:10])[CH:3]1[NH:4][C:5]([NH2:9])=[N:6][CH2:7][CH2:8]1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NC1=NCCC(C(F)(F)F)N1

Procedure:
To a solution of 10 g (45.11 mmol) of 4-trifluoromethyl-pyrimidin-2-ylamine and 0.065 g of palladium 10 wt. % on activated carbon in 5 ml of isopropanol was added 45 ml of a solution of hydrochloric acid in isopropanol (5-6 N). The mixture was shaken at 40° C. under hydrogen pressure of 4 atmospheres until hydrogen uptake ceased. The catalyst was removed by filtration and washed with isopropanol. The filtrate was evaporated to dryness to afford 12.14 g of pure product as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.O>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 19.9 %

Procedure:
1-Bromo-4-(methylsulfonyl)benzene (275 mg, 1.169 mmol), piperazine (302 mg, 3.507 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BINAP (44 mg, 0.070 mmol), and sodium-tert-butoxide (169 mg, 1.754 mmol) were suspended in toluene (5 ml), and then the resulting liquid was stirred at 100° C. under nitrogen stream for 15 hours. Distilled water (15 ml) was added to the resulting reaction liquid, followed by extraction with MC (20 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (15% MeOH/MC), to obtain 56 mg of pale yellow solid (20%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: O[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1N1CCC[C@H](O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (S)-3-hydroxypiperidine and triethylamine in DMF yielding (S)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 28.6 %

Procedure:
A mixture of tert-butyl-dimethyl-((R)-3-oxiranyl-propoxy)-silane (13 g, 60 mmol, prepared according to Org. Lett. 2005, 7, 3997) and 6-amino-4H-benzo[1,4]thiazin-3-one (10.8 g) in EtOH/H2O (9:1, 325 mL) was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue purified by CC (Hept/EA 1:1) to give the desired intermediate (6.8 g, 28% yield) as a brown oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:47]=[CH:46][C:12]([O:13][C:14]([C:16]2[CH:17]=[C:18]([N:39]3[C:43](=[O:44])[CH:42]=[CH:41][C:40]3=[O:45])[CH:19]=[C:20]([C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][Si](C(C)(C)C)(C)C)=[CH:27][CH:26]=3)=[O:23])[CH:21]=2)=[O:15])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.F.[F-].[Na+].O>C1COCC1>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]([C:20]2[CH:19]=[C:18]([N:39]3[C:43](=[O:44])[CH:42]=[CH:41][C:40]3=[O:45])[CH:17]=[C:16]([C:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:47][CH:46]=3)=[O:15])[CH:21]=2)=[O:23])=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OC(=O)c2cc(C(=O)Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc(N3C(=O)C=CC3=O)c2)cc1
Agent: F
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Oc1ccc(O)cc1)c1cc(C(=O)Oc2ccc(O)cc2)cc(N2C(=O)C=CC2=O)c1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
N-[3,5-di-(4-(tert-butyldimethylsilyloxy)phenoxycarbonyl)phenyl]maleimide (35 g 0.052 mole) was dissolved in THF (500 ml). Hydrogen fluoride (2.5 M, 70 ml), sodium fluoride (3 g) and water (280 ml) were added. The reaction mixture was stirred overnight and most of the solvent was removed. Filtration of the product over a silica bed and concentration in vacuo afforded N-[3,5-di-(4-hydroxyphenoxycarbonyl)phenyl]maleimide (22.2 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:13][C:7]=2[C:6]=1[OH:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:22])[C:8]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:13][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: COC(=O)c1ncc2c(-c3ccc(F)cc3)csc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(-c3ccc(F)cc3)csc2c1O
Yield: 61.8 %

Procedure:
A suspension of 3-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (100 mg, 0.33 mmol), example 31-f, N-bromosuccinimide (61.6 mg, 0.346 mmol), and benzoyl peroxide (8.0 mg, 0.033 mmol) in 0.83 mL of carbon tetrachloride was heated at reflux temperature for 5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate, brine, saturated ammonium chloride solution, and brine. The organic solution was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in methylene chloride to produce 77.9 mg of a light yellow solid. MS: (−) m/z 380.3, 382.1 (M−1, 79Br/81Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]=1[F:17].C(O[C:25]1[CH:30]=[CH:29][C:28](Br)=[C:27](F)[CH:26]=1)CCCCC>>[CH2:9]([O:8][C:4]1[CH:5]=[CH:6][C:7]([C:2]2[CH:7]=[CH:6][C:5]([C:25]3[CH:26]=[CH:27][C:28]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:29][CH:30]=3)=[CH:4][CH:3]=2)=[C:2]([F:1])[C:3]=1[F:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCOc1ccc(Br)c(F)c1
Reactant: CCCCCCCCOc1cccc(F)c1F
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)cc2)c(F)c1F

Procedure:
This compound is prepared by an analogous route using 1,2-difluoro-3-octoxybenzene instead of 8B. This is prepared using the method as for 3A.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([OH:20])=O)=[O:12].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:35]1[CH2:41][CH2:40][CH2:39][C@H:36]1[CH2:37][OH:38]>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:35]1[CH2:41][CH2:40][CH2:39][C@H:36]1[CH2:37][OH:38])=[O:20])=[O:12]
Reactant: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
3-(Indan-2-ylacetyl)-L-thioproline (11.7 g) and triethylamine (5.6 ml) were dissolved in 100 ml of methylene chloride, followed by dropwise addition of 4.95 g of pivaloyl chloride under agitation while cooling in ice for 15 minutes. Subsequently, 4.05 g of L-prolinol and 5.6 ml of triethylamine were added dropwise and stirred at room temperature for another one hour. The reaction solution were washed in 1N HCl, saturated aqueous solution of sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, followed by distillation of the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 8.80 g of 1-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-prolinol. Yield; 59%.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC([CH2:32][N:33]3[CH2:38][CH2:37][N:36](C4C=CC=CC=4)[CH2:35][CH2:34]3)=C(C(OC)=O)N=1)CC2)=O.C1C=CC(N2CCNCC2)=CC=1.[OH:65][C:66]1[CH:73]=[CH:72][C:69]([CH:70]=O)=[CH:68][CH:67]=1.CN1CCNCC1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:70][C:69]2[CH:72]=[CH:73][C:66]([OH:65])=[CH:67][CH:68]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: CN1CCNCC1
Agent: c1ccc(N2CCNCC2)cc1
Product: CN1CCN(Cc2ccc(O)cc2)CC1

Procedure:
Compound 89A was prepared in a similar manner to the synthesis of compound 62A by substituting compound 45C and phenylpiperazine with 4-hydroxybenzaldehyde and 1-methylpiperazine, respectively: ESI (+)/MS: 207 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=2)[NH2:7])[CH2:3][CH2:2]1.C[Al](C)C.C[O:16][C:17]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:37][CH3:38])[N:31]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:7][C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][C:30]5[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:37][CH3:38])[N:31]=5)=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: COCc1nccc(Oc2ccc3c(C(=O)OC)cccc3c2)n1
Reactant: Nc1cccc(C2CC2)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCc1nccc(Oc2ccc3c(C(=O)Nc4cccc(C5CC5)c4)cccc3c2)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 32.8 mg (0.247 mMol) 3-cyclopropyl-aniline [preparation see: Tet. Lett. 43 (2002) 6987] are dissolved in 4.3 ml toluene and cooled to 10° C. Then 370 μl Me3Al (2 M in toluene; 0.74 mMol) are added via syringe. After 1 h at rt, a solution of 80 mg (0.247 mMol) 6-(2-methoxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester (Step 15.4) in 1 ml THF is added and the reaction mixture is stirred for 30 min in an oil bath of 110° C. The solution is cooled in ice and hydrolyzed with 11 ml of a sat. NH4Cl. After 15 min stirring, the mixture is diluted with EtOAc and water, the aq. phase separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; toluene/acetone 99:1→4:1) gives the title compound: MS: [M+1]+=426; TLC (toluene/acetone 4:1): Rf=0.09.
Reaction SMILES: CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC(C)([O-])C.[Na+].Br[C:36]1[CH:45]=[C:44]2[C:39]([C:40]([O:46][C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]4[C:63]5[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=5)[C:57]([C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)=[N:56][N:55]=4)=[CH:49][CH:48]=3)=[CH:41][CH:42]=[N:43]2)=[CH:38][CH:37]=1.[NH:70]1[CH2:75][CH2:74][O:73][CH2:72][CH2:71]1.O1CCOCC1.C(O)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[O:73]1[CH2:74][CH2:75][N:70]([C:36]2[CH:45]=[C:44]3[C:39]([C:40]([O:46][C:47]4[CH:52]=[CH:51][C:50]([NH:53][C:54]5[C:63]6[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=6)[C:57]([C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)=[N:56][N:55]=5)=[CH:49][CH:48]=4)=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)[CH2:71][CH2:72]1
Reactant: Brc1ccc2c(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: c1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(N6CCOCC6)ccc45)cc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
The title compound was prepared according to a method described in Ali, M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560. Pd2(dba)3(21 mg, 23 μmol), DavePhos (18 mg, 46 μmol), and sodium tert-butoxide (110 mg, 1141 μmol) were added into a screw-capped tube equipped with a stir bar. The tube was purged with argon. N-(4-(7-Bromoquinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (237 mg, 456 μmol) was added to the purged tube, followed by morpholine (159 μl, 1825 μmol), 1,4-dioxane (2074 μl, 456 μmol), and tert-butanol (1037 μl, 456 μmol). The tube was sealed and heated to 100° C. in an oil bath for 1 h. The reaction was cooled to rt, and 22 mg of Pd2(dba)3, 20 mg of DavePhos, and 80 mg of NaOt-Bu were added. The tube was resealed and placed in a preheated oil bath at 100° C. After another 3.5 h, LCMS showed mainly product at 1.434 min as [M+H]+=526. The mixture was passed through a pad of celite with an aid of CH2Cl2. The filtrate was concentrated. The product was purified by column chromatography on silica gel eluting with 70:30 to obtain top spot, then washing with 60:40 CH2Cl2:(90:10:1 CH2Cl2:MeOH:NOH) to collect the product. Fractions containing the product were concentrated. A yellow solid was obtained and dried in the vacuum oven. The yellow solid was further purified by RPLC on the acidic Gilson workstation. Fractions containing the product were diluted with CH2Cl2 and neutralized with sat. NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated. Yellow solid was obtained. HPLC showed 100% pure. LCMS confirmed product. MS Calcd for C33H27N5O2: [M]+=525. Found: [M+H]+=526.
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=12.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25][C:2]2[C:3]([S:25][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)=[C:4]([S:25][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)[C:5]([S:25][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)=[C:6]3[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=23)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c21

Procedure:
2 g (7.02 millimols) of tetrachlorophthalimide, 4.36 g (28.08 millimols) of p-nitrothiophenol, 5.82 g (42.12 millimols) of potassium carbonate and 30 ml of tetrahydrofuran are stirred at 25° C. for 14 hours. The mixture is acidified and extracted with tetrahydrofuran/toluene and the extracts are dried and evaporated. The residue is washed with methylene chloride and recrystallised from dioxane/toluene. This yields 3.02 g (57% of theory) of tetrakis-(p-nitrophenylthio)-phthalimide; melting point 297°-301° C.