Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:49](B(O)O)([CH3:51])=[CH2:50].C(=O)([O-])[O-].[K+].[K+].C1COCC1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C(Cl)Cl>[F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([C:49]([CH3:51])=[CH2:50])[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)B(O)O
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(Cl)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(C)c1ccc(-c2cc(-c3ccc(C(=O)OC)cc3C)ccc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1

Procedure:
Methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (120 mg, 0.966 mmol), isopropenylboronic acid (74.4 mg, 0.865 mmol), 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (23.5 mg, 20%), aqueous potassium carbonate (1.21 mL, 1M, 1.21 mmol) and THF (1.2 mL) were heated in an 80° C. oil bath for 1 h and 25 min. Volatiles were then removed from the crude mixture under reduced pressure. The pot residue was treated with water followed by EtOAc extraction. The combined extracts were dried over Na2SO4 followed by filtration and concentration to afford a dark colored oil. The resulting oil was purified by a reversed-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TPA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Related fractions were pooled and evaporated in vacuo to afford a light yellow oil. The oil was dissolved with CH2Cl2 and then washed with NaHCO3 (sat. aq.). The organic layer was separated and back washed with water, separated and dried over Na2SO4, filtered and concentrated in vacuo to afford methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropenylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate, as a light yellow glass. LCMS calc.=698.22; found 699.23 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Cl:22])[C:12]=2[Cl:23])[N:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25].O>CS(C)=O>[N:1]([C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[C:13]([Cl:22])[C:12]=2[Cl:23])[N:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1cnn(-c2c(Cl)cc(C(F)(F)F)c(Cl)c2Cl)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.2 %

Procedure:
1.0 g (0.015 mol) of sodium azide is added to 3.0 g (0.007 mol) of 5-bromo-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 50 ml of dimethylsulphoxide, the mixture is stirred at room temperature for 15 hours, poured into 150 ml of water and extracted several times with chloroform and ethyl acetate, the combined organic phases are dried over magnesium sulphate and concentrated in vacuo and the oily crude produc is purified by chromatography (silica gel; mobile phase: chloroform/acetone 9:1). 0.68 g (24% of theory) of 5-azido-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 84° C.-88° C. is obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.[CH3:40][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][O:35][CH:32]1[CH2:31][CH2:30][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(C)=O)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(C)(C)O)CC2)c2ncnn12
Reaction time: 3 h
Yield: 78 %

Procedure:
4′-({5-oxo-4-[4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.17 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.27 mL) was added at room temperature. The reaction mixture was stirred for 3 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:7]([NH2:8])=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([NH:8][C:7]1[C:6]([C:15]([F:16])([F:17])[F:18])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:10][C:9]=1[C:11]([F:12])([F:13])[F:14])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)Nc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
A mixture of 8.2 g. of 4-nitro-2,6-bis-trifluoromethylaniline, 3.6 g. acetic anhydride, and 20 ml. of pyridine is heated for 48 hours on a steam bath. The reaction mixture is poured onto ice water and the solid material is filtered, dried and recrystallized from isopropanol affording 4-acetylamino-3,5-bis-trifluoromethylnitrobenzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1)#[N:2].[OH-].[Na+].C([O:35]CCOCCO)C>O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH2:19][CH2:20]1)(=[O:35])[NH2:2]
Reactant: CCOCCOCCO
Reactant: N#Cc1ccc2[nH]cc(CCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 3.1 g of 6-[4-(3-(5-cyanoindol-3-yl)propyl)piperazino]-1,4-benzodioxane, 2.7 g of NaOH, 100 ml of water and 50 ml of diethylene glycol monoethyl ether is stirred at a bath temperature of 140° for 3 hours. It is cooled, worked up in the conventional manner and gives 6-[4-(3-(5-carbamoylindol-3-yl)propyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[O:19]=[C:20]1[N:25]2[CH:26]=[CH:27][S:28][C:24]2=[N:23][CH:22]=[C:21]1[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:29]([C:21]2[C:20](=[O:19])[N:25]3[CH:26]=[CH:27][S:28][C:24]3=[N:23][CH:22]=2)=[O:30])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1cnc2sccn2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cnc3sccn3c2=O)CC1
Temperature: 25 °C
Yield: 47 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (500 mg), 5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylic acid (371 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (395 mg), 1-hydroxy-1H-benzotriazole monohydrate (315 mg), triethylamine (0.558 mL), and N,N-dimethylformamide (10 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (320 mg, 47%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[N:18]1([CH:23]([CH3:27])[CH2:24][CH2:25]O)[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.CO.C1COCC1>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:24][CH:23]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH3:27])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(CCO)N1CCCC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(CCOc1ccc(C2(CN(C)C)CCOCC2)cc1)N1CCCC1
Yield: 23.7 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (925 mg, 3.93 mmol), 3-pyrrolidin-1-yl-butan-1-ol (450 mg, 3.14 mmol), PPh3 (1.03 g, 3.93 mmol), THF (9 ml) and DIAD (0.77 ml, 3.93 mmol) were reacted together according to general procedure C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH (99.5:0.5) to provide the title compound (268 mg, 24%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.88 (d, 2H), 4.11-3.97 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.66-2.52 (m, 5H), 2.40 (s, 2H), 2.19-2.05 (m, 3H), 1.96 (s, 6H), 1.93-1.70 (m, 7H), 1.16 (d, 3H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[Cl:25])=[N:11][CH:12]=1.[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:34]([CH2:35][C:36]=1OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]2)=[O:29]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:34]([CH2:35][C:36]=1[C:7]1[CH:12]=[N:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[Cl:25])=[CH:9][CH:8]=1)[CH2:33][CH2:32]2)=[O:29]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(Br)cn2)c(Cl)c1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
BuLi (1.6 M in hexane, 12.0 mL, 19.2 mmol) was added to the sol. of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine (5.45 g, 14.4 mmol) in THF (120 mL) at −78° C. The mixture was stirred at −78° C. for 60 min, and ZnCl2 (1M in THF, 28.9 mL, 28.9 mmol) was added. The mixture was allowed to warm up to rt, and compound A1 (4.00 g, 9.63 mmol) in dry THF (50 mL) and Pd(PPh3)4 (277 mg, 0.240 mmol) in THF (2 mL) were added. The mixture was heated to 70° C. for 1 h, and was quenched with aq. sat. NH4Cl (70 mL). The mixture was extracted with EtOAc (3×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of crude by FC(CH2Cl2/MeOH 99:1→98:2→97:3→96:4→95:5) yielded the title compound (4.25 g, 78%). LC-MS: tR=1.16 min; ES+: 563.11.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CCCCN.N[C@H](C(O)=O)CCSC.N[C@H](C(O)=O)[C@@H](C)O.N[C@H](C(O)=O)C(C)C.[Ca].[P]>[Fe]>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Fe]
Agent: CC(C)[C@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
L-leucine (1.8 g); L-lysine 1.3 ); L-methionine (1.76 g); L-methylalanine (2.5 g); L-threonine (1.4 g); L-valine (1.5 g); suitable salts containing calcium (1 g); phosphorus (0.8 g) and iron (15 g).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:14]3[N:15]=[CH:16][CH:17]=[C:18]([OH:19])[C:13]=3[CH:12]=[N:11]2)=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].OS([O-])(=O)=O.[K+]>C(O)C>[I:1][C:17]1[CH:16]=[N:15][C:14]2[N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:21][CH:20]=3)[N:11]=[CH:12][C:13]=2[C:18]=1[OH:19]
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: II
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(O)c(I)cnc32)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Diiodine (0.547 g, 2.16 mmol) in ethanol (5 mL) was added dropwise over 5 minutes to a solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (0.50 g, 1.96 mmol, prepared similarly as that described in WO 2007/103308) in absolute ethanol (20 mL) at 0° C. The reaction was stirred at 0° C. for 3 hours, followed by addition of 5% sodium bicarbonate (20 mL). The mixture was concentrated to give a slurry. The pH was then adjusted with saturated KHSO4 to a pH of 4. The resulting solid was collected by filtration and dried to give 5-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (0.70 g, 94%). MS APCI (+) m/z 382.0 detected.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[OH:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[OH:23][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:20][C:21](=[O:22])[C:12]=1[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH:2]([OH:3])[CH3:1]
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 0 °C

Procedure:
To a milky white suspension of 924 mg of commercially available warfarin in diethyl ether at 0° C. under an argon atmosphere is slowly added 125 mg of lithium aluminum hydride in portions. After 3 hours at 0° C. the reaction is warmed to room temperature. After 1 hour the mixture is re-cooled to 0° C. and slowly treated with 5 mL of water followed by 10 mL of 1N sodium hydroxide. After the bubbling ceases the layers are separated and the aqueous phase is washed with diethyl ether, acidified with 6 N hydrochloric acid, and repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined organic layers are dried (magnesium sulfate) and concentrated under reduced pressure. The residue is flash column chromatographed using 2% to 20% methanol in dichloromethane to afford 590 mg of a diastereomeric mixture of the title product as a white solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[S:7][N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12>>[N:6]1[S:7][N:8]=[C:9]2[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: c1ccc2nsnc2c1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2nsnc12
Temperature: 25 °C

Procedure:
To a stirred solution of 100 mL of chlorosulfonic acid at 0° C. was added 10.0 g of 2,1,3-benzothiadiazole under an inert atmosphere. The resulting mixture was heated at reflux for 30 minutes and cooled to room temperature. The reaction mixture was added dropwise to 1000 mL ice. The precipitates was collected, washed with water, and air dried to give the title compound as a beige solid, m.p. 146°-148° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][O:30][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.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(N(CC)CC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([NH:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[O:30][CH3:29])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(I)cn1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ccccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccccc1Nc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Temperature: 100 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-iodopyridin-2-yl)cyclopropanecarboxamide (816 mg, 0.200 mmol) was suspended in 1,4-dioxane (0.4 mL) and triethylamine (0.2 mL) containing cesium carbonate (91.2 mg, 0.0280 mmol), tris(dibenzylideneacetone)dipalladium (0) (1.8 mg, 0.0020 mmol), 2-methoxyaniline (0.027 mL, 0.24 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (XANTPHOS, 2.3 mg, 0.0040 mmol). The reaction mixture was heated to 100° C. for 15 hours. The crude product was then filtered, evaporated to dryness, dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product (2.6 mg, 0.0049, 2.4%). ESI-MS m/z calc. 403.2. found 404.5 (M+1)+. Retention time 2.73 minutes.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[CH:19][C:20]2[CH:24]=[CH:23][S:22][C:21]=2[CH:25]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:22]1[CH:23]=[CH:24][C:20]2[CH:19]=[CH:18][C:17]([N:12]3[CH2:13][CH2:14][N:10]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:4]=4[CH:1]4[CH2:3][CH2:2]4)[C:11]3=[O:15])=[CH:25][C:21]1=2
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Brc1ccc2ccsc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ccsc3c2)CCN1c1cnccc1C1CC1
Yield: 72.7 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 6-bromobenzo[b]thiophene (195 mg, 0.541 mmol), 1,4-dioxane (6 mL), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (6.9 mg, 0.049 mmol) and potassium phosphate (260 mg, 1.23 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in CHCl3) afforded 120 mg of the product (73% yield).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[CH:17]1[CH:22]=[N+:21]([C@@H:23]2[O:27][C@H:26]([CH2:28][O:29][P:30]([O:33][P:34]([O:37][CH2:38][C@H:39]3[O:43][C@@H:42]([N:44]4[C:48]5[N:49]=[CH:50][N:51]=[C:52]([NH:53]CCN)[C:47]=5[N:46]=[CH:45]4)[C@H:41]([OH:57])[C@@H:40]3[OH:58])([OH:36])=[O:35])([OH:32])=[O:31])[C@@H:25]([OH:59])[C@H:24]2[O-:60])[CH:20]=[C:19]([C:61]([NH2:63])=[O:62])[CH:18]=1.C1(N=C=NCCN2CCOCC2)CCCCC1.Cl>O.[OH-].[Na+].CC(C)=O>[CH:17]1[CH:22]=[N+:21]([C@@H:23]2[O:27][C@H:26]([CH2:28][O:29][P:30]([O:33][P:34]([O:37][CH2:38][C@H:39]3[O:43][C@@H:42]([N:44]4[C:48]5[N:49]=[CH:50][N:51]=[C:52]([NH2:53])[C:47]=5[N:46]=[CH:45]4)[C@H:41]([OH:57])[C@@H:40]3[OH:58])([OH:36])=[O:35])([O-:32])=[O:31])[C@@H:25]([OH:59])[C@H:24]2[OH:60])[CH:20]=[C:19]([C:61]([NH2:63])=[O:62])[CH:18]=1.[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: NCCNc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H]([n+]3cccc(C(N)=O)c3)[C@H]([O-])[C@@H]2O)[C@@H](O)[C@H]1O
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reaction time: 5 h

Procedure:
A 16 mg quantity of biotin was suspended in 1 ml of water containing 22 mg of nicotinamide 6-(2-aminoethylamino) purine dinucleotide prepared as in Example 1. A few drops of 0.1 N sodium hydroxide was added to aid dissolution of the biotin. A 240 mg quantity of 1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho-p-tolulene sulfonate was added to the resulting solution and brought into solution by dropwise addition of 0.1 N hydrochloric acid. The reaction mixture was allowed to incubate at room temperature for 5 hours and was then poured into 10 ml of acetone at -10° C. The oil which formed was separated, washed twice with from 5 to 10 ml of ether and dissolved in from 1 to 2 ml of water. The resulting material was purified by electrophoresis on paper as in Example 1. Two fluorescent bands appeared after spraying with sodium cyanide, one having migrated toward the cathode and the other toward the anode. The latter band, which contained the NAD-biotin conjugate, was eluted with water and stored at -20° C.