Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[C:6]([SH:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:11]([N:18]([CH3:29])[CH2:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)CC)(C)C>C(#N)CC>[S:1]1[C:5]2[C:6]([S:10][CH:19]([N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:29])[CH2:20][CH2:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Sc1cccc2ccsc12
Reactant: CN(CCC(O)c1ccccc1)Cc1ccccc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1ccccc1)C(CCc1ccccc1)Sc1cccc2ccsc12
Temperature: 25 °C

Procedure:
A solution of 1-benzothiophene-7-thiol (0.32 g, 1.96 mmol), 3-[benzyl(methyl)amino]-1-phenyl-1-propanol (0.5 g, 1.96 mmol), (cyanomethyl) trimethylphosphonium iodide (Ref Tetrahedron, 2001, 57, 5451–5454) (0.714 g, 2.94 mmol), diisopropylethylamine (0.379 g, 2.94 mmol) in propionitrile (5 mL) was stirred at 90° C. in a reacti-vial for 72 h. After this time the reaction was allowed to cool to room temperature. The reaction mixture was purified by an SCX-2 column eluting with methanol followed by ammonia:methanol solution (7 N). The organics were then evaporated and the compound taken directly onto the next step without any further purification LCMS determined successful product formation (M+H+1 [404]).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an 100 mL three-necked RB flask equipped with a magnetic bar, a condenser and a nitrogen gas inlet, 2-bromo-6-methoxynaphthalene (7.32 g, 30 mmol), 4-methoxybenzene boronic acid (4.86 g, 32 mmol) and 1-propanol (50 mL) were mixed and stirred at room temperature for approx. 30 min. Palladium acetate (0.02 g, 0.09 mmol), triphenylphosphine (0.07 g, 0.27 mmol), Na2CO3 solution (2M, 18 mL, 36 mmol) and water (10 mL) were added and the mixture was refluxed for 1.5 h. When the mixture was still hot, 30 mL of water was added and the mixture was stirred and cooled to room temperature. The resultant crystals were filtered, washed with water and recrystallized from acetone to give the DMPN title compound as colorless flakes (6.86 g, 86%). mp 194-196° C. (DSC 196° C.). 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 3H), 3.95 (s, 3H), 7-8 (m, 10H). IR (KBr) ν (cm−1): 3058 (Ph—H, w), 1028 (OCH3, s). Anal. Calcd for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.80; H, 6.25. GC-MS (m/z) 264 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([NH:24][C:25]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:16]([NH:24][C:25]1[CH:37]=[C:36]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-n2ccc3ccccc32)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
33 mg of 1H-indole, 0.12 g of cesium carbonate, 5.1 mg of tris(dibenzylideneacetone)dipalladium(0), 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 4.4 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, 33 mg of 1H-indole, 79 mg of tripotassium phosphate, 5.1 mg of tris(dibenzylideneacetone)dipalladium(0), 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 4.4 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated, and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=20:1] to obtain 45 mg of tert-butyl 2-(benzamido)-4-(1H-indol-1-yl)benzoate as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([CH2:14][CH:15]=[CH2:16])[CH3:13].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:14]/[CH:15]=[CH:16]/[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1)[CH3:13]
Reactant: Cc1ccc(Br)cc1N
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A mixture of 4-bromo-2-aminotoluene (1.55 g, 7.17 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.71 g, 8.60 mmol ), prepared as previously described, palladium(II) acetate (16 mg, 0.07 mmol), tri-o-tolylphosphine (87 mg, 0.28 mmol), triethylamine (4.5 mL, 32.28 mmol), and acetonitrile (10 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water (40 mL) and extracted with chloroform (4×75 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by column chromatography on neutral alumina eluting with ethyl acetate-hexane (2:3 to 4:1) to yield 1.57 g (72.3%) of a brown liquid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[OH:19][CH2:20][CH:21]1[NH:26][CH:25]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[CH2:24][N:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:22]1>C(Cl)Cl.O.C(=O)(O)[O-].[Na+]>[CH3:39][O:38][C:36]([N:23]1[CH2:24][CH:25]([C:27]2[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=2)[N:26]([C:2]([O:4][CH2:5][CH:6]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:3])[CH:21]([CH2:20][OH:19])[CH2:22]1)=[O:37]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)N1CC(CO)NC(c2cc(F)c(F)c(F)c2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC(CO)N(C(=O)OCC2c3ccccc3-c3ccccc32)C(c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
9-Fluorenylmethyl chloroformate (958 mg) was added to a mixed solution of methyl 3-hydroxymethyl-5-(3,4,5-trifluorophenyl)piperazine-1-carboxylate (867 mg) in methylene chloride (20 mL) and saturated sodium bicarbonate water (20 mL), and the reaction solution was stirred at room temperature for 14 hours. The organic layer was separated from the reaction solution. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->ethyl acetate) to obtain 916 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20].C([O-])=O.[NH4+:24].C1COCC1.CO>[Pd].C(Cl)Cl.CCCCCC>[NH2:24][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20]
Reactant: [NH4+]
Reactant: CCCC1CC(=O)N(Cn2cnc3c(Cl)ncnc32)C1
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: CCCC1CC(=O)N(Cn2cnc3c(N)ncnc32)C1
Yield: 60 %

Procedure:
A solution of intermediate x75 (600 mg, 2.04 mmol), ammonium formiate (644 mg, 5 eq, 10.21 mmol) and palladium on charcoal (10% wt, 109 mg, 0.1 mmol) in a 1 to 1 mixture of THF and methanol (20 ml) is allowed to react at ambient temperature for 16 hours. After filtration on celite and solvent evaporation, the crude product is purified using preparative chromatography on silicagel to furnish a crude compound which is recristallized in a mixture of CH2Cl2 and hexane to furnish 1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one 283 as a white crystalline product (320 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:52]=[CH:51][C:50]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])=[CH:49][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:48]=[CH:49][C:50]([NH:53][S:54]([CH3:57])(=[O:55])=[O:56])=[CH:51][CH:52]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccc(NS(C)(=O)=O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 62 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (94 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (31 mg, 0.04 mmol) and 3 ml 1,2-dimethoxyethane and 0.75 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 65 mg (62% yield, 82% purity) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-])=O>CCOC(C)=O.[Pd]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=2[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2C1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2c1cnn2C1CCCCO1
Reaction time: 22 h
Yield: 96.7 %

Procedure:
A solution of 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.05 g, 4247 μmol) in EtOAc (100 mL) was treated with 10% Pd/C (60 mg) and stirred under an atmosphere of H2. The reaction was monitored by LCMS and found to be complete after 22 h. The reaction was filtered and concentrated (caution: tends to foam/bump). The residue was triturated with Et2O to give 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (892 mg, 96.7% yield) as an off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H); 7.03 (t, J=7.82 Hz, 1H); 6.74 (d, J=8.22 Hz, 1H); 6.18 (d, J=7.43 Hz, 1H); 5.78 (s, 2H); 5.59-5.67 (m, 1H); 3.82-3.92 (m, 1H); 3.63-3.74 (m, 1H); 2.30-2.45 (m, 1H); 1.96-2.08 (m, 1H); 1.84-1.94 (m, 1H); 1.65-1.80 (m, 1H); 1.55 (br. s., 2H). m/z (ESI, +ve) Found 218 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.[CH3:13][O:14][C:15](=[O:17])[CH3:16].[Na]>>[CH2:10]([O:9][CH:5]([O:6][CH2:7][CH3:8])[C:4](=[O:12])[CH2:16][C:15]([O:14][CH3:13])=[O:17])[CH3:11]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: COC(C)=O
Agent: [Na]
Product: CCOC(OCC)C(=O)CC(=O)OC
Temperature: 0 °C

Procedure:
Ethyldiethoxyacetate (32 g.) and methylacetate (25 g.) are placed in a flask equipped with stirred and reflux condenser and heated to reflux. Metallic sodium wire (6.5 g.) is introduced into the flask in small portions and heating continued until the sodium is completely dissolved. Methylacetate (25 g.) and metallic sodium wire (6.5 g.) are then added and heating continued until the solution is clear. The mixture is cooled, a large volume of ice water cautiously added and the mixture extracted with ether. The aqueous solution is acidified with hydrochloric acid at 10° C. to 15° C. and the desired product extracted with ether. The ethereal extract is dried (Na2SO4), the ether removed and the residue distilled in vacuo to give methyl γ,γ-diethoxyacetoacetate.
Reaction SMILES: O=C1C=CC(=O)[N:3]1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[NH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])=[O:21])=[O:17].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:9]([CH2:8][NH2:3])[CH2:10][C:11]([OH:13])=[O:12].[NH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])=[O:21])=[O:17]
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Agent: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: NCCCC(=O)O
Reaction time: 3 h

Procedure:
513 mg (2.8 mmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic acid, 800 mg (0.2.8 mmol) tert-butyl 3-(2-(2-(2-aminoacetamido)acetamido)acetamido)propanoate and 583 mg (3.0 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were dissolved in 12 mL of dimethyl formamide and stirred for 3 hours. The reaction mixture was purified in four equal portions by reverse phase HPLC using a 5.0 cm×25 cm C18 column. The column was eluted at 100 mL/min with deionized water containing 0.3% formic acid and 5% acetonitrile for 10 min followed by a 13 min linear gradient from 5% acetonitrile to 33% acetonitrile. Product fractions (retention time of 21 min) were combined and solvent was removed by rotary evaporation under vacuum to give 832 mg (62%) of the title compound. 1H NMR (d6-DMSO) 8.10-8.16 (m, 2H), 8.07 (t, J=4.8 Hz, 1H), 7.0-7.15 (m, 1H), 3.747 (t, J=6.0 Hz, 3H), 3.64 (d, J=5.6 Hz, 2H), 3.41 (t, J=6.8, 2H), 3.1-3.33 (m, 1H), 3.19-3.26 (m, 2H), 2.348 (t, J=6.8, 2H), 2.132 (t, J=7.2 Hz, 2H), 1.67-1.76 (m, 2H), 1.39 (s, 9H). 13C NMR (d6-DMSO) 171.80, 170.98, 170.39, 169.48, 168.96, 168.56, 134.37, 79.83, 42.05, 41.83, 37.38, 34.82, 34.71, 32.26, 27.83, 23.95. HRMS (M+Na+) Calc. 504.2070 found 504.2046
Reaction SMILES: [CH:1]1([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[ClH:29]>C1COCC1>[ClH:29].[CH:1]1([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COc1ccc(C(=O)NC2CCCCCCC2)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC2CCCCCCC2)cc1OC

Procedure:
A solution of 5.0 g of 3,4-dimethoxy-benzoic acid cyclooctylamide in 20 ml of absolute THF was added dropwise to a suspension of 1.4 g of lithium-aluminium hydride in 30 ml of absolute THF, the reaction mixture was heated for 4 hours to the boiling temperature and, after having cooled, it was cautiously combined with water. The residue was treated with 50 ml of THF, the combined organic phases were dried over Na2SO4, the solvent was removed and the oil obtained was combined with methanolic hydrochloric acid. After concentration, 3.9 g of N-cyclooctyl-3,4-dimethoxy-benzylamine-hydrochloride were obtained. Melting point 161°-163° C (from ethanol/ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.OO.S([O-])([O-])=[O:13].[Na+].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N+:4]([O-:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: N#Cc1ncccc1Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(Cl)ccc[n+]1[O-]
Temperature: 90 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
A solution of 3-chloro-2-cyanopyridine (40 g, 0.29 mol) in acetic acid (500 mL) was treated dropwise with hydrogen peroxide (30%, 52 g, 0.45 mol), stirred at 90° C. for 18 hours, cooled to 25° C., treated dropwise with a solution of sodium sulfite (57 g, 0.45 mol) in water, concentrated to remove the bulk of the acetic acid and partitioned between 1M NaOH and methylene chloride. The methylene chloride layer was dried (MgSO4) and concentrated, and the residue was recrystallized from ethyl acetate to provide 23 g of 3-chloro-2-cyanopyridine--N-oxide, a portion of which (12.2 g, 79 mmol) was dissolved in DMF (160 mL) cooled to 0° C., treated sequentially with ethyl thioglycolate (7.1 mL, 79 mmol) and portionwise with sodium methoxide (8.5 g, 160 mmol), stirred for 1 hour and poured onto ice. The resulting solid was collected by filtration, washed with water, dissolved in methylene chloride, dried (MgSO4), concentrated and recrystallized from ethyl acetate to provide 10.6 g of methyl 3-amino-thieno[3,2-b]pyridine-4-oxide carboxylate, a portion of which (10.6 g, 47 mmol) was mixed with phosphorous oxychloride (100 mL), heated to 80° C. for 30 minutes, concentrated and partitioned between methylene chloride and 5% aqueous NaHCO3 solution. The methylene chloride layer was dried (MgSO4) and concentrated, and the residue was chromatographed on silica gel with 5:1 hexanes/ethyl acetate to first provide methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate followed by the title compound. MS (DCI/NH3) m/e 243 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2.Br.OS([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=2)[C:9]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(Cl)cc2CC1Br
Reaction time: 2 h

Procedure:
A solution of 37.9 g (0.237 mole) of bromine in 120 ml of glacial acetic acid is slowly added dropwise, whilst stirring, to a solution of 40.0 g (0.237 mole) of 5-chloro-1-indanone in 590 ml of glacial acetic acid, to which 0.2 ml of 48% strength aqueous hydrobromic acid has been added. The mixture is stirred for a further 2 hours and the reaction solution is poured into 1 l of water, to which 2.5 g of NaHSO3 have been added. The product, which initially precipitates in the viscous form, becomes crystalline after stirring for a relatively long time. The crude product is filtered off (melting point 69°-76° C.), washed with water and recrystallized from petroleum ether. The pure 2-bromo-5-chloro-1-indanone melts at 89°-90° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N4CCOCC4)cc3)cc2)CC1
Yield: 39.7 %

Procedure:
The title compound (37 mg, 32%) was prepared from [4-(4-morpholinylcarbonyl)phenyl]boronic acid (47 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.58 (m, 2H) 7.51 (d, 2H, J=8.8 Hz), 7.46 (d, 2H, J=8.2 Hz), 6.96 (d, 2H, J=8.8 Hz), 4.97-4.86 (m, 1H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.2 Hz), 3.72 (bs, 6H), 3.53 (bs, 2H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.36-1.26 (m, 2H), 1.24 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 467 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>N1C=CC=CC=1>[CH2:31]([O:30][C:28]([N:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[N:11]=[C:10]1[S:20][C:21]([F:26])([F:25])[CH:22]([F:23])[F:24])=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: Fc1ccc(-c2nc(SC(F)(F)C(F)F)[nH]c2-c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Yield: 67.5 %

Procedure:
To an ice-cooled mixture of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylthio)imidazole (1.5 g) in pyridine (20 ml) was added ethyl chloroformate (1.3 g). The progress of the reaction was monitored by thin layer chromatography. Additional ethyl chloroformate (7.0 g, added in three portions) and warming to room temperature were required to force the reaction to completion. The reaction mixture was poured into water, and the crystalline solid was collected and washed with water. There was obtained 1.2 g of colorless product, mp 137°-139°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:13]([CH3:27])[O:12][N:11]=1>N1C=CC=CC=1>[CH3:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:13]([CH3:27])[O:12][N:11]=1
Reactant: Cc1ccc(N)nc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylpyridin-2-amine (54 mg, 0.5 mmol) in pyridine (5 mL) stirred at room temperature, was added 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (0.151 g, 0.5 mmol). The reaction was stirred at room temperature overnight. The solvent was then removed under a stream of nitrogen to give the crude product, which was used directly in the next reaction with no purification. LCMS (2 min, formic) Rt 0.84 min, m/z (ES+) 374 (M+H).