Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH3:23][Sn](C)(C)C.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:23][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: C[Sn](C)(C)C
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Temperature: 120 °C

Procedure:
5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), dichlorobis(triphenylphosphine)palladium(II) (50 mg, 0.07 mmol, 0.15 equiv) and tetramethyltin (270 μL, 1.91 mmol, 4.0 equiv) were combined in 5 mL of a 1:1 solution of DMF:HMPA. The solution was degassed and heated to 120° C. for 24 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C14H18N3O4S (M+H+): 324.1013. Found 324.1014.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:10])[CH:4]=1.[CH3:11][O:12][CH:13]([O:17][Si](C)(C)C)[CH:14]([CH3:16])[CH3:15]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:11][O:12][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[CH:9]([OH:10])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: COc1ccnc(C=O)c1
Reactant: COC(O[Si](C)(C)C)C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(O)c1cc(OC)ccn1
Reaction time: 18 h

Procedure:
A solution of 0.58 g of 4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem. Pharm. Bull. 38, 2446-2458 (1990)) and 21 mg of scandium trifluoromethanesulfonate in 14 ml of dichloromethane is treated dropwise with 0.9 ml of 1-methoxy-2-methyl-1-trimethylsilyloxypropane under ice-cooling. After 10 min the cooling bath is removed and the mixture is stirred for 18 h. Thereafter, 12 ml of methanol and 12 ml of aqueous hydrochloric acid (3 M) are added and stirring is continued for further 14 h. The solvents are removed in vacuo, the residue is dissolved in dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer is dried using sodium sulfate and concentrated to give 0.845 g of the title compound as a colorless oil. MS: 240.0 (MH+). TLC: Rf=0.46 (toluene/acetone 2:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])(C)(C)[CH3:2].FC(F)(F)C(O)=O.ClC(OCC)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cc2)C1

Procedure:
(S)-3-(4-nitro-phenylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was deprotected with trifluoroacetic acid according to known procedures. After concentration, the amine trifluoroacetate salt was treated with ethyl chloroformate (1 equiv.) and triethylamine (3 equiv.) in methylene chloride to afford (S)-3-(4-nitro-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C13H17N3O4 (m/e) 279.3, obsd 280.1 (M+H).
Reaction SMILES: C([O:8][C:9]([C:11]1([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:16][CH2:15][P:14](=[O:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[O:23]=[P:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16][C:11]([C:9]([OH:10])=[O:8])([C:24]([OH:26])=[O:25])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCP(=O)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCP(=O)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a 500 mL Parr flask was added 1-oxo-1-phenyl-1λ5-phosphinane-4,4-dicarboxylic acid dibenzyl ester (8.5 g, 18 mmol), ethanol (250 mL), and palladium on carbon (10%, 1.1 g). The flask was charged with hydrogen (51 psi), and agitated on a mechanical shaker. After 1 hour, the ballast was re-charged to 50 psi (from 40 psi) and shaking continued overnight (14 hours). The reaction mixture was filtered and the solvent removed in vacuo to provide 1-oxo-1-phenyl-1λ5-phosphinane-4,4-dicarboxylic acid (1.8 g, 35%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.9-7.4 (m, 5H), 2.6-1.4 (m, 8H); ESMS m/z: found, 283 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C[O-].[Na+]>CO.O>[N:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:20][CH:21]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCc2cc(OCCCCSc3ccncc3)ccc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.0 gm of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril were added to a solution of 1.3 gm of 4-mercapto-pyridine and 2.3 gm of a 30% sodium methylate solution in 15 ml of methanol, and the mixture was stirred for 14 hours at room temperature. Subsequently, the reaction solution was diluted with 20 ml of water and the resulting precipitate was recrystallized from ethanol.
Reaction SMILES: [NH2:1]/[C:2](=[C:5](\[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)/[C:6]#[N:7])/[C:3]#[N:4].S(=O)(=O)(O)O.[CH2:23](O)C>C(OC(OCC)OCC)C>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:8]1[C:5]([C:6]#[N:7])=[C:2]([C:3]#[N:4])[N:1]=[CH:23]1
Reactant: N#C/C(N)=C(\C#N)NCc1ccc(Cl)c(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(OCC)OCC
Product: N#Cc1ncn(Cc2ccc(Cl)c(Cl)c2)c1C#N

Procedure:
2-Amino-3-(3,4-dichlorobenzylamino)maleonitrile (10.7 g) was heated on a steam bath in a mixture of ethanol (4 ml) and triethylorthoformate (12 g) containing concentrated sulphuric acid (0.02 ml) for 1 hour. The solution was evaporated to dryness to give a semi-solid, which was crystallised from ethanol (50 ml) to give 1-(3,4-dichlorobenzyl)-4,5-dicyanoimidazole (3.0 g), m.p. 131°-132.5° C., as pale yellow crystals.
Reaction SMILES: I.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:13])SC)=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Na+].[OH2:26]>CCOCC>[C:14]1([CH3:24])[CH:15]=[CH:16][C:17]([S:20]([OH:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[CH3:24][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[O:26][CH:9]([CH3:6])[CH2:10][NH:13][C:10](=[NH:13])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CSC(=N)Cc1ccc(Cl)cc1
Reactant: O
Agent: I
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cccc(OC(C)CNC(=N)Cc2ccc(Cl)cc2)c1

Procedure:
The reaction between methyl 4-chlorophenyl(thioacetimidate)hydriodide (3.7 g.) and 2-3'-methylphenoxypropylamine (1.7 g.) was carried out as in Example 78, except that the reaction solution was diluted, not with ether, but with 2N-aqueous sodium p-toluenesulphonate (5.5 ml.) followed by water. The resulting crystalline product was recrystallised from a mixture of ethanol and ether, and then from a mixture of acetone and water, to give N-(2-3'-methylphenoxypropyl)-4-chlorophenylacetamidine p-toluenesulphonate, m.p. 145°-147°, undepressed on admixture with the product of Example 29.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH:23]=[CH:24]B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:24]=[CH:23]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)nc1
Reactant: OB(O)C=CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(/C=C/C2CCCCC2)nc1
Temperature: 90 °C
Yield: 70.2 %

Procedure:
Combine 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (1.42 g, 5.85 mmol), 2-cyclohexylvinyl boronic acid (1.35 g, 8.78 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with DCM (239 mg, 0.293 mmol), and 2M aqueous Na2CO3 (9.65 mL, 19.2 mmol) in 1,4-dioxane (60 mL). Purge the resulting solution with nitrogen for 5 min and heat at 90° C. overnight. Cool the reaction mixture to room temperature and partition the mixture between EtOAc and water. Separate the aqueous phase and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min, 19:1 over 5 min, 9:1 over 5 min and 85:15 over 5 min; 50 mL/min) to obtain the desired intermediate (1.3 g, 70%). MS (APCI+) m/z: 317 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:19]
Reactant: CC(C)I
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)C)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
1-(4-Hydroxyphenyl)ethanone (15.0 g, 110 mmol) was dissolved in acetone (125 mL), added sequentially with potassium carbonate (30.4 g, 220 mmol) and 1-methylethyl iodide (16.5 mL, 165 mmol), and the mixture was stirred at 70° C. for 8 hours. The reaction solution was filtered, washed with acetone and concentrated in vacuo. The obtained residue was added water and ethyl acetate, extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 1-[4-(1-methylethoxy)phenyl]ethanone (18.2 g (yield 93%)) was obtained as a white crystal.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH:13][CH3:14])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1.[Cl:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]([CH3:14])[CH2:18][CH2:17][Cl:16])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1
Reactant: ClCCBr
Reactant: CNCCc1ccc2c(c1)S(=O)CN2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(CCCl)CCc1ccc2c(c1)S(=O)CN2C
Temperature: 60 °C
Reaction time: 48 h

Procedure:
In a ground-necked flask, 6 mmol of 3-methyl-6-[2-(N-methylamino)ethyl]benzothiazolinone are dissolved in 50 ml of dioxane, 20 mmol of 1-chloro-2-bromoethane and 20 mmol of potassium carbonate. The mixture is stirred for 48 hours at a temperature of 60° C. After cooling, the mixture is evaporated and the reaction medium is extracted with chloroform after adding water. After washing, drying and evaporation of the organic phase, 3-methyl-6-{2-[N-methyl-N-(2-chloroethyl) amino]ethyl}benzothiazolinone is obtained, which product is transferred to a ground-necked flask. A catalytic amount of potassium iodide, 25 cm3 of methanol and 10 cm3 of chloroform are added. A stream of gaseous ammonia is bubbled into the solution to the point of saturation and a reflux condenser is then fitted. The temperature is stabilized at 50° C. with an oil bath and the mixture is then left stirring magnetically for 72 hours. After cooling, the reaction mixture is evaporated on a water bath under vacuum. The residue is ground with distilled water acidified with 5% HCl solution, and then drained. The filtrate is recovered, washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with chloroform, leaving the 2 phases agitating for 1/2 hour, and the organic phase is washed with distilled water and then dried over calcium chloride. The organic phase is evaporated on a water bath under vacuum, the residue is then taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the mixture is then evaporated to dryness on a water bath under vacuum. The product is dried and then recrystallized.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([S:12][CH3:13])[CH:3]=1.[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[CH3:13][S:12][C:4]1[CH:3]=[C:2]([N:1]2[CH:14]=[N:26][N:25]=[N:24]2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(OCC)OCC
Reactant: CSc1cc(N)ccc1CC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1cc(-n2cnnn2)ccc1CC(=O)O
Temperature: 100 °C

Procedure:
A solution of [4-amino-2-(methylsulfanyl)phenyl]acetic acid (200 mg, 1 mmol) and triethyl orthoformate (451 mg, 3 mmol) in 10 mL of HOAc was added sodium azide (99 mg, 1.5 mmol), and the mixture was heated to 100° C. for 3 hours. The reaction mixture was cooled to ambient temperature. The solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative TLC to give [2-(methylsulfanyl)-4-(1H-tetrazol-1-yl)phenyl]acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([NH2:15])[CH3:14]>C(Cl)Cl>[CH2:13]([NH:15][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:14]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN
Solvent: ClCCl
Product: CCNS(=O)(=O)c1ccc(OC)cc1
Yield: 112 %

Procedure:
4-Methoxybenzene-1-sulfonyl chloride (619.5 mg, 2.999 mmol) was dissolved in DCM (10 mL) and ethylamine (4.6 mL, 2.0 M in THF, 9.2 mmol) was added, and the reaction flask was put in a water bath and stirred under nitrogen. After stirring at RT over the weekend, the suspension was filtered, and the solid was washed with DCM. The filtrate was concentrated and dried under high vacuum to provide N-ethyl-4-methoxybenzenesulfonamide (723 mg, 89% yield). MS (ESI pos. ion) m/z: 216 (MH+). Calculated exact mass for C9H13NO3S: 215.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]([CH3:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:20][C:12]1[CH:11]=[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:9])[CH:15]=[CH:14][C:13]=1[NH:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1N
Yield: 92.1 %

Procedure:
A solution of 14.7 parts of (4-fluorophenyl) [4-[(1-methylethyl)amino]-3-nitrophenyl]methanone in 120 parts of ethanol was hydrogenated at 2.105Pa with 3 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated, yielding 12.3 parts (92.1%) of [3-amino-4-[(1-methylethyl)amino]phenyl](4-fluorophenyl)methanone as a residue (int. 2).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1.[CH2:33]=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:33][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1
Reactant: CC(Nc1cc(-c2cc(N3CC4CC3CN4)c3ccccc3n2)ccn1)c1ccccc1
Reactant: C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2cc(N3C[C@@H]4C[C@H]3CN4C)c3ccccc3n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 60 mg (0.14 immol) {4-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-quinolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.11 mL (1.42 mmol) formaldehyde 37% water solution, 113 mg (1.8 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+): 436 (M+H)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=1)=O.[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][CH2:15][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=2)=[CH:44][CH:43]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2C=O)cn1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (446 mg, 2.1 mmol) was added to a DCE solution (7 mL) of ethyl 3-(5-(2-formyl-4-methoxyphenyl)picolinamido)propanoate, prepared as in Example 58 (500 mg, 1.4 mmol), 4-bromoaniline (362 mg, 2.1 mmol), and AcOH (0.08 mL, 1.4 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#N)=[CH:31][CH:30]=1.C[OH:38]>C1(C)C=CC=CC=1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:38])=[CH:31][CH:30]=1
Reactant: CO
Reactant: N#Cc1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Di-iso-butylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 4-(16-bromohexadecylamino)benzonitrile (11.4 g.) under a nitrogen atmosphere. The temperature rises to 40° C. during the 30 minute addition and then the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) was added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (50 ml., 5%). After 10 minutes diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The crude product is recrystallized from dichloromethane-hexane to yield 4-(16-bromohexadecylamino)benzaldehyde as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](C=O)=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:24][CH:22]=[O:23])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1OC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(OC=O)ccc1OC(C)=O
Temperature: 50 °C
Yield: 98.9 %

Procedure:
To a solution of 4-formyl-2-methoxyphenyl acetate (15 g, 77 mmol) in CH2Cl2 (100 mL) was added m-CPBA (31 g, 154 mmol). The solution was refluxed at 50° C. for 2.5 h. The solution was washed with saturated Na2SO3 solution (50 mL), saturated Na2CO3 solution (50 mL) and brine (50 mL), dried over Na2SO4, filtrated and concentrated in vacuo to afford 16 g of crude product as a white solid, which was used for next step without further purification.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17](Cl)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:21]>>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([NH2:21])=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=C(c1ccc(C2(C(=O)Cl)CC2)cc1)c1cccs1
Agent: [OH-]
Product: NC(=O)C1(c2ccc(C(=O)c3cccs3)cc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 4.2 parts of 1-[p-(2-thenoyl)phenyl]cyclopropanecarbonyl chloride and 50 parts of ammonium hydroxide is stirred for 3 hours. The precipitated product is filtered off, washed with water, dried and crystallized from 2-propanol, yielding 2 parts of 1-[p-(2-thenoyl)phenyl]cyclopropanecarboxamide; mp. 173.7° C (dec.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[NH2:15])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc(CN)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1-c1ccc(CN)cc1

Procedure:
A solution of 2-(4-aminomethylphenyl)-4-nitroanisole (4.50 g) in methanol (200 mL) was treated with 10% palladium on carbon (200 mg). The reaction mixture was stirred under one atmosphere of hydrogen for 2.5 hours. The reaction mixture filtered through Celite, and the filter cake washed with methanol (3×25 mL). The filtrate was concentrated to dryness and the residue was purified by flash chromatography on silica gel (80 g) eluting with 0-6% methanol/0.5% triethylamine/dichloromethane. Pure fractions were combined and concentrated to give 3-(4-aminomethylphenyl)-4-methoxyaniline as an off white powder.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].[Cl:13][C:14]1[S:15][C:16]([CH2:20]Br)=[C:17]([Cl:19])[N:18]=1>C1COCC1>[Cl:13][C:14]1[S:15][C:16]([CH2:20][O:1][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])=[C:17]([Cl:19])[N:18]=1
Reactant: CCOP(=O)(CO)OCC
Reactant: Clc1nc(Cl)c(CBr)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(COCc1sc(Cl)nc1Cl)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of diethyl hydroxymethylphosphonate (1.2 mmol) in THF (10 mL) at 0° C. was added 60% sodium hydride (1.1 mmol) and allowed to stir for 15 minutes before adding 2,4-dichloro-5-(bromomethyl)thiazole (1 mmol). The mixture was warmed to room temperature and allowed to stir for 3 h. The reaction was extracted and chromatographed to yield 2,4-dichloro-5-(diethylphosphonomethoxymethyl)thiazole.