Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH:10]=[C:9]1[CH3:16]>C(O)CO>[O:17]=[C:5]([CH2:6][CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH:10]=[C:9]1[CH3:16])[CH2:4][C:3]([OH:18])=[O:2]
Reactant: COC(=O)CC(=O)CCC1C(C)=CCCC1(C)C
Solvent: OCCO
Product: CC1=CCCC(C)(C)C1CCC(=O)CC(=O)O
Temperature: 180 °C

Procedure:
A mixture of 25.2 g 3-oxo-5-(2,6,6-trimethyl-cyclohex-2-enyl)-pentanoic acid methyl ester and 4.3 g ethylene glycol was slowly heated to 180° C. while distilling off methanol. On completion, the reaction mixture was chromatographed over silica gel to yield a colourless liquid.
Reaction SMILES: [CH2:1]([C:8]([N:26]([CH3:28])[CH3:27])([CH2:24][CH3:25])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]O)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:10])[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(Br)(Br)(Br)[Br:49]>C(Cl)Cl>[CH2:1]([C:8]([N:26]([CH3:28])[CH3:27])([CH2:24][CH3:25])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][Br:49])=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(OCCCO)c(OC)c1)N(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(OCCCBr)c(OC)c1)N(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
14.3 g (37.1 mmol) of 2-benzyl-2-dimethylamino-1-[4-(3-hydroxy-propoxy)-3-methoxy-phenyl]-butan-1-one are dissolved in 200 ml of methylene chloride, and 10.7 g (40.8 mmol) of triphenylphosphine and 13.5 g (40.8 mmol) of carbon tetrabromide are added at 0° C. successively. The solution is stirred at 0° C. for 0.5 h. Then the solution is concentrated to give the crude product, which is purified by column chromatography on silica gel with ethyl acetate-hexane (20:80) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.69 (t, 3H), 1.83-1.92 (m, 1H), 2.03-2.13 (m, 1H), 2.38 (s, 6H), 2.38-2.45 (m, 2H), 3.17-3.25 (m, 2H), 3.64 (t, 2H), 3.88 (s, 3H), 4.22 (t, 2H), 6.86 (d, 1H), 7.15-7.28 (m, 5H), 7.93 (d, 1H), 8.20 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:3]=1[C:19]([OH:21])=O.[F:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH2:40])[CH:38]=3)[NH:33][N:32]=2)[CH:26]=[C:27]([F:29])[CH:28]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH:40][C:19]([C:3]4[CH:4]([C:9]5[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=5)[NH:5][C:6](=[O:8])[NH:7][C:2]=4[CH3:1])=[O:21])[CH:38]=3)[NH:33][N:32]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(C(F)(F)F)cc2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](O)[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[C:5]1=[O:28])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:30]>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccccc32)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A suspension of 11.4 g of 1-acetyl-3-(1-hydroxy-1-(4-acetylamino-3-nitro-phenyl)methylene)-2-indolinone (educt VII.21) and 9.37 g of phosphorus pentachloride in 200 ml dioxane is stirred for 4 hours at 100° C. After the addition of a further 2.0 g of phosphorus pentachloride the mixture is stirred for a further 3 hours at 100° C. Then the solvent is distilled off, the residue is stirred with 100 ml of ethyl acetate, suction filtered, washed with ethyl acetate and dried at 60° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=1)[CH2:8][CH2:7]2.CS(O[CH2:32][CH:33]1[CH2:37][O:36][C:35]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)([CH2:38][Br:39])[O:34]1)(=O)=O>CN(C)C=O>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([C:35]2([CH2:38][Br:39])[O:34][CH:33]([CH2:32][O:3][C:4]3[CH:5]=[C:6]4[C:11](=[CH:12][CH:13]=3)[CH2:10][N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:17][CH:16]=3)[CH2:8][CH2:7]4)[CH2:37][O:36]2)=[CH:45][CH:44]=1
Reactant: CS(=O)(=O)OCC1COC(CBr)(c2ccc(Cl)cc2)O1
Reactant: Oc1ccc2c(c1)CCN(Cc1ccc(-c3ccccc3)cc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(CBr)OCC(COc3ccc4c(c3)CCN(Cc3ccc(-c5ccccc5)cc3)C4)O2)cc1
Reaction time: 1 h

Procedure:
1.1 g of sodium hydride (50% suspension in oil) are added in portions, with cooling, to a solution of 6.3 g of 6-hydroxy-2-(4-phenylbenzyl)-1,2,3,4-tetrahydroisoquinoline in 100 ml of dry dimethylformamide. The mixture is stirred at 50° for 1 hour and then 7.7 g of (2RS,4SR)-2-(4-chlorophenyl)-2-bromomethyl-1,3-dioxolan-4-ylmethyl methanesulfonate (preparation as in European Offenlegungsschrift No. 0,050,298) are added. The mixture is stirred at 80° C. for 5 hours and cooled, the solvent is removed under oil pump vacuum, and the residue is taken up with a mixture of water and methylene chloride. After washing twice with water and drying over magnesium sulfate, the solution is evaporated in a rotary evaporator, and the residue is chromatographed on silica gel with a mixture of methylene chloride and ethyl acetate in the ratio 3:1. 7.0 g of a highly viscous oil (58% of theory) are obtained.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 120 °C

Procedure:
A mixture of 722 mg of 4-(n-hexadecylamino)benzoic acid, 736 mg of glycerol, and 412 mg of p-toluene sulfonic acid is heated for 4 hours at 120° C, allowed to cool, and then is treated with ether and 2% aqueous sodium carbonate solution. Filtration affords a white solid which is recrystallized from chloroform to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, mp 112° C.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([F:13])[CH:12]=1.[CH:15](N1CCOCC1)=[O:16]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([F:13])[C:12]=1[CH:15]=[O:16]
Reactant: Cc1cc(F)cc(Cl)c1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)c(C=O)c(Cl)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under Ar, a 2.5M solution of n-BuLi (6.0 mL, 15.0 mmol) was added slowly to a solution of 3-chloro-5-fluorotoluene (2.0, 13.8 mmol) in THF (20 mL) cooled in a dry ice/acetone bath at approximately −70° C. After the addition was complete, the reaction was stirred for 1 h at approximately −70° C. and a solution of N-formylmorpholine (2.3 g, 2.0 mmol) in THF (10 mL) was added dropwise. After stirring for 10 min, the reaction was allowed to warm to rt with stirring over 1 h, then cooled to −30° C. and quenched by the addition of H2O then 1M citric acid. The mixture was allowed to warm to rt with stirring and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O, dried with MgSO4 and concentrated to yield the title compound as an oil which solidified on standing (2.2 g, 12.8 mmol).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[NH:22][C:21](=[O:23])[CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][C:37]([NH:22][C@@H:18]([C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:19][CH2:20][CH2:21][OH:23])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CC[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5R)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (12 g) in tetrahydrofuran (THF) (200 ml) were added butyllithium (26 ml, 1.6N solution in hexane) and benzyloxycarbonyl chloride (6.8 ml) at −78° C. under N2. The mixture was stirred for 1 hour at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo, the residue was dissolved in THF (200 ml), and 1N-NaOH (87 ml) was added at 0° C. After being stirred for 12 hours at room temperature, the solvent was evaporated in vacuo. After the residue was partitioned between hexane and water, aqueous layer was adjusted to pH=2 and extracted with ethyl acetate. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was dissolved in THF (200 ml). To the solution were added triethylamine (9.0 ml) and ethyl chloroformate (5.0 ml) at −5° C. under N2 and the mixture was stirred for 1 hour at the same temperature. After the filtration, the solution was dropwise added to the solution of NaBH4 (3.2 g) in a mixture of THF (100 ml) and water (100 ml) at 0° C. and stirred for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (13 g).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][OH:30].[H-].[Na+]>CN(C)C=O.O>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[O:30][CH2:29][C@H:25]3[CH2:26][CH2:27][CH2:28][N:24]3[C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: OC[C@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2OC[C@H]2CCCN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a solution of 2,5-difluorobenzoic acid (1.0 g; 6.325 mmol) in dimethylformamide (5 ml) was added 1,1′-carbonyldiimidazole (1.07 g; 6.64 mmol) and the solution stirred at room temperature for 1 h, followed by the addition of (R)-(−)-2-pyrrolidinemethanol (0.655 ml; 6.64 mmol). The reaction. was stirred at room temperature overnight whereupon 60% sodium hydride in mineral oil (0.507 g; 12.7 mmol) was carefully added and the mixture was heated to 120° C. for 2 h. The reaction was cautiously diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated to give the crude product. Trituration with ether and filtration afforded the title compound (0.29 g). M.p.: 85-86° C.; EIMS: m/z=222.2[M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][CH2:12][Cl:13].[OH-].[K+]>C(O)C>[Cl:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: ClCCBr
Reactant: N#Cc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(OCCCl)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A suspension of 3-hydroxybenzonitrile (5.00 g, 42.0 mmol), 1-bromo-2-chloroethane (9.00 g, 62.8 mmol) and potassium hydroxide (2.5 g, 44.6 mmol) in ethanol (100 mL) was stirred at 90° C. for 24 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with diethyl ether and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (2%-50% ethyl acetate/hexane) to give the title compound as a colorless oil (1.39 g, 18%).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClC(Cl)Cl>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:26](=[O:27])[CH2:25][Cl:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
For protecting thiol groups, take 2-thioethylamine hydrochloride and triphenylmethanol as reactants and boron trifluoride-diethyl ether complex is used as a catalyst to get 2-[(triphenylmethyl)thio]ethylamine. The reaction temperature is 72 degrees Celsius and the reaction time is 4 hours. Step (2): Use 2-[(Triphenylmethyl)thio]ethylamine and chloroacetyl chloride to carry out the amidation reaction in trichloromethane solution so as to produce N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide. Step (3): Take 2-[(Triphenylmethyl)thio]ethylamine, N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide and use triethylamine used as a reagent to carry out the substitution reaction in dichloromethane solution. Thus an amine-amide-thiol ligand is produced. The reaction temperature of the substitution reaction is 55° C. and the reaction time is 48 hours. Step (4): Dissolve 6-bromohexanoic acid and thionyl chloride in absolute methanol solution to carry out the esterification reaction and get methyl 6-bromohexanoate. The reaction temperature of the esterification reaction is 25° C. and the reaction time is 24 hours. Step (5): Take the amine-amide-thiol ligand and methyl 6-bromohexanoate and use sodium hydroxide (NaOH) as a reagent to carry out the substitution reaction in acetonitrile solution and get methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate. The reaction temperature of the substitution reaction is 85° C. and the reaction time is 24 hours. Step (6): Hydrolyze methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate in alkaline methanol solution to get 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenyl-methyl)thio]dodecanoic acid.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:11][O-:12].[Na+].O>CN(C=O)C.[Cu](I)I>[CH3:11][O:12][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccsc12
Reactant: C[O-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2ccsc12
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a solution of 7-bromobenzo[b]thiophene (10.0 g, 46.9 mmol) in dry DMF (234 mL) is added copper iodide (8.90 g, 46.9 mmol), followed by the addition of sodium methoxide (30% in MeOH, 176 mL, 938 mmol) at room temperature under nitrogen atmosphere. The mixture is heated at 100° C. for 2 hours and cooled to room temperature. Water (400 mL) is added and the mixture is extracted with diethyl ether (4×200 mL). Organic layers are washed with cooled water (3×75 mL), saturated aqueous sodium chloride (100 mL), dried (MgSO4), and concentrated to give the title compound as yellow oil (7.58 g, 98% yield).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([OH:13])=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=1>>[OH:16][CH:14]([C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]=1[OH:13])[CH3:15]
Reactant: CC(=O)c1cc(Cl)cc(C(C)=O)c1O
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(Cl)cc(C(C)O)c1O

Procedure:
Sodium borohydride was added in small portions to a methanolic solution of 4-chloro-2,6-diacetylphenol (5 g) until the colour was completely discharged. The solvent was removed by distillation under reduced pressure to give a white solid which was washed with water and dilute hydrochloric acid. The product, 2,6-bis(1-hydroxyethyl)-4-chlorophenol, was obtained as a pale yellow gum (4.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2>CO.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2
Reactant: Nc1c([N+](=O)[O-])ccc2nc[nH]c(=O)c12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2nc[nH]c(=O)c2c1N
Yield: 98.5 %

Procedure:
A suspension of the above amine (250 mg, 1.21 mmol) in MeOH (50 mL) was hydrogenated over 10% Pd/C (50 mg) at 50 psi for 5 h. The catalyst was removed by filtration and the filtrate concentrated to yield 5,6-diaminoquinazolin-4-one (210 mg, 98% crude).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([C:33](O)=[O:34])[CH:12]=[C:13]2[C:18]=1[NH:17][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=1)[C:15]([CH3:32])([CH3:31])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:12]=[C:13]2[C:18]=1[NH:17][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:20]=1)[C:15]([CH3:31])([CH3:32])[CH2:14]2
Reactant: CC1(C)Cc2cc(C(=O)O)cc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)cc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (118 mg, 2.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (285 mg, 3.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.3 mmol) and 1,1′-carbonyldiimidazole (98 mg, 0.6 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (43 mg, 30%) as a white solid: LC/MS m/e calcd for C23H28ClN3O4S (M+H)+: 479.05, observed: 478.1.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[Cl:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=1[NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1C(N)=O>O1CCCC1>[Cl:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=1[NH:32][C:33]1[CH:34]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=O)c1Cl
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2)c1Cl
Reaction time: 72 h
Yield: 70.6 %

Procedure:
Lawesson's Reagent (2.67 g, 6.60 mmol) is added to a colorless solution of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzamide (2.83 g, 9.60 mmol) in 50 ml of tetrahydrofuran at room temperature. The resulting mixture is stirred under nitrogen for three days. The clear yellow solution is then heated at reflux for two hours. The solution is concentrated in vacuo and chromatographed, eluting with hexane:ethyl acetate (gradient of 6:1 to 3:1), providing 1.71 g (57%) of a pale yellow solid.
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=O.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH2:18]([N:25]1[C:3]2[CH:4]=[CH:5][Se:1][C:2]=2[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccc[se]2)cc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)cc1

Procedure:
Compound 63 (5.86 g, 0.02 mole), benzylhydrazine 50 (4.88 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 67. Yield: 2.49 g (31.4%); white crystals; mp 150-153° C.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCCNc1ccccn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCCCN(Cc1ccccc1)c1ccccn1
Yield: 36.3 %

Procedure:
Sodium hydride (1.6 g) was disolved in DMSO (35 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(4-aminobutylamino)pyridine (10 g) in DMSO (10 ml) added at room temperature. Benzyl bromide (10.35 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 25°-30° C. After a further 2 hr water (200 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with 2N hydrochloric acid and the aqueous layer basified to pH 4. After extracting with chloroform the pH was raised to 14 and again extracted with chloroform. After stripping the latter extract the residue was taken up in ether and the solution washed with water. The ether layer was dried (K2CO3) and stripped to give 2-[N-(4-aminobutyl)-N-benzylamino]pyridine (5.61 g) as an oil which was used without further purification. (ii) 2-[N-(4-aminobutyl)-N-benzylamino]pyridine (1 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.82 g) were heated together under reflux in pyridine (5 ml) for 22 hr. After cooling the mixture was stripped, the residue triturated with ether and crystallised from ethanol/ether to give 2-[4-(N-benzyl-N-pyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 0.4H2O, 1.15 g (80%) mp softens 98°-100° C. melts 120°-22° C. (from ethanol/water).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6]([Cl:12])=[O:7]
Reactant: O=C(O)CC1CC1(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC1CC1(F)F

Procedure:
A mixture of 39.8 g (0.29 mmol) 2,2-difluorocyclopropylacetic acid and 38.5 ml (0.53 mmol) thionyl chloride was heated under reflux for 5 hours. Excess thionyl chloride was distilled and the residue was distilled in vacuo.