Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][P:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:4][CH3:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:19]Cl)([CH3:15])([CH3:14])[CH3:13]>>[CH3:5][O:4][P:3]([CH2:19][C:18]1[CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: COP(OC)c1ccccc1
Product: COP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccccc1
Temperature: 110 °C
Yield: 82.9 %

Procedure:
A mixture of 5 grams (29 mmol) of dimethylphenylphosphonite with 7.5 grams (29 mmol) of 3,5-di-tert-butyl-4-hydroxybenzyl chloride (CAS REG #955-01-1) is heated at 110° C. for 1 hour and cooled to obtain a white solid. The resultant solid is crystallized from 100 mL of hexane to give 9 grams (83% yield) of (3,5-di-tert-butyl-4-hydroxy-benzyl)-phenyl-phosphinic acid methyl ester as a white solid mp 112-114° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27]Br.CCOCC>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:9][C:2]=1[O:1][CH2:27][C:23]1[O:22][CH:26]=[CH:25][CH:24]=1)#[N:5]
Reactant: N#Cc1ccc(Nc2nccs2)cc1O
Reactant: BrCc1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#Cc1ccc(Nc2nccs2)cc1OCc1ccco1
Yield: 57 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-hydroxy-4-(thiazol-2-ylamino)benzonitrile (70 mg, 0.32 mmol) and Cs2CO3 (105, 0.32 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (0.60 mL, 0.32 mmol) at room temperature. Reaction control by TLC showed full conversion after 7.5 hrs. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 57% yield (54 mg).
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[NH2:16][C@@H:11]1[C:10](=[O:17])[N:9]2[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][C@@H:8]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1CCC2CCCCC(N)C(=O)N21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CCCC[C@H]2CC[C@@H](C(=O)O)N2C1=O
Reaction time: 8 h

Procedure:
The crude 6-amino-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 18, obtained from the previous reaction is dissolved in a mixture of THF:water (3:1) (40 mL) and treated with a catalytic amount of LiOH. The reaction solution is allowed to stir overnight then concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: O=C(C1CCCc2c1c1ccccc1n2CCOCc1ccccc1)N1CCCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(C1CCCc2c1c1ccccc1n2CCO)N1CCCCC1
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a solution of [9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (22) (600 mg, 1.4 mmol) in methanol (15 mL) was added a slurry of Pd/C (200 mg) in methanol (10 mL). The mixture was placed on the Parr hydrogenator and shaken for 24 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and concentrated in vacuo. The crude material was triturated to afford 332 mg (71%) of [9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (23) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC21.2, 21.9, 24.7, 27.4, 36.4, 43.4, 45.0, 47.0, 60.9, 107.8, 109.0, 117.7, 119.0, 120.7, 126.6, 136.2, 137.2, 173.5
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[CH2:14]([C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH:23]=[CH:5][C:6]#[N:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1Cc1ccccc1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 10.5 g (0.437 mole) of mineral oil free sodium hydride in 1.2 liters of tetrahydrofuran was added dropwise 58.4 g (0.328 mole) of diethylcyanomethyl phosphonate. After the hyrogen evolution had ceased ca 60 min, 69.4 g (0.3 mole) of 2-benzyl-4-chlorobenzaldehyde, in 75 ml of tetrahydrofuran was added dropwise. The mixture was stirred overnight at room temperature. The tetrahydrofuran solution was decanted, and concentrated at room temperature. The residue was partitioned between 2 liters of water and 1.5 liters of ether. The ether solution was separated, washed with water, and dried with sodium sulfate. The ether was removed at reduced pressure to give a yellow oil which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH3:11])[CH:9]=[O:10].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)\[CH2:34][CH2:35]C(O)=O)=[CH:28][CH:27]=1>O1CCCC1>[CH3:11][NH:8][C:9](=[O:10])[CH2:35][CH2:34]/[C:33](=[N:32]\[O:31][CH2:30][C:29]1[CH:45]=[CH:46][C:26]([O:25][CH2:24][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:17][C:13]=2[CH3:12])=[CH:27][CH:28]=1)/[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixture of a 40% aqueous methylamine (20 ml) and ethyl acetate (30 ml) at 0° C. After stirred at room temperature for 1 hour, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain E-N-methyl-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutaneamide (466 mg, yield 65%) as colorless crystals. m.p. 141-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1cc(C)ccc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(C)ccc1F

Procedure:
(RS)-(2-Fluoro-5-methyl-phenyl)-methoxy-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-5-methyl-phenyl)-2-methoxy-acetamide. Colorless amorphous solid. MS 313.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[F:16][C:17]([F:24])([F:23])[C:18]([NH:20][CH2:21]O)=[O:19]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:21][NH:20][C:18](=[O:19])[C:17]([F:24])([F:23])[F:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(NCO)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To a solution of 2-chlorobenzoic acid (500 mg, 3.49 mmol) in cone. H2SO4 was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (547 mg, 3.49 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and the precipitate obtained, was collected by filtration, dried and the re-crystallized from toluene/butan-2-one (7:1) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 13.47 (br s, 1H), 10.06 (br s, 1H), 7.71 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.43 (d, J=9.9 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H); MS (m/z): 280.18 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:24]([OH:26])=[CH:23][CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:30]([O:35][CH3:36])(=[O:34])[C@H:31]([CH3:33])O>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:31]([CH3:33])[C:30]([O:35][CH3:36])=[O:34])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: COC(=O)[C@H](C)O
Product: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 69 %

Procedure:
4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-ol was reacted with (S)-methyl lactate as described in Example 5, starting material to give methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (760 mg, 69%); Mass spectrum 472.
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH:27]=[CH:28][C:29]([O:31]C)=[O:30])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[S:15][C:9]=2[N:8]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:7]1=[O:37]>O1CCCC1>[CH3:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:24])[F:25])[S:15][C:9]=2[N:8]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:7]1=[O:37]
Reactant: COC(=O)C=Cc1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C=CC(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
Lithium hydroxide monohydrate (0.20 g) and water (6 ml) were added to a solution of 3-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidin-5-yl]-2-propenoic acid, methyl ester (0.20 g) in tetrahydrofuran (7 ml) and stirred at room temperature for 20 hours. The solution was neutralised to pH7 and extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a white solid (0.10 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([C:22](O)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH2:23])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(C(C)(O)c4ccccc4)cc3c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of the product of step A (60.0 mg, 0.14 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (0.5 mL). After stirring for 2 h at ambient temperature the reaction mixture was quenched with 10% sodium bicarbonate solution (15 mL) and extracted with dichloromethane. The organic extract was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 dichloromethane/methanol) affording 6-chloro-8-(1-phenylvinyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (40 mg, 74%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.36-7.31 (m, 5H), 7.24-7.20 (m, 2H), 5.47 (d, J=11.4 Hz, 2H), 3.92 (t, J=1.8 Hz, 2H), 3.24 (t, J=5.7 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[C:6]([O:14][CH3:15])=[N:5]2.[CH:16](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:16]=[N:13][N:12]=[C:7]1[C:6]([O:14][CH3:15])=[N:5]2
Reactant: CCOC(OCC)OCC
Reactant: COc1nc2cc(Cl)ccc2nc1NN
Product: COc1nc2cc(Cl)ccc2n2cnnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 1.4 g. (0.0062 mole) of 6-chloro-2-hydrazino-3-methoxyquinoxaline and 20 ml. of triethyl orthoformate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 1.0 g. (69%) of pure 7-chloro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 250°-252° C.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[C:15]([O:25][CH:26]([CH3:30])[C:27]([OH:29])=O)=[N:16][C:17]([CH3:24])=[N:18][C:19]=1[C:20]([F:23])([F:22])[F:21].[NH2:31][C:32]([CH3:39])([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]#[N:34].O>O1CCCC1>[Cl:13][C:14]1[C:15]([O:25][CH:26]([CH3:30])[C:27]([NH:31][C:32]([C:33]#[N:34])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])=[N:16][C:17]([CH3:24])=[N:18][C:19]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Cc1nc(OC(C)C(=O)O)c(Cl)c(C(F)(F)F)n1
Reactant: CC(C)(C)C(C)(N)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(OC(C)C(=O)NC(C)(C#N)C(C)(C)C)c(Cl)c(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (0.8 g) was added to a solution containing 2-(5-chloro-2-methyl-6-trifluoromethylpyrimidin-4-yloxy)propionic acid (1.0 g) dissolved in tetrahydrofuran (30 ml), at room temperature, and the mixture was stirred for 30 min. Subsequently, 2-amino-2,3,3-trimethylbutyronitrile (0.5 g) was added to the mixture, and the reaction mixture was stirred for 10 hours at room temperature. After completion of the reaction, water was added to the resulting mixture and the organic layer was extracted with ethyl acetate, and subsequently dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 0.3 g of the A-configurational diastereomer having a melting point of 1 33° C. to 1 34° C. and 0.2 g of the B-configurational diastereomer having a melting point of 137° C. to 139° C.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[CH2:3][O:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[CH2:1][O:2][CH2:3][C:4]=3[CH:9]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc2c(c1)COC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)COC3)cc1
Yield: 97.4 %

Procedure:
A solution of 1,3-dihydro-2-benzofuran-5-ol (Intermediate 73, 100 mg, 0.734 mmol), 1-fluoro-4-nitrobenzene (109 mg, 0.771 mmol) and potassium carbonate (508 mg, 3.67 mmol) in acetonitrile (10 ml) was stirred under argon at 100° C. in a closed vial for 2 hours. The solid was filtered and washed with dichloromethane. The organic phase was concentrated under vacuum to afford title compound (184 mg, 96% yield)
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(Cl)CCl.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:21][CH:20]=1>>[CH3:5][O:4][N:3]([CH3:2])[C:27](=[O:29])[CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)N(C)OC)cc1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (5.41 g, 55.5 mmol), EDC (12.77 g, 66.6 mmol), followed by triethylamine (17 mL, 122 mmol) were added to a cooled 0° C. solution of 3-(4-methoxyphenyl)propionic acid (10 g, 55.5 mmol). The reaction mixture was stirred for 15 h under N2 and then concentrated. The residue was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by silica gel chromatography (40% EtOAc in hexanes) to give a clear oil (10.6 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([NH2:17])[C:10]([NH2:16])=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[O:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]3[NH:16][C:20]([C:19]([F:24])([F:23])[F:18])=[N:17][C:9]3=2)[CH2:14][CH2:15]1)=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C1CCc2ccc(N)c(N)c2O1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Yield: 65 %

Procedure:
A solution of ethyl-7,8-diamino-chroman-2-carboxylate (927 mg, 3 mmol) in trifluoroacetic acid (20 mL) was heated to reflux for 6 hours and then concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and then washed with saturated NaHCO3 solution (30 mL) and water (2×30 mL), dried over anhydrous Na2SO4. Purification by flash chromatography (30% CH2Cl2-hexanes) afforded 612 mg (65% yield) of the title compound as white solid: mp 134° C.; 1H NMR (400 MHz, CDCl3):[tautamer a]: δ:1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.14 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 14.09 (bs, 1H). [tautamer b]: δ1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.03 (m, 1H), 7.07 (s, 2H), 13.77 (bs, 1H); IR 3450, 3250, 2980, 2600, 1730, 1600, 1500, 1230 cm−1.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4]C1C=CC(C2C=CC(O)=CC=2)=CC=1.CC(CC)CO[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Br:37])[CH:31]=2)=[CH:26][CH:25]=1.BrBr>O1CCOCC1>[CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4][C:31]1[C:32]([Br:37])=[C:33]([OH:36])[CH:34]=[CH:35][C:30]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=1
Reactant: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCC(C)COc1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: BrBr
Solvent: C1COCCO1
Product: CCC(C)COc1c(-c2ccccc2)ccc(O)c1Br
Temperature: 40 °C

Procedure:
4'-(2-Methylbutyloxy)-4-hydroxybiphenyl (15 g) obtained in Example 1, (i) was dissolved in 1,4-dioxane (50 ml), followed by dropwise adding a mixture of bromine (10.5 g) and 1,4-dioxane (140 ml), heating on a water bath at 40° C. for 4 hours with stirring, thereafter distilling off 1,4-dioxane under reduced pressure, adding toluene (300 ml) to the remaining solution, adding a 10% aqueous solution of sodium hydrogen sulfite till the color of bromine disappeared, three times washing with saturated aqueous solution of NaCl to make the liquid neutral, drying and distilling off toluene to obtain a raw product of 4'-(2-methylbutyloxy-3-bromo-4-hydroxybiphenyl (21 g).
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+].O.O>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][S:1][C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:22][CH:21]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: O=c1[nH]c(S)nc2ccccc12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSc2nc3ccccc3c(=O)[nH]2)cc1
Yield: 80.3 %

Procedure:
A solution of 2-mercapto-4(3H)-quinazolinone (1.78 g), 4-(4-chlorobenzoyl)benzyl bromide (3.07 g) and 1N-sodium hydroxide/water (10.5 ml) in ethanol (20 ml) was stirred at room temperature for 30 minutes. To the reaction mixture was added water and the resulting precipitate was collected by filtration, washed with water, methanol and ethyl acetate, dried, and recrystallized from ethyl acetate to provide the title compound as colorless solid (3.24 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:39][CH2:40][NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.O1CCCC1>[CH2:44]([O:43][C:42](=[O:51])[NH:41][CH2:40][CH2:39][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:17][CH:16]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: Oc1ccc(-c2nc(-c3ccccc3)cs2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCOc1ccc(-c2nc(-c3ccccc3)cs2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
4-(4-Phenyl-thiazol-2-yl)-phenol (516 mg, 2.03 mmol) was dissolved in toluene (6.8 ml), and triphenylphosphine (786 mg, 3.00 mmol) and benzyl N-(2-hydroxyethyl)-carbamate (585 mg, 3.00 mmol) were added. The solution was cooled to about 0° C. and 1,1-(azodicarbonyl)-dipiperidine (757 mg, 3.00 mmol) was added. The mixture was allowed to stir for about 10 minutes at about 0° C. and was then allowed to warm to room temperature. An additional 6.8 ml of toluene and 6.8 ml of tetrahydrofuran were added to the viscous solution. The reaction mixture was stirred for about forty-eight hours, and then the solids were filtered off and rinsed with a minimum volume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to a semisolid which was then purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride) to give 396 mg of pure product (45% yield). LRMS ([M+H]+)=430.9.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)(=[O:4])[NH:2][NH2:3].[C:18](OC)(=[O:21])[NH:19][NH2:20]>CO>[NH:19]([C:18]([NH:3][NH:2][C:1]([O:5][CH:6]1[CH2:7][C:8]([CH3:17])([CH3:16])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]1)=[O:4])=[O:21])[NH2:20]
Reactant: COC(=O)NN
Reactant: CON1C(C)(C)CC(OC(=O)NN)CC1(C)C
Solvent: CO
Product: CON1C(C)(C)CC(OC(=O)NNC(=O)NN)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound of Example 28 (1 mole) with methyl carbazate (1 mole) by refluxing the reaction mixture in methanol.