Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[H-].[Na+].C1(S(OC)=O)C=CC=CC=1>O1CCCC1.O>[OH:15][C:10]1[C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:2]([CH3:1])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Agent: COS(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c2ccccc2c2c(O)cccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of 9-methyl-4-oxo-1,2,3,4-tetrahydrocarbazole (prepared by the methods described by Osuka, A.; Mori, Y.; Suzuki, H. Chem. Lett. 1982, 2031-2034; and Elz, S.; Heil, W. L. Biorg. Med. Chem. Lett. 1995, 5, 667). (0.20 g, 1.0 mmol) in 3 mL tetrahydrofuran was sonicated and heated to 50° C. Sodium hydride (60% dispersion in mineral oil; 0.07 g, 1.8 mmol) was added in one portion. Sonication and heating was continued for 1 hour and then methyl phenylsulfinate (0.2 g, 1.2 mmol) was added in one portion. The mixture was diluted after 3 hours with retrahydrofuran and water to give a homogenous solution. The solution was concentrated by rotary evaporation and the residue was partitioned between dichloromethane and water. The organic layer was washed with sodium bicarbonate and brine and then dried over magnesium sulfate, filtered and concentrated. The residue was Dissolved in dioxane and heated to reflux for 1 hour. The mixture was concentrated and partitioned between dichloromethane and water. The organic fraction was dried over magnesium sulfate, filtered and concentrated. The mixture was purified by silica gel chromatography (20% EtOAc, hexanes) to 0.075 g of the desired product (38%). TLC Rf=0.49 (20% ethyl acetate, hexanes); 13C NMR (CDCl3) d 151.5, 142.6, 140.1, 126.0, 124.6, 122.4, 121.5, 118.8, 110.7, 107.7, 104.6, 101.0, 28.9; mass spectrum, m/z (FD, M+1) 198.
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:37]>[Pd]>[CH2:34]([O:33][CH2:32][CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:13]2[CH2:14][C@H:15]([OH:20])[C@@H:16]([OH:19])[C@H:17]([OH:18])[C@@H:12]2[C:10]([OH:37])=[O:11])(=[O:22])=[O:23])=[CH:29][CH:28]=1)[CH3:35]
Reactant: CO
Reactant: CCOCCOc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Product: CCOCCOc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The above compound (6) (1.66 g) was dissolved in methanol (70 mL) and 10% Pd—C (350 mg) was added, and then the mixture was stirred under a hydrogen atmosphere at 40° C. for one hour. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=10:1→5:1) to obtain the titled compound (815 mg) as a colorless powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]1[N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1)([CH3:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37].Cl>ClCCl.CN(C)C=O>[CH2:35]([NH:39][C:23]([CH:19]1[CH2:20][C:21](=[O:22])[N:17]([CH:11]2[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][CH:10]2[CH:7]([CH3:8])[CH3:9])[CH2:18]1)=[O:25])[CH:36]([CH3:38])[CH3:37]
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Reactant: CC(C)CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CNC(=O)C1CC(=O)N(C2CC(C)CCC2C(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
Oxalyl chloride ((COCl)2) (350 mg, 2.8 mmol, 240 mL) and dimethylformamide (DMF; (CH3)2NC(O)H catalytic) (20 μL) were carefully added to 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (obtained as in EXAMPLE II, 500 mg, 1.87 mmol) suspended in anhydrous dichloromethane (CH2Cl2) (10 mL). The reaction mixture slowly turned into a homogeneous solution over about 3 hours, which was then concentrated in vacuo to remove (COCl)2. The resulted raw oil was dissolved in anhydrous CH2Cl2 and subsequently added dropwise to a mixture of N,N-diisopropylethylamine (DIEA; (CH3CH2)3N) (290 mg, 2.24 mmol) and isobutylamine (H2NCH2CH(CH3)2) (160 mg, 2.24 mmol) at 0° C. with stirring. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into HCl (1 N) and extracted with CH2Cl2. The organic phases were collected, washed with brine, dried, and evaporated. Column chromatography with ethyl:acetate (50:50) provided 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid isobutyl-amide (390 mg, 1.2 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O.CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]([CH:11]2[CH2:12][CH2:13]2)[CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CC(C)(C)OC(=O)CCCNC1CC1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCN(c1ccc(Br)cc1C=O)C1CC1
Yield: 23 %

Procedure:
5-bromo-2-fluorobenzaldehyde (20 g), t-butyl N-cyclopropyl-4-aminobutyrate (14.5 g), sodium carbonate (13.8 g), water (70 ml) and DMSO (70 ml) were heated at 80° C. for 5 days and at 110° C. for 3 days, which was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give t-butyl N-(4-bromo-2-formylphenyl)-N-cyclopropyl-4-aminobutyrate (6.4 g) as red oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-])=O.NC1C=CC(O)=CC=1F>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: Nc1ccc(O)cc1F
Product: COc1cc(N)ccc1O
Yield: 63.2 %

Procedure:
This compound was prepared from 4-nitro-2-methoxyphenol (10.0 g, 59.1 mmol) in the manner described for 4-amino-3-fluorophenol, affording 5.20 g (56.9%) of 4-amino-2-methoxyphenol as a dark brown solid. 1H-NMR (DMSO-d6) δ 7.79 (br s, 1H), 6.44 (d, J=8.1 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 5.97 (dd, J=8.4, 2.4 Hz, 1H), 4.43 (br s, 2H), 3.65 (s, 3H); TLC (66% EtOAc/Hex), Rf=0.42.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[C:18]1([S:24]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Mix 3-amino-2-carbethoxy-4,6-dichloroindole (3.31 g, and anhydrous pyridine (50 mL). Add, by dropwise addition, phenylsulfonyl chloride (2.35 g, 13.33 mmol). Stir for 48 hours at room temperature. Pour into 1N hydrochloric acid (500 mL), extract with ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound (3.15 g, 63%); mp 245°-7° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:26](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:26])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CC(c1ccc(Br)cc1)C1CCCC1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=388.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Cl.Cl[CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][CH2:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]#[N:11]
Reactant: COc1cccc(CC#N)c1
Reactant: CN(C)CCCCl
Agent: Cl
Product: COc1cccc(C(C#N)CCCN(C)C)c1

Procedure:
reacting 3-methoxybenzeneacetonitrile with 3-chloro-N,N-dimethylpropanamine, monohydrochloride in the presence of a base to obtain α-[3-(dimethylamino)propyl]-3-methoxybenzeneacetonitrile
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: c1cncc(CN2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.030 g, 0.14 mmol) and isopropanol (3.0 ml) was added 1-[(3-pyridyl)-methyl)-piperazine (0.028 g, 0.16 mmol) followed by diisopropylethylamine (0.03 ml, 0.18 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature, and diluted with isopropanol (2.5 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.036 g, 75%); 1H-NMR (500 MHz, DMSO-d6) 3.06 (br t, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2pyridyl), 6.95 (s, 2H, NH2), 7.36 (dd, J=7.8, 5.4 Hz, 1H, pyridine 5-H), 7.73 (dt, J=7.8, 1.8 Hz, 1H, pyridine 4-H), 8.07 (s, 1H, 6-H), 8.47 (dd, J=4.8, 1.6 Hz, 1H, pyridine 6-H), 8.51 (d, J=1.7 Hz, 1H, pyridine 2-H);
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7](=[O:18])[CH:6]([CH3:19])[N:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2.FC(F)(F)C(O)=O>C(O)C(F)(F)F.C(OCC)(=O)C>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:2]3[N:11]=[CH:10][C:9]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:7](=[O:18])[CH:6]([CH3:19])[N:5]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:4]=4[N:3]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CC1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1c1ccccc1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC1C(=O)N(c2ccccc2)c2cnc(Nc3ccc4[nH]ncc4c3)nc2N1c1ccccc1
Temperature: 125 °C
Yield: 40 %

Procedure:
To a mixture of 2-chloro-7-methyl-5,8-diphenyl-7,8-dihydropteridin-6(5H)-one (175 mg, 0.5 mmol), 5-aminoindazole (99 mg, 0.75 mmol), in trifluoroethanol (2 mL) in a microwave reactor vial was added trifluoroacetic acid (171 mg). The vial was then sealed and heated in a microwave reactor at 125° C. for 30 minutes. The reaction mixture was then diluted with ethyl acetate (25 mL) and washed with aqueous saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4) and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (40%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1.[O:13]=[C:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[Br:12][C:10]1[N:11]=[C:7]([C:14]2([OH:13])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17]2)[S:8][CH:9]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2nc(Br)cs2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
n-Butyllithium (1.6 M in THF, 6.3 mL, 10.1 mmol) was added dropwise to a −78° C. solution of 2,4-dibromothiazole (2.00 g, 8.30 mmol) in tetrahydrofuran (50 mL), and the mixture stirred at −78° C. for 1 h. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (2.83 g, 16.55 mmol) in tetrahydrofuran (5 mL) was added, and the resulting mixture stirred for 1 h at room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 20% with ethyl acetate/petroleum ether) to afford tert-butyl 3-(4-bromothiazol-2-yl)-3-hydroxyazetidine-1-carboxylate (0.890 g, 32%) as a white solid. MS (ESI, pos. ion) m/z 335, 337 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A mixture of ethyl 4-(4-pyridyl)benzoate (1.0 g), 1 N NaOH (8.8 ml) and ethanol (8.8 ml) was stirred at room temperature for 1 hour and diluted with water, to which was added 1 N hydrochloric acid (8.8 ml) to give the title compound as crystals (0.76 g, 86.4%).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([NH:28][C@@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.ClC(OCC(C)C)=O>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([NH:28][C@@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](N)CCc1ccccc1
Agent: CC(C)COC(=O)Cl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 70 %

Procedure:
Condensation of ZPheOH (7.5 g.) and HDPheOMe (5.4 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-DPheOMe in 66% yield. Debenzyloxycarbonylation of ZPhe-DPheOMe (6.9 g.) by hydrogenation with palladium catalyst gave HPhe-DPheOMe in 100% yield. Condensation of BocProOH (3.23 g.) and HPhe-DPheOMe (4.9 g.) by the mixed anhydride method using isobutyl chloroformate gave BocPro-Phe-DPheOMe in 70% yield. Hydrazinolysis of BocPro-Phe-DPheOMe (5.0 g.) gave BocPro-Phe-DPheNHNH2 in 84% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[C:19]2[CH:20]=[CH:21][C:22](=[O:24])[O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][C:22](=[O:24])/[CH:21]=[CH:20]/[C:19]1[C:14]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:15][CH:16]=[CH:17][C:18]=1[OH:23]
Reactant: C[O-]
Reactant: O=c1ccc2c(C#CCCCCOC3CCCCO3)cccc2o1
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Yield: 59.2 %

Procedure:
A solution of 1.09 g (3.3 mmol) of rac-5-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]-2H-1-benzopyran-2-one and 1.8 mL (7.9 mmol) of 25% methanolic sodium methoxide in 5 mL of methanol was stirred and refluxed for 24 hr and then concentrated under reduced pressure. The residue was treated with 1N hydrochloric acid and worked-up with ethyl acetate in the usual manner (the organic extracts were additionally washed with saturated aqueous sodium bicarbonate). The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexane-ether. There was obtained 0.7 g (59%) of rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester as a yellow oil. Trituration of a sample prepared in this way with hexane gave a colorless solid, mp 66°-67.5° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:10][C:11](=O)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:8][CH3:9]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][NH:10][CH2:7][CH2:8][CH3:9])=[CH:15][CH:16]=1
Reactant: CCCNC(=O)CCc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNCCCc1ccc(OC)cc1
Temperature: 50 °C

Procedure:
To a stirred mixture of LiAlH4 (8.0 g, 200 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of 3-(4-methoxyphenyl)-propionic acid n-propyl amid (10.7 g, 49 mmol) (from a) above) in tetrahydrofuran (100 mL). After refluxing for 12 h the mixture was cooled to 50° C. and excess hydride was destroyed by careful addition of water (10 mL), 5% aqueous NaOH (40 mL) and water (20 mL) allowing reflux conditions. The hot slurry was filtered and the white precipitate was washed thoroughly with ethanol. Volatiles were evaporated and the resulting oil dissolved in ethyl acetate (50 mL) what was extracted with 0.5 N aqueous HCl (4×50 mL). The acidic phase was made alkaline (pH=9) by addition of 30% aqueous NaOH and extracted with ethyl acetate (4×50 mL). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to dryness to give an oil that partially crystallized in diethyl ether as the hydrochloride salt. Recrystallization from acetone/diethyl ether gave white flacky crystalline material. Total yield (as free base): 9.9 g, 48 mmol, 98%, mp 176-177° C. IR (neat) cm−1 2960, 2772, 1611, 1514; 1H-NMR (CDCl3) δ 9.46 (br s, 1H), 7.16 (d, 2H), 6.90 (d, 2H), 3.72 (s, 3H), 2.82 (br s, 4H), 2.59 (t, 2H), 2.15 (p, 2H), 1.83 (h, 2H), 0.89 (t, 3H) ppm; 13C-NMR (CDCl3) δ 156.6, 130.3, 127.7, 112.4, 53.7, 47.9, 45.66, 30.3, 25.9, 17.8, 9.7 ppm; MS (EI) m/z 207 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.N=[C:11]([CH3:15])[CH2:12][C:13]#[N:14]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:13]([NH2:14])=[CH:12][C:11]([CH3:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CC(=N)CC#N
Solvent: CCO
Product: Cc1cc(N)n(-c2ccc(Cl)nn2)n1

Procedure:
A mixture of 14.5 g (0.1 moles) of 3-chloro-6-pyridazinyl-hydrazine, 8.5 g (0.1 moles) of 3-iminobutyronitrile and 150 ml of ethanol is heated to reflux for 9 hours. After cooling the separated crystals are filtered, washed with ethanol and dried. Yield: 15.6 g (74.0%); m.p.: 148°-150° C. The hydrochloride melts at 157°-159° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:30])[CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:18][CH:17]=3)=[O:14])=[CH:7][C:6]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(O[CH2:42][CH3:43])(=O)C>O.C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:10]([N:11]([CH2:42][CH3:43])[C:5]1[CH:6]=[CH:31][C:2]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:30])[CH:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:18][CH:17]=4)=[O:14])=[CH:7][C:6]=3[CH:31]=2)=[CH:3][CH:4]=1)[CH3:9]
Reactant: CCOC(C)=O
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
In water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved (4-diethylamino)phenyl borate (234 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (391 mg). To the solution was added potassium carbonate (268 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (37 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (45 g, ethyl acetate:ethanol=20:1) and recrystallized from ethanol to give 7-(4-diethylaminophenyl)-1-methyl-N-(4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (145 mg, 33%) as yellow crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:36]=[CH:37][CH:38]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:35])[C@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[NH:19]C(OC(C)(C)C)=O)[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]>C(O)=O>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:36]=[CH:37][CH:38]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:35])[C@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[NH2:19])[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)OC(C)(C)C)c1
Solvent: O=CO
Product: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@@H](N)Cc2cccc(C)c2)c1

Procedure:
N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-(t-butoxycarbonyl)-L-phenylalaninamide (4.36 g, 8.37 mmol) in formic acid (47 mL) is stirred at room temp. for 6 h, after which time the formic acid is evaporated at 25° C. The residue is then dissolved in water (50 mL), basified with sat'd aqueous NaHCO3, and extracted with ethyl acetate (3×50 mL). The combined organic layers are then washed with water (50 mL), brine (50 mL), dried (MgSO4) and evaporated to yield N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-L-phenylalaninamide, as a clear oil, which is utilized without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[NH:9][C:8]2=O)(=[O:3])[CH3:2].S(Cl)([Cl:29])=O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[Cl:29])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2cc1OC(C)=O

Procedure:
A mixture of the 7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (1.70 g, 4.79 mmol), thionyl chloride (30 mL) and anhydrous DMF (0.6 mL) were refluxed for 2.5 h. The volatiles were removed in vacuo and the residue dissolved in CH2CL2 (500 mL) and was washed with water, sat. NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate. (1.6 g, 4.23 mmol, 88%). HPLC retention time 9.75 min.