Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][N:19]1[CH:23]=[C:22]([NH:24][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH:13]4[O:14][CH2:15][CH:16]([OH:17])[CH:12]4[O:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH:21]=[N:20]1
Reactant: OC1COC2C(Nc3ccnc(Cl)n3)COC12
Reactant: Cn1cc(N)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2nccc(NC3COC4C(O)COC34)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a suspension of 6-((2-chloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (354 mg, 1.37 mmol) in n-BuOH (3 mL) were added 1-methyl-1H-pyrazol-4-amine (220 mg, 1.65 mmol) and DIPEA (531 mg, 4.11 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow solid (120 mg, 22%).
Reaction SMILES: [Na].N[C:3]1[C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:7][C:6](N)=[CH:5][CH:4]=1.Cl.[OH2:15]>>[OH:15][C:5]1[C:6]2[C:7](=[CH:8][CH:3]=[CH:4][CH:5]=2)[C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][CH:4]=1
Reactant: O
Reactant: Nc1ccc(N)c(S(=O)(=O)O)c1
Agent: Cl
Agent: [Na]
Product: O=S(=O)(O)c1ccc(O)c2ccccc12

Procedure:
A solution of 21 parts of the sodium salt of 1,4-diaminobenzene-6-sulphonic acid in 100 parts of water is stirred with a neutral solution of 24.5 parts of (4,6-dichloro-s-triazin-2-yl)-phosphoramide-acid in 200 parts by volume of H2O at 20° to 40° C, whilst constantly neutralising the hydrochloric acid liberated to keep the pH at 6 to 7, until a sample, on diazotisation and coupling with 1-hydroxynaphthalene-4-sulphonic acid, gives a clear, yellowish-tinged red dyeing. After addition of ice, the resulting dyestuff intermediate product is directly diazotised with 7 parts of sodium nitrite and 28 parts of concentrated hydrochloric acid and subsequently combined with a previously prepared solution of 47 parts of the sodium salt of 1-benzoylamino-8-hydroxynaphthalene-3,6-disulphonic acid and 12 parts of sodium carbonate in 200 parts of water, whereupon coupling to give 4-chloro-6-(3'-sulpho-4'-[1"-benzoylamino-2"-hydroxy-3",6"-disulphonaphthyl-7"-azo]-phenylamino)-s-triazine-2-phosphoramide-acid takes place; the latter is salted-out, filtered off, washed and dried in vacuo at 40° to 50° C. The dyestuff readily dissolves in water to give a red colour and gives, by one of the processes described, clear bluish-tinged red dyeings and prints on cellulose materials.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[C:15]2[C:22]([I:23])=[CH:21][N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=2[N:17]=[CH:18][N:19]=1.[CH:32](OCC)=[O:33]>O1CCCC1>[Cl:13][C:14]1[C:15]2[C:22]([I:23])=[C:21]([CH:32]=[O:33])[N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (2.9 g, 29 mmol) in tetrahydrofuran (30 mL) was cooled to −78° C. and treated drop-wise with n-butyllithium (2.5 M, 11.6 mL, 29 mmol). The reaction mixture was stirred at 0° C. for 1 hour, and then cooled to −78° C. A solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (8.0 g, 20 mmol) in tetrahydrofuran (10 mL) was added drop-wise, and stirred was continued at −78° C. for 1 hour. After drop-wise addition of a solution of ethyl formate (2.6 g, 35 mmol) in tetrahydrofuran (10 mL) to the −78° C. reaction mixture, it was allowed to warm to room temperature and stir for 18 hours. It was then cooled to 0° C., and the reaction was quenched by addition of saturated aqueous ammonium chloride solution (20 mL), then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification via silica gel chromatography (Gradient: 0% to 25% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 5.0 g, 11 mmol, 55%. 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.80 (s, 1H), 6.05 (s, 2H), 3.55-3.62 (m, 2H), 0.89-0.96 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=[C:19]([I:27])[CH:18]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:23]([C:22]1[CH:17]=[CH:18][C:19]([I:27])=[CH:20][CH:21]=1)(=[O:25])=[O:24])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a magnetically stirred solution of 2-amino-5-chlorobenzophenone (1.62 g, 7.0 mmol) in dry pyridine (30 mL) was added dropwise a solution of pipsyl chloride in toluene (12 mL) and the reaction was stirred at ambient temperature. The reaction was added to cold (ice bath) 6M hydrochloric acid with stirring and the mixture was extracted with ethyl acetate (3×50 mL). The extracts were washed with water and with saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated to give a crystalline solid. The product was filtered, washed with hexane and dried (vacuum) to get white crystalline solid. 1H NMR (CDCl3) δ 9.63 (br s, 1H, NH), 7.75 (dm, 1H, J=8.8 Hz), 7.62 (tm, 1H, J=7.6 Hz), 7.56 (dm, 1H, J=7.6 Hz), 7.48 (m, 3H), 7.32 (m, 5H). MS: m/z 498.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[NH2:15])([O:3]C)=[O:2].[OH-].[Na+].C(O)(C)C>O>[NH2:15][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:8]=2[S:9][C:5]=1[C:1]([OH:3])=[O:2]
Reactant: COC(=O)c1sc2cc(F)ccc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Nc1c(C(=O)O)sc2cc(F)ccc12
Temperature: 8.5 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
At 50° C., add to a stirring solution of 2-carbomethoxy-3-amino-6-fluoro-benzo[b]thiophene (prepared according to U.S. Pat. No. 5,143,923), (90.1 g, 0.4 mol) in H2O (450 mL), a 50% aqueous solution of NaOH (64 g, 0.8 mol) over 2-3 min. Heat the reaction to 70-73° C. and continue to stir for 3 h. Add 10% aqueous isopropanol (45 mL) and bring to reflux. Remove the isopropanol under N2 and add H2O (300 mL). Cool the reaction mixture to between 7-10° C. and add concentrated HCl (80 mL). Add H2O (650 mL), cool to 5-70° C., filter the resulting solid, and wash the filter cake with H2O (2×150 mL). Dry the solid under vacuum at 35° C. to obtain 80.6 g (94.7%) of solid mp 160-163° C., TLC on silica gel (dichloromethane/methanol, 3:1), Rf=0.69.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:23]=[C:22]([NH2:24])[NH:21][N:20]=2)[CH2:15][CH2:14]1.[Cl:25][C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=1.O>CS(C)=O>[Cl:25][C:26]1[N:27]=[N:28][C:29]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:23]=[C:22]([NH2:24])[NH:21][N:20]=3)[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Nc1cc(C2CCNCC2)n[nH]1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Nc1cc(C2CCN(c3ccc(Cl)nn3)CC2)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]-7-undecene (0.750 mL, 5.02 mmol) was added to a suspension of 3-(piperidin-4-yl)-1H-pyrazol-5-amine hydrochloride (0.400 g, 1.67 mmol) produced in Reference Example 33 in dimethyl sulfoxide (4 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 3,6-dichloropyridazine (0.249 g, 1.67 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour and at 60° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: ethyl acetate/methanol=95/5-90/10 (gradient)] to obtain the title compound (0.330 g, yield: 71%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:12]=[C:13]([OH:18])[C:14](=[CH:16][CH:17]=3)[OH:15])[N:10]=[C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=1.CC(O[CH2:24][C:25]1[CH2:34][S:33][C@@H:28]2[C@H:29]([NH2:32])[C:30](=[O:31])[N:27]2[C:26]=1[C:35]([OH:37])=[O:36])=O.S1(CCCC1)(=O)=O.B(F)(F)F.CCOCC>ClCCl>[NH2:32][C@@H:29]1[C:30](=[O:31])[N:27]2[C@@H:28]1[S:33][CH2:34][C:25]([CH2:24][S:1][C:2]1[N:7]3[N:8]=[C:9]([C:11]4[CH:17]=[CH:16][C:14]([OH:15])=[C:13]([OH:18])[CH:12]=4)[N:10]=[C:6]3[N:5]=[C:4]([CH3:19])[CH:3]=1)=[C:26]2[C:35]([OH:37])=[O:36]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)n2nc(-c3ccc(O)c(O)c3)nc2n1
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
4-(7-Mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)pyrocatechol (1.8 g) and 1.63 g of 7-amino-cephalosporanic acid are suspended in 30 ml of a 1:1 mixture of dichloromethane and sulpholane. 2.63 g of boron trifluoride etherate are added thereto at 3° C. and the solution is left at the same temperature for 11/2 hours. Thereafter, it is diluted dropwise with 60 ml of dichloromethane, the resulting precipitate is filtered off under suction, rinsed with diethyl ether and dissolved immediately in 40 ml of water. Sufficient 20% aqueous sodium hydroxide solution is added while cooling with ice until pH 3.1 has been reached, whereby the product precipitates. This is filtered off under suction, washed with a small amount of water and finally with 20 ml of acetone and dried in a vacuum at 0.1 mmHg. There are obtained 2.17 g of (6R,7R)-7-amino-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7 -yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH3:27])[CH3:22]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[2-[N-(4-Fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine are reacted and worked up in analogous fashion. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:10][CH2:11][C:12]([NH:14][NH2:15])=[N:13][C:7]=2[CH:6]=[CH:5][C:4]=1[C:23]#[N:24])#[N:2].[Cl:25][CH:26]([CH3:30])[C:27](Cl)=O.C([O-])(=O)C.[Na+]>>[C:1]([C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:10][CH2:11][C:12]3[N:13]([C:27]([CH:26]([Cl:25])[CH3:30])=[N:15][N:14]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:23]#[N:24])#[N:2]
Reactant: CC(Cl)C(=O)Cl
Reactant: N#Cc1ccc2c(c1C#N)C(c1ccccc1Br)=NCC(NN)=N2
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(Cl)c1nnc2n1-c1ccc(C#N)c(C#N)c1C(c1ccccc1Br)=NC2

Procedure:
In the manner given in Example 1, 6,7-dicyano-5-(o-bromophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with α-chloropropionyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 7,8-dicyano-1-(α-chloroethyl)-6-(o-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 59.3 %

Procedure:
A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) δ 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:30][C:29]#[CH:28])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=[N:11]1
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Then, 3.2 g of 2-[2-fluoro-4-chloro-5-hydroxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 50 ml of DMF, to which 2.0 g of potassium carbonate was added at room temperature. Furthermore, 1.3 g of propargyl bromide was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was mixed with 100 m of water, and the precipitated crystals were collected by filtration and washed with hexane. The resulting crystals were recrystallized from isopropanol to give 3.4 g of 2-[2-fluoro-4-chloro-5-(2-propynyloxy)phenyl]-4-methyl-5-trifluoromethylpyridazin-3-one (hereinafter referred to as compound A) (m.p., 140.7° C.; decomposition).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1C=CN=C1)=[O:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14]N.NCC[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.O>O1CCCC1>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:11][CH2:12][NH:8][C:1]([NH:3][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:2])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCc1ccc(O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (1.621 g, 9.994 mmol) in anhydrous tetrahydrofuran (20 ml) was added tert-butyl carbazate (1.322 g, 10.00 mmol), and the mixture was stirred at room temperature for 1.5 hr. 4-(2-Aminoethyl)phenol (1.371 g, 9.991 mmol) was added and the mixture was stirred at room temperature for 6 hr. Water (40 ml) was added to the reaction mixture and the precipitate was collected by filtration, washed 3 times with water and twice with ethyl acetate, and dried under reduced pressure to give tert-butyl 2-{[2-(4-hydroxyphenyl)ethyl]carbamoyl}hydrazinecarboxylate (2.417 g, 8.184 mmol, yield 81.9%) as a white solid.
Reaction SMILES: [CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([CH2:16][OH:17])[NH:4]1)[CH3:2].C(N(CC)CC)C.[C:25](=[S:27])=[S:26].[CH3:28]I>CS(C)=O>[CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([CH2:16][OH:17])[N:4]1[C:25]([S:27][CH3:28])=[S:26])[CH3:2]
Reactant: CI
Reactant: CC[C@@H]1N[C@@H](CO)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@H]1c2[nH]c3ccccc3c2C[C@H](CO)N1C(=S)SC

Procedure:
In the same manner as described in Example 13 by using (1RS, 3SR)-trans-1-ethyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (300 mg), triethylamine (330 mg), CS2 (250 mg), methyl iodide (460 mg) and dimethylsulfoxide (3 ml), there is prepared the title compound (320 mg, 77%) as colorless needles, m.p. 170°-172° C. (recrystallized from aqueous ethanol). NMR (CDCl3, δ): 0.85 (t, J=7.0 Hz, 3H, C1 --CH2CH3), 2,68 (s, 3H, CSSCH3), Mass m/e: 320 (M+), 272 (M+ --CH3SH).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[CH:36]1([CH2:42][NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:77][C:78]([C:80]1([NH:85][C:86]([CH:88]2[CH2:92][CH:91]([O:93][C:94]3[C:103]4[C:98](=[CH:99][C:100]([O:104][CH3:105])=[CH:101][CH:102]=4)[N:97]=[C:96]([C:106]4[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=4)[CH:95]=3)[CH2:90][N:89]2C(=O)NC(C(=O)NC2C3C(=CC=CC=3)CC2O)C(C)(C)C)=[O:87])[CH2:82][CH:81]1[CH:83]=[CH2:84])=[O:79])C>>[CH:36]1([CH2:42][NH:43][C:17]([C@@H:9]([NH:8][C:6]([N:89]2[CH2:90][C@H:91]([O:93][C:94]3[C:103]4[C:98](=[CH:99][C:100]([O:104][CH3:105])=[CH:101][CH:102]=4)[N:97]=[C:96]([C:106]4[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=4)[CH:95]=3)[CH2:92][C@H:88]2[C:86]([NH:85][C@:80]2([C:78]([OH:79])=[O:77])[CH2:82][C@H:81]2[CH:83]=[CH2:84])=[O:87])=[O:7])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC1CCCCC1)C(=O)O

Procedure:
N-(tert-butoxycarbonyl)-L-phenylalanine was attached to the resin as described for the preparation of compound 16 followed by reaction with cyclohexanemethylamine as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC>95%. M+H+760.4.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:19][N:18]=3)[CH2:13][CH2:12]2)=[N:7][CH:6]=1)C.[OH-].[Li+].C1COCC1.Cl>O.CO>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][N:7]=4)[CH2:16][CH2:15]3)=[N:18][N:19]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Reaction time: 16 h

Procedure:
6-{4-[4-(4-Fluoro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (188 mg, 0.4 mmol), Lithium hydroxide (96 mg, 4.0 mmol), THF (750 μL), MeOH (750 μL), and H2O (400 μL) are combined at room temperature and stirred 16 h. Adjust pH to between three and four with 1N HCl. Extract with CH2Cl2/EtOH 4:1 and combined organics are washed with brine. Concentrate in vacuo to yield the title compound without further purification (165 mg, 93%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH2:14]([CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16].[CH2:24]([C@H:28]1[CH2:33][CH2:32][C@H:31](C2C=CC(C(OC3C=CC(CCCCC)=C(F)C=3F)=O)=CC=2)[CH2:30][CH2:29]1)[CH2:25][CH2:26]C.Cl>CCCCCC.O1CCCC1>[CH2:14]([CH:17]1[CH2:22][CH2:21][C:20]([C:9]2[CH:10]=[CH:11][C:12]([C:31]3[CH2:32][CH2:33][CH:28]([CH2:24][CH2:25][CH3:26])[CH2:29][CH:30]=3)=[C:7]([F:6])[C:8]=2[F:13])=[CH:19][CH2:18]1)[CH2:15][CH3:16]
Reactant: Fc1ccccc1F
Reactant: CCCC1CCC(=O)CC1
Reactant: CCCCCc1ccc(OC(=O)c2ccc([C@H]3CC[C@H](CCCC)CC3)cc2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1CC=C(c2ccc(C3=CCC(CCC)CC3)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.2 mol of n-butyllithium in 65 ml of hexane is added to a mixture of 0.1 mol of 1,2-difluorobenzene, 0.2 mol of potassium tert.-butylate and 100 ml of tetrahydrofuran at -100° C. After the mixture has been stirred for 10 minutes, a mixture of 0.2 mol of 4-propylcyclohexanone and 20 ml of tetrahydrofuran is added at -90° C. After the mixture has been stirred at -40° C. for 2 hours, it is warmed to room temperature and 30 ml of 2 normal hydrochloric acid solution are added. Heating for 2 hours and customary working up give 1,4-bis-(4-propylcyclohex-1-enyl)-2,3-difluorobenzene, C 59° N 120° I.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH3:41][NH:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>C1COCC1>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][N:42]([CH3:41])[C:4](=[O:5])[CH2:3][S:7](=[O:8])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: CNCC(O)CO
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CC(=O)N(C)CC(O)CO)c3ccccc3)c2)c1
Temperature: 75 °C

Procedure:
To the solution of (S)-ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate (3.5 g, 6.3 mmol) in anhydrous THF (50 mL) was added dropwise 3-methylamino-1,2-propanediol (6.77 g) and the resulting reaction solution was heated at 75° C. for 8.5 hours. The reaction was then concentrated under reduced pressure and the yellow oily residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was separated and washed with saturated aqueous NaHCO3 (1×), brine (1×), and dried with sodium sulfate. The upper clear solution was decanted and evaporated, the resulting yellowish foamy residue was subjected to a gradient column chromatography (from EtOAc-Hex 6:1 to MeOH-EtOAc 1:50) yielding the title compound as white foam in amount of 2.56 g (66%).