Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:37][CH2:38][CH2:39][CH2:40]O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)(Cl)Cl.CO>[CH2:30]([O:37][CH2:38][CH2:39][CH2:40][O:24][C:23]([C:18]1([C:20]([O:22][CH2:40][CH2:39][CH2:38][O:37][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCCCOCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCCCOCc1ccccc1)(C(=O)OCCCOCc1ccccc1)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 38 %

Procedure:
The title compound was prepared as a yellow gum from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-benzyloxy-propanol according to the procedure of Example 1; yield: 38%; Rf =0.52 (9/1 CHCl3 /MeOH); 1H NMR (300 MHz, CDCl3): δ 1.32 (d, 3H), δ 2.00 (m, 4H), δ 2.75 (m, 1H), δ 3.30 (s, 2H), δ 3.50 (m, 4H), δ 4.40 (br m, 12H), δ 5.49 (s, 1H), δ 6.68-6.85 (m, 3H), δ 7.24-7.40 (m, 13H), δ 7.43 (s, 1H); MS (ES) m/z (relative intensity): 518 (M+ -HCl, 100).
Reaction SMILES: [S:1]1[C:5]([SH:6])=[N:4][N:3]=[C:2]1[SH:7].[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[SH:6][C:5]1[S:1][C:2]([S:7][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=2)=[N:3][N:4]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Sc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#Cc1nccnc1Sc1nnc(S)s1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 1,3,4-thiadiazole-2,5-dithiol (945 mg, 6.05 mmol), NaH (60% dispersion in mineral oil, 264 mg, 6.60 mmol), and 3-chloropyrazine-2-carbonitrile (840 mg, 6.00 mmol) in DMF and benzene (10 ml, 1/1) by stirring at 50° C. under nitrogen atmosphere for 4 hr.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33]([NH:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([NH:36][CH2:37][C:38]([NH:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC(=O)NCC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (13 mg, 28 μmol) was dissolved in abs. pyridine (2.0 ml). At room temperature, acetamidoacetyl chloride (8 mg, 57 μmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.6 mg, 65% of theory).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[CH:8]=1>C(#N)C>[CH3:12][C:9]1[CH:8]=[C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH2:4])[O:11][N:10]=1
Reactant: Cc1cc(CBr)on1
Reactant: NCCN
Solvent: CC#N
Product: Cc1cc(CNCCN)on1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Ethylenediamine (30 g) was dissolved in 120 g of acetonitrile, and a solution of 17.6 g of 5-bromomethyl-3-methylisoxazole in 30 ml of acetonitrile was added dropwise at 5° to 10° C. After the addition, the mixture was stirred for 1 hour with a care taken not to permit the temperature of the reaction system to rise above 20° C. Then, most of the volatile materials were removed under vacuum (less than 2 mmHg) while maintaining the bath temperature at 20° C. Ice water was added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was dehydrated, and dichloromethane was distilled off under reduced pressure to give 10.0 g of N-(3-methyl-5-isoxazolylmethyl)ethylenediamine (purity about 95%) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[I:12]N1C(=O)CCC1=O>CN(C)C=O>[I:12][C:5]1[S:1][C:2]([S:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[CH:3][CH:4]=1
Reactant: N#CCCCSc1cccs1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: N#CCCCSc1ccc(I)s1
Yield: 95.9 %

Procedure:
2.3 g of thiophen-2-thiol, 3.0 g of 4-bromobutyronitrile and 5.5 g of potassium carbonate were stirred in N,N-dimethylformamide at room temperature to give 3.4 g of 4-(2-thienylsulfanyl)butane nitrile. 3.4 g of 4-(2-thienylsulfanyl)butane nitrile was reacted with 5.4 g of N-iodosuccinimide in N,N-dimethylformamide, whereby 5.5 g of the title compound was obtained as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](C2C=CC=CC=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reactant: O=Cc1ccccc1I
Product: O=Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde was prepared according to the method of Example 135, Step 2 using 2-iodobenzaldehyde in place of (S)-1-(2-iodophenyl)ethanol and Intermediate 2 in place of Intermediate 1.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2[Br:24])[O:7][C@@H:6]1[CH2:35][O:36]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Br:24][C:23]1[C:22]([CH3:25])=[C:21]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=2)[S:20][C:19]=1[C@H:8]1[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:35][OH:36])[O:7]1
Reactant: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(Br)c2C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(Br)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a suspension of acetate (56) (200 mg, 0.320 mmol) in MeOH (5 mL) was added NaOMe (25 wt % in MeOH, 0.1 mL) at room temperature. The mixture was stirred at room temperature for 1 hr. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 58 (80 mg, 55%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH2:24][NH:23][C:14](=[O:16])[C:13]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:31]
Reactant: COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)O)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC)ccc1OC/C=C(\C)CCC=C(C)C
Yield: 86 %

Procedure:
In a manner identical to Example 15, 2-geranyloxy-5-methoxybenzoic acid (1.52 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.78 g (86%) of the aimed compound.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]2([NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].[C:15]1([C:25](Cl)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([C:25]([N:9]2[C:7](=[O:8])[C:4]3([CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]3)[NH:12][C:10]2=[O:11])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NC(=O)C2(CCCCC2)N1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC2(CCCCC2)C(=O)N1C(=O)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
5,5-Pentamethylenehydantoin (2.00 g) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (60%, in oil) (0.49 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthoyl chloride (2.33 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the white solid. Further recrystallization with IPE and ethyl acetate afforded 1.87 g of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][NH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([N:7]1[C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:12][C:9]2([CH2:10][CH2:11]2)[CH2:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2c(c1)NCC1(CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)N(Cc1ccccc1)CC1(CC1)O2
Temperature: 60 °C
Yield: 26.5 %

Procedure:
To a stirred solution of 6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane] (3.11 g, 12.9 mmol) in DMF (20 mL) was added potassium carbonate (3.6 g, 26.0 mmol) and benzyl bromide (1.61 mL, 13.6 mmol). The reaction mixture was heated at 60° C. for 6 h then cooled to room temperature and quenched by the addition of water. The reaction mixture was extracted with ethylacetate (2×50 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL), then dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to furnish 4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1-cyclopropane] (1.13 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[OH:36])[O:7][CH2:8][CH2:9][N:10](CC1C=CC=CC=1)[CH2:11][CH:12]([OH:25])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[OH:36])[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(OCCO)cc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(OCCO)cc2)ccc1O

Procedure:
A solution of 23 g of crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]-benzylamino]-3-[4-(2-hydroxyethoxy)phenoxy]-2-propanol in 500 ml of methanol is hydrogenated, under normal conditions, with the addition of 2 g of 5% palladium on carbon catalyst, until hydrogen absorption has ceased. The catalyst is then removed by filtration and the filtrate is concentrated by evaporation under reduced pressure. The crystalline residue is stirred in a mixture of 50 ml of methanol and ether. The crystals so obtained are isolated by filtration and dried in vacuo, affording 1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-hydroxyethoxy)phenoxy]-2-propanol with a melting point of 150°-151° C. Reaction with the equivalent amount of hydrogen chloride, as solution in methanol, affords the hydrochloride with a melting point of 205°-206° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[OH:28].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc2cc(Br)ccc2c1Br
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4cc(Br)ccc4c3Br)c2cc1OC
Temperature: 150 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (223 mg), 1,6-dibromo-2-naphthol (910 mg), and 4-dimethylaminopyridine (366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-[(1,6-dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (326 mg, yield 67%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][CH2:17][O-:18].[Na+]>>[CH2:17]([O:18][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1)[CH3:16]
Reactant: COc1ccc2c(O)nc(Cl)nc2c1C
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1nc(O)c2ccc(OC)c(C)c2n1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
The quinazolinol (140) (530 mg, 2.36 mmol) was added in small portions to freshly prepared EtONa (740 mg of Na added in 20 mL EtOH). The resulting solution was heated to reflux and after 24 h, the reaction mixture was cooled down to room temperature and evaporated. The residue was re-dissolved in water (10 mL) and the pH of the resulting solution was adjusted to 5 with AcOH. The precipitate was collected by filtration, washed with ice-cooled water and dried to give the title compound (534 mg, 96.6%) as a white solid, m/z=235 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C@H:18]1[O:23][CH2:22][C@@H:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@@H:34]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:8])=[O:4].C(Cl)Cl.[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78]>>[NH:20]1[C@H:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@@H:34]([NH:48][C:49](=[O:50])[O:51][CH3:52])[CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:22][O:23][C@H:18]([CH2:17][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:61]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH2:19]1.[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CCc2ccccc2NC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CO[C@H](CCc2ccccc2NC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)CN1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-Butyl(2R,5R)-2,5-bis {2-[2-({(2S)-2-[(methoxycarbonyl)amino]-3,3-diphenyl propanoyl}amino)phenyl]ethyl}morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]([CH2:18][C:19]([NH2:21])=[S:20])#[N:17]>>[NH2:21][C:19](/[C:18](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:16]#[N:17])=[S:20]
Reactant: N#CCC(N)=S
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Product: CC(C)c1cc(/C=C(\C#N)C(N)=S)cc(C(C)C)c1O

Procedure:
M25 was prepared using 3,5-diisopropyl-4-hydroxybenzaldehyde and cyanothioacetamide under similar conditions as described for M11.
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][N:13]3[CH2:14][CH2:15][N:10]([CH2:1][C:2]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:3])[CH2:11][CH2:12]3)[CH2:21][CH2:22]2)=[CH:28][CH:29]=1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(CCCN2CCN(Cc3ccc(Cl)cc3)CC2)CC1)c1ccccc1
Yield: 77.5 %

Procedure:
A mixture of 4.1 g of 1-phenacylpiperazine, 5.7 g of 1-chloro-3-[4-(4-chlorobenzyl)-1-piperazinyl]propane, 2.6 g of triethylamine and 35 ml of reagent ethanol was refluxed for 5 hours. The solvent was removed by rotary evaporation, 150 ml of water were added, and the mixture was extracted with ether (3×150 ml). The ether solution was evaporated to an oil, which was chromatographed on a silica column, the eluant being CH2Cl2 /CH3OH/ammonium hydroxide (45:5:1), to yield crude 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-(4-phenacyl-1-piperazinyl)propane (7.0 g, 50% of theory). This oil was dissolved in 200 ml of ether and precipitated with excess anhydrous hydrogen chloride. The precipitate was then dissolved in water and reprecipitated by addition of acetone to give 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-(4-phenacyl-1-piperazinyl)propane tetrahydrochloride monohydrate as a white crystalline product (m.p. 211°-218° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)/[CH:18]=[CH:19]/[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1.[OH-].[Na+]>O1CCOCC1>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[NH:16][C:17](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[N:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)/C=C/c2cc(OC)c(OC)c(OC)c2)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)c(OC)c3)nc2n(CCC)c1=O
Yield: 70.8 %

Procedure:
To 10.02 g (22.5 mmol) of Compound E were added 100 ml of dioxane and 100 ml of an aqueous 2N.sodium hydroxide solution, and the solution was heated under reflux for 10 minutes. After cooling, the solution was neutralized, and deposited crystals were collected by filtration. Then, the collected crystals were recrystallized from dioxane/water to give 6.83 g (yield 91%) of Compound 9 as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:7]=2[NH:6][C:5]1=[O:38].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:11]3[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:13][C:7]4[N:6]([CH2:46][C:47]#[N:48])[C:5](=[O:38])[CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]=4[N:10]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC#N)C(=O)C(CCO)O4)cc2)CCC1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 1-(4-(3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (51 mg, 0.099 mmol) in DMF(2 ml) was added potassium carbonate (41 mg) and 2-bromoacetonitrile (35.5 mg, 0.297 mmol). The reaction mixture was stirred at 50 degree for 3 h.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:28][B:29]([O:33]CC)[O:30]CC)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][C:10]1[C:9]([S:19][CH3:20])=[N:8][N:7]2[C:2]([O:28][B:29]([OH:33])[OH:30])=[CH:3][CH:4]=[CH:5][C:6]=12)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nn2c(OB(O)O)cccc2c1NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
After dissolving tert-butyl N-(7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl)carbamate (200 mg) in tetrahydrofuran (2 mL), the mixture was cooled to −78° C. and n-butyllithium (1.6 M; 0.66 mL) was added dropwise. The mixture was stirred for 1 hour at the same temperature, triethoxyborane (109 μL) was added and the temperature was increased to room temperature. Saturated aqueous ammonium chloride was added to the obtained reaction mixture, and extraction was performed with ethyl acetate. The obtained organic layer washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (106 mg) as grayish white crystals.