Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Cl:2][C:3]1([C:6]([OH:22])([CH2:15][N:16]2[C:20]([SH:21])=[N:19][CH:18]=[N:17]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][CH2:4]1.[C:23](=[O:26])([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:2][C:3]1([C:6]([OH:22])([CH2:15][N:16]2[C:20]([S:21][C:23](=[O:26])[C:8]3[CH:13]=[CH:12][C:11]([Cl:1])=[CH:10][CH:9]=3)=[N:19][CH:18]=[N:17]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: [Cl-]
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Sc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
At room temperature, a solution of 0.63 ml (5 mmol) of 4-chloro-benzo)yl chloride in 5 ml of absolute tetrahydrofuran is added dropwise with stirring to a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 0.69 g (5 mmol) of anhydrous potassium carbonate and 20 ml of absolute tetrahydrofuran. The reaction mixture is stirred at room temperature for a further 20 hours and then filtered off with suction and concentrated under reduced pressure. In this manner, 2.4 g (99% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-[5-(4-chloro-benzoyl-mercapto)-1,2,4-triazol-1-yl]-propan-2-ol are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].S([O-])([O-])(=O)=O.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][O:20][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(COC)nc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)OC(C)(C)C)c(COC)nc21
Reaction time: 2 h
Yield: 68.1 %

Procedure:
[1-Ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (57 mg), toluene (0.3 ml), 50% aqueous NaOH solution and tetrabutylammonim sulfate (32 mg) were stirred at room temperature. tert-Butyl bromoacetate (53 mg) was added dropwise and stirring was continued for 2 hours. Water (3 ml) was added and organic layer was separated. Water layer was extracted with EtOAc (×2). Organic layer was combined and dried over MgSO4. The solvent was evaporated to give dark brown oil. The crude compound was purified by flash column chromatography on silica gel (CHCl3:MeOH=50:1) to give tert-butyl {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetate (53 mg) as colorless oil
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.C[CH:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:26]1(C)C=CC=CC=1>>[CH3:26][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:23][C:24](=[O:25])[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]2[CH:5]=[CH:6][C:1]([CH3:14])=[CH:2][CH:3]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CNc1ccc(C)cc1
Reactant: Cc1ccccc1
Reactant: CC(N=C=O)c1ccccc1
Product: CCOC(=O)CN(C(=O)NCc1ccc(C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
Ethyl bromoacetate (4.0 g, 30.0 mmol) was added to a solution of p-toluidine (2.1 g, 20 mmol) and sodium acetate (2.1 g, 26 mmol) in ethanol (26 mL). The resulting solution was warmed to 80° C. and stirred for 1 h before being cooled to room temperature. The reaction was quenched with water (20 mL) and the aqueous fraction extracted with ethyl acetate (3×20 mL). The organic fractions were combined, dried (MgSO4) and filtered, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-(p-tolylamino)acetate as a pale oil (1.9 g, 50%). Ethyl 2-(p-tolylamino)acetate (260 mg, 1.4 mmol) was dissolved in toluene (5 mL). Methyl benzylisocyanate (200 mg, 1.4 mmol) was added to this solution. The mixture was heated to reflux and stirred for 5 h, until TLC analysis demonstrated that the reaction was complete. The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate as a pale oil (455 mg, 98%). Ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate (455 mg, 1.3 mmol) was dissolved in THF (10 mL) and added dropwise to a solution of NaH (68 mg, 2.8 mmol) in THF (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature slowly and stirred for 18 h before the reaction was quenched with water (5 mL). The aqueous fraction was then extracted with dichloromethane (3×20 mL). The organic fractions were combined, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. Column chromatography (0-20% ethyl acetate/hexane) provided 14 as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([C:20]2[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]2[S:21][CH:22]=[C:23]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(-c3ccccc3)n2)CC1
Yield: 90 %

Procedure:
This compound was synthesized from tert-butyl piperazine-1-carboxylate and 2-phenylthiazole-4-carboxylic acid as described for example 37 step 3 (500 mg, yield 90%). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.00-7.96 (m, 2H), 7.56-7.53 (m, 3H), 3.76-3.64 (m, 4H), 3.43 (m, 4H), 1.42 (s, 9H). MS (ESI) m/z: Calculated for C19H23N3O3S: 373.15. found: 374.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=3)[C:36](O)=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[C:47]([O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]2[C:29]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:36]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:37])=[CH:45][CH:44]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CCOC(CNCc1ccccn1)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(Cc1ccccn1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 90.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, 2,2-diethoxy-N-(pyridin-2-ylmethyl)ethanamine (Compound IX-16) (34.0 g, 150 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (72.3 g, 150 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1) to obtain the title compound (90.0 g, 90%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:15]([O:19][C:20]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:1]([N:26]1[CH2:27][CH2:28][CH:24]([NH:23][CH2:22][C:20]([O:19][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:21])[CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC1CCNC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NCC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
Under nitrogen atmosphere, acetic anhydride (707 μl, 7.49 mmol) and triethylamine (1.39 ml, 9.98 mmol) were added to a dichloromethane (25 ml) solution of 3-(tert-butoxycarbonylmethylamino)pyrrolidine (1.00 g, 4.99 mmol) with cooling with ice, followed by stirring at room temperature for 17 hours. The solvent was evaporated away under reduced pressure, then the resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate gave the entitled compound (1.10 g, 91%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)Cc1ccc(C(C)=O)cc1

Procedure:
Ethyl 4-acetylphenylacetate was prepared by the general experimental method from 4-acetylphenylboronic acid (164 mg, 1.00 mmol). After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 4-acetylphenylacetate is obtained as a colourless solid in a yield of 60% of theory. 1H NMR (400 MHz, CDCl3): δ=7.90 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 4.11-4.17 (m, 2H), 3.66 (s, 2H), 2.58 (s, 3H), 1.20-1.27 (m, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ=197.7, 170.8, 139.5, 136.0, 129.6, 128.6, 61.1, 41.3, 26.6, 14.2 ppm; MS (70 eV), m/z (%): 192 (100), 164 (16), 134 (14), 105 (19), 89 (11); IR (KBr): ν=2981 (w), 1735 (s), 1682 (m), 1274 (m), 1178 (m) cm−1; elemental analysis: (theor): C=69.89, H=6.84, (exp): C=69.95, H=6.99. Melting point: 55-56° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]1)=[N:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[CH2:36]([C@@H:38]1[O:40][CH2:39]1)[Cl:37]>C1COCC1.CO>[Cl:37][CH2:36][C@H:38]([OH:40])[CH2:39][N:13]([CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:34][CH3:35])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1
Reactant: ClC[C@H]1CO1
Reactant: COc1ccc2ncc(F)c(CNCCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(F)c(CN(CCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C[C@@H](O)CCl)c2n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of the compound of Example 78 (0.135 g, 0.27 mmol) in THF/MeOH (1:1, 2 mL) was treated with (R)-epichlorohydrin (0.032 mL, 1.5 eq.). The mixture was heated at 70° C. overnight, concentrated in vacuo and purified by FC (EA/MeOH 19:1+1% NH4OH) to give the title compound as a colourless foam (0.1 g, 52% yield).
Reaction SMILES: C([C@@:8]([C:15]([OH:17])=[O:16])([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[NH2:9])(OC(C)(C)C)=O.[Cl:18][O:19][N:20]=[CH:21][C:22]([F:25])([F:24])[F:23]>>[ClH:18].[ClH:18].[OH:19][N:20]=[C:21]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:8]([C:15]([OH:17])=[O:16])[NH2:9])[C:22]([F:25])([F:24])[F:23]
Reactant: CC(C)(C)OC(=O)[C@](N)(CCCCN)C(=O)O
Reactant: FC(F)(F)C=NOCl
Product: Cl
Product: N[C@@H](CCCCNC(=NO)C(F)(F)F)C(=O)O

Procedure:
α-Boc-L-lysine is reacted with chlorotrifluoroacetaldoxime (J. Org. Chem. 49, (1984) 919-922) as described in Example 1 to afford the title compound.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]1([CH2:13][CH2:14][CH2:15][Cl:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O>>[CH:1]1([C:10]2[CH:11]=[CH:12][C:7]([CH2:13][CH2:14][CH2:15][Cl:16])=[CH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCc1ccccc1
Reactant: C1=CCCCC1
Agent: O=S(=O)(O)O
Product: ClCCCc1ccc(C2CCCCC2)cc1
Reaction time: 14 h
Yield: 57 %

Procedure:
16.5 parts by weight of cyclohexene are added dropwise at +10° C. to a mixture of 31 parts by weight of 3-phenylpropyl chloride and 20 parts by weight of 96% strength sulfuric acid. Stirring is continued for 14 hours at room temperature. The crude product is dissolved in CHCl3 /ice water and the organic solution is thoroughly washed with ice water, dried over Na2CO3 and distilled. 27 parts by weight of 3-(4-cyclohexylphenyl)-propyl chloride are obtained; boiling point 126°-130° C./0.2 mm Hg, yield 57% (based on 3-phenylpropyl chloride).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:33]
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
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: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)c1
Yield: 17.7 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), {3-[(methylsulfonyl)amino]phenyl}boronic acid (31 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (5 mg, 18%)
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[N:3]1.[NH2:15][C:16]1[N:21]=[C:20]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:24])[CH:19]=[CH:18][C:17]=1Br.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.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>[NH2:15][C:16]1[N:21]=[C:20]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:24])[CH:19]=[CH:18][C:17]=1[C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=1
Reactant: Cn1nc(-c2ccco2)cc1B(O)O
Reactant: Nc1nc(NC(=O)c2ccccc2F)ccc1Br
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cn1nc(-c2ccco2)cc1-c1ccc(NC(=O)c2ccccc2F)nc1N
Temperature: 110 °C
Yield: 28.6 %

Procedure:
The boronic acid 91 (19.2 mg, 0.1 mmol) and 61 (31 mg, 0.1 mmol) was dissolved in 1 mL dimethoxyethane and 1 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-pallacium(0) (Pd(Ph3P)4, 11 mg, 0.01 mmol). The reaction was heated at 110° C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 100 (10.8 mg, 29%) as white solid. LC-MS: calcd. for C20H16FN5O2: 378 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.[CH:22](OC)(OC)OC>CN(C=O)C.Cl.C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:22][N:9]([CH:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)ccc2N)C1
Reactant: COC(OC)OC
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3ccc(Br)cc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2-amino-5-bromophenyl)amino)pyrrolidine-1-carboxylate (320 mg, 0.938 mmol), HC(OCH3)3 (5 mL) in DMF (10 mL) was added concentrated HCl (two drops). The mixture was then stirred at room temperature for 16 h before concentration. The residue was then diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (25 mL), water (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude desired product (250 mg, Yield 80%) which was used on the next step without further purification. LCMS (m/z): 366.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([SH:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.[CH3:21][NH2:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:12][CH:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:22]([CH3:21])[C:9]2=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(S)c1ccc(Cl)cc1
Reactant: CN
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2ccc(Cl)cc2)SC1c1cccnc1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
α-(4-Chlorophenyl)-α-mercaptoacetic acid (5.0 g, 0.025 mol) prepared in Reference Example 4, nicotinaldehyde (2.64 g, 0.025 mol) and 40% aqueous methylamine solution (5.75 g, 0.074 mol) were added to toluene (50 ml) and the mixture was subjected to azeotropic dehydration for 3 hours. After cooled, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (5% acetone-chloroform) and then recrystallized from ether to obtain 5-(4-chlorophenyl)-3-methyl-2-(3-pyridyl)-thiazolidin-4-one (6.59 g, yield 87.6%). m.p. 100°-101.5° C.
Reaction SMILES: [ClH:1].O1CCOCC1.C(ON=O)CC(C)C.C(N(CC)CC)C.[NH:23](C(OCC1C=CC=CC=1)=O)[C@H:24]([C:27]([NH:29][C@H:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][C:32](=[O:34])[NH2:33])=[O:28])[CH2:25][OH:26]>CN(C)C=O>[ClH:1].[NH2:23][C@H:24]([C:27]([NH:29][C@H:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][C:32](=[O:34])[NH2:33])=[O:28])[CH2:25][OH:26]
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO
Temperature: -70 °C
Reaction time: 0.58 h

Procedure:
pGlu-Ala-Lys(Xys)-Ser(Bzl)-Gln-Gly-Gly-NHNH2 (140 mg) is dissolved in dimethylformamide (5 ml). While the solution is cooled to -70° C., 6.51 N HCl-dioxane (0.05 ml) and isoamylnitrite (0.02 ml) are added. The mixture is stirred at -30° C. for 35 minutes and cooled again to -70° C., followed by addition of triethylamine (0.05 ml). HCl-H-Ser-Asn-OBut which is prepared by reducing Z-Ser-Asn-OBut (123 mg) is dissolved in dimethylformamide (2 ml) and this solution is added to the mixture, followed by addition of triethylamine (0.05 ml). The mixture is stirred between -15° C. and 5° C. for 30 hours. Insolubles are filtered off and the filtrate is distilled to evaporate the solvent. Ether is added and resulting powder is collected by filtration. Into a mixture of the powder and anisole contained in a cylinder of teflon resin, is introduced hydrogen fluoride (5 ml) and the mixture is stirred at 0° C. for one hour. Immediately the hydrogen fluoride is distilled off under reduced pressure and the residue is extracted twice-with water (10 ml each). The aqueous extract is washed three times with ether (3 ml each) and passed through a column (1.5×10 cm) of Amberlite IRA-410 (acetate form).
Reaction SMILES: [N:1]([C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1)=[N+]=[N-].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.O.ClCCl>[NH2:1][C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1.[C:26]1([P:19](=[O:7])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC1OC(=O)C=C1N=[N+]=[N-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC1OC(=O)C=C1N
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 304.5 %

Procedure:
A mixture of 4-azido-5-ethoxy-5H-furan-2-one (0.10 g, 0.59 mmol) and triphenylphosphine (0.15 g, 0.59 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was stirred for 20 h at room temperature, followed by 3d at 65° C. under nitrogen. The reaction was diluted with dichloromethane, washed with water, dried over sodium sulfate and evaporated to afford 4-amino-5-ethoxy-5H-furan-2-one in a mixture with triphenylphosphine oxide (0.25 g, 100% yield).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][C:8]1([CH3:20])[CH2:13][CH:12]([CH3:14])[CH2:11][CH:10]([O:15][C:16](=S)[NH:17][NH2:18])[CH2:9]1.[C:21](#N)[CH3:22]>>[CH3:7][C:8]1([CH3:20])[CH2:13][CH:12]([CH3:14])[CH2:11][CH:10]([O:15][C:16]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:21]([CH3:22])[NH:18][N:17]=2)[CH2:9]1
Reactant: CC#N
Reactant: CC1CC(OC(=S)NN)CC(C)(C)C1
Reactant: COC(=O)CCl
Product: COC(=O)c1c(OC2CC(C)CC(C)(C)C2)n[nH]c1C
Temperature: 25 °C

Procedure:
At room temperature and while stirring, 84 l g of methyl 2-chloroacetate is added to a solution, in 250 ml of acetonitrile, of the thiocarbazic acid-O-(3,3,5-trimethylcyclohexyl)-ester obtained in this manner. After stirring for 12 hours at room temperature, the mixture of solids which has precipitated out is separated by filtration and washed with acetone. The solids mixture is then stirred into 200 ml of aqueous ammonia solution (12 wt%) and subsequently extracted twice with methylene chloride (150 ml each time). After the methylene chloride solution has been dried over sodium sulfate, the solvent is evaporated. The solid which remains has, after recrystallization from a 2:1 mixture of toluene and n-hexane, a melting point of 167° to 168° C. and has, according to combustion analysis and nmr spectroscopy, the composition: ##STR11##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[NH:22][C:21]1=[O:28]>>[ClH:16].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[NH:22][C:21]3=[O:28])[CH2:12][CH2:13]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: Cc1cc(=O)n(CCCCl)c(=O)[nH]1
Reactant: COc1cc(F)ccc1N1CCNCC1
Product: COc1cc(F)ccc1N1CCN(CCCn2c(=O)cc(C)[nH]c2=O)CC1
Product: Cl

Procedure:
substituting 1-(4-fluoro-2-methoxyphenyl)piperazine and 3-(3-chloropropyl)-6-methyl-2,4(1H,3H)-pyrimidinedione gave 3-{3-[4-(4-fluoro-2-methoxyphenyl)piperazin-1-yl]propyl}-6-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 235-237° C.; Anal.: Calcd. for C19H25FN4O3.(HCl)2 : C, 49.20; H, 6.21; N, 12.08%; Found: C, 49.02; H, 6.22; N, 12.01%;