Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[S:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[N:10]([S:21]([CH:24]3[CH2:26][CH2:25]3)(=[O:23])=[O:22])C2=O)=[C:4]([Cl:28])[CH:3]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19]2[C:11]([NH:10][S:21]([CH:24]3[CH2:25][CH2:26]3)(=[O:22])=[O:23])=[CH:12][C:13]3[S:17][CH:16]=[N:15][C:14]=3[C:18]=2[F:20])=[C:4]([Cl:28])[CH:3]=1
Reactant: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3ncsc3cc2n1S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.10 mmol) in THF (5 mL) was added potassium trimethylsilanolate (13 mg, 0.10 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) and the product was obtained (30 mg, 63.3% yield). 1H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 8.00 (s, 1H), 7.89 (d, 1H), 7.84 (s, 1H), 7.75 (d, 1H), 7.43 (m, 1H), 5.48 (s, 1H), 2.84 (m, 1H), 1.29 (m, 2H), 1.23 (m, 2H). MS APCI (+) m/z: 477.9, [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:30])([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=O)[CH:8]=2)[N:3]=1.[CH2:31]([NH2:33])[CH3:32]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:30])([CH2:27][CH2:28][CH3:29])[C:24]([NH:33][CH2:31][CH3:32])=[O:26])[CH:8]=2)[N:3]=1
Reactant: CCCC(C)(C(=O)O)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Reactant: CCN
Product: CCCC(C)(C(=O)NCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoic acid [“A67”] with ethylamine);
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH2:15][CH2:16]/[C:17](/[C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=1)=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:8]2.Cl>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH2:15][CH2:16]/[C:17](/[C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=1)=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:8]2
Reactant: CCOC(=O)/C=C(\CCc1ccc2cc(OCOC)ccc2c1)c1ccc2ccccc2c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)/C=C(\CCc1ccc2cc(O)ccc2c1)c1ccc2ccccc2c1

Procedure:
A solution of (E)-ethyl 5-(6-(methoxymethoxy)naphthalen-2-yl)-3-(naphthalen-2-yl)pent-2-enoate (0.25 g, 0.57 mmol) in methanol (10 mL) was treated with 10% HCl (2 mL) and the resulting mixture was refluxed for 2 h. After cooling the solvent was removed, the residue was extracted with ethyl acetate (3×) and dried with MgSO4. Then the crude product was concentrated to obtain the product; yellow oil; yield: 0.095 g (quant, without further purification);
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:28])=[O:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH:34]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CN(c1ccc(N)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-methyl-N-methylsulphonyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1.[C:16]([O:20][C:21]([N:23]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:24]1[CH:25]=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[C:16]([O:20][C:21]([N:23]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:24]1[CH:25]([OH:26])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:10]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Brc1cccc(COC2CCCCO2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cccc(COC2CCCCO2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 55.1 %

Procedure:
A solution of 3-(tetrahydropyranyloxymethyl)bromobenzene (11.8 g, 43.5 mmol) in tetrahydrofuran (20 ml) was added dropwise to a solution of 1.6M n-butyl lithium-hexane solution (30 ml, 48 mmol) in tetrahydrofuran (100 ml) at -78° C. in a nitrogen stream over 15 minutes. This reaction solution was stirred at -78° C. for 40 minutes and then a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (7.2 g, 21.9 mmol) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. The reaction solution was stirred at -78° C. for 30 minutes and then allowed to gradually warm and saturated aqueous ammonium chloride was added thereto. This solution was poured into a liquid mixture of ethyl acetate with water and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=6:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[α-hydroxy-3-(tetrahydropyranyloxymethyl)benzyl]pyrrolidine (6.3 g, yield: 55.0%) as a yellow oily substance.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1([C:12](Cl)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1>C(OCC)(=O)C>[CH3:1][NH:2][C:12]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:13]
Reactant: CN
Reactant: O=C(Cl)C1CCc2ccccc21
Solvent: CCOC(C)=O
Product: CNC(=O)C1CCc2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 150 ml of ethyl acetate and 50 ml of 40% aqueous methylamine (approx. 0.5M) was stirred in an ice bath, while a solution of 11.7 g (65 mmol) of indane-1-carboxylic acid chloride, a compound of Formula 4 prepared, for example, as described in Preparation 4, dissolved 40 ml of ethyl acetate was added over a period of 15 minutes. Stirring was continued at ambient temperature for an additional 4 hours. The organic layer is separated, washed three times with water, once with 10% HCl, and once with saturated sodium bicarbonate. Evaporation of the ethyl acetate yielded 9.0 g of 1-methylaminocarbonyl-indane, an amide of Formula 13; (mp 107°-109° C.; ir 1635 cm-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C@@H:15]2[CH2:19][CH2:18][N:17]([C@@H](C3C=CC=CC=3)CO)[CH:16]2[CH:29]2[CH2:31][CH2:30]2)[CH2:11][CH2:10]1>CCO.[OH-].[OH-].[Pd+2]>[CH:29]1([CH:16]2[C@H:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:14][CH2:13]3)[CH2:19][CH2:18][NH:17]2)[CH2:30][CH2:31]1
Reactant: COc1ccccc1C1CCN([C@@H]2CCN([C@H](CO)c3ccccc3)C2C2CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C1CCN([C@@H]2CCNC2C2CC2)CC1
Yield: 100.7 %

Procedure:
A solution of (2S)-2-((3R)-3-(4-(2-methoxyphenyl)piperidin-1-yl)-2-cyclopropylpyrrolidin-1-yl)-2-phenylethanol (preparation #26) (1.708 g, 4.06 mmol) in EtOH (25 mL) was hydrogenated under hydrogen at about 60 bar at about 60° C. in a H-cube™ apparatus using palladium hydroxide on carbon (20%) as a catalyst until all starting material was converted to product. The solvent was removed in vacuo to afford 1-((3R)-2-cyclopropylpyrrolidin-3-yl)-4-(2-methoxyphenyl)piperidine (1.23 g, 4.09 mmol) as an orange oil. RP-HPLC (Table 1, Method a) Rt 1.48 min; m/z: (M+H)+ 301.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7](N)[CH:6]=1)=[O:4].[I:20]C1C=C(C#N)C=C2C=1C1C=C(C)C=NC=1N2>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7]([I:20])[CH:6]=1)=[O:4]
Reactant: Cc1cnc2[nH]c3cc(C#N)cc(I)c3c2c1
Reactant: COC(=O)c1cc(N)c2c(c1)[nH]c1ncc(C)cc12
Product: COC(=O)c1cc(I)c2c(c1)[nH]c1ncc(C)cc12
Yield: 69 %

Procedure:
The title compound was prepared in 69% yield from Compound 130 according to the procedure outlined for the preparation of Compound 125. MS (ES) [m+H] calc'd for C14H11IN2O2, 367; found 367.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(Cl)CCl.[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([O:8][C:7](=[O:9])[CH2:6][CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)SC(CC(=O)O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)SC(CC(=O)OCc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
The product from Step B (5.4 g, 26.2 mmol) was taken up in DCM (50 mL) with stirring and cooled to 0° C. EDC (6.0 g, 31.4 mmol) and DMAP (164 mg, 1.31 mmol) were added followed by benzyl alcohol (2.4 mL, 23.6 mmol). The resulting solution was stirred at room temperature overnight with the exclusion of moisture. The reaction was diluted with DCM and washed successively with 1 M HCl, water, 5% Na2CO3 solution, brine and dried, filtered and evaporated to give a dark oil. This was purified by silica gel column chromatography eluting with hexane/ethyl acetate 1:1 to give the product as an orange oil (5.98 g, 70%). 1H-NMR δ (CDCl3) 7.38-7.17 (10H, m); 5.11 (2H, s), 4.08 (1H, m), 2.96 (2H, d, J=6.4 Hz), 2.64 (2H, d, J=6.4 Hz) and 2.27 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[NH2:15][C:16]1[N:21]([CH3:22])[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[CH:17]=1>C(O)CC>[NH2:9][C:8]1[C:5]([C:6]#[N:7])=[C:4]([C:3]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=2[Cl:1])[C:17]2[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:16]=2[N:15]=1
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Solvent: CCCO
Product: Cn1c(=O)c2c(-c3ccc(Cl)cc3Cl)c(C#N)c(N)nc2n(C)c1=O

Procedure:
A mixture of 1a (150 mg, 0.6 mmol) and 6-amino-1,3-dimethyl uracil (200 mg, 1.2 mmol) in propanol (5 ml) was refluxed overnight, concentrated, redissolved in DCM, washed with 5% aqueous HCl, water, dried over Na2SO4, and concentrated to give the crude product 7-amino-5-(2,4-dichlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (1b).
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][C:12]=3[N:3]12.[CH2:26]([C@H:33]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH:36]=[C:35](OS(C(F)(F)F)(=O)=O)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:26]([C@H:33]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH:36]=[C:35]([C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:4]4=[N:5][NH:6][C:7](=[O:8])[C@@H:2]([CH3:1])[N:3]4[C:12]=3[CH:13]=2)[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)[C@H](Cc5ccccc5)C4)cc3N21
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of (R)-1-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (0.515 g, 1.5 mmol), (R)-tert-butyl 6-benzyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.900 g, 2.13 mmol), Pd(dppf)Cl2—CH2Cl2 complex (0.309 g, 0.375 mmol) and K2CO3 (0.622 g, 4.50 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was heated at 90° C. for 4 h. The reaction was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give (R)-tert-butyl 6-benzyl-4-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.330 g, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:46]2[C:41](=[N:42][C:43]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])=[CH:44][CH:45]=2)[O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:43]4[N:42]=[C:41]5[O:40][CH2:39][CH2:38][O:37][C:46]5=[CH:45][CH:44]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2ccc3c(n2)OCCO3)NC(=O)NC1=O
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(n3)OCCO4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7]N)=[O:6])[CH2:3][OH:4].N(OCCC(C)C)=O.C(N(CC)CC)C.N[C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37].Cl>CN(C)C=O.Cl.O1CCOCC1>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:6])[CH2:3][OH:4]
Reactant: NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
5.06 Grams of Z-Ser-NHNH2 was dissolved in 50 ml of dimethylformamide with 6.66 ml of 6N-hydrochloric acid/dioxane, the solution was cooled to -15° C. then 2.68 ml of isoamyl nitrite was added thereto, and the mixture was stirred for 5 minutes. Next, 5.60 ml of triethylamine was added to neutralize the reaction mixture. This reaction mixture was added to 30 ml of dimethylformamide solution containing 3.11 g of H-Ser-OMe.HCl and 2.80 ml of triethylamine, then this mixture was stirred at 4° C. for 20 hours. Dimethylformamide was removed by distillation, the residue obtained was extracted with ethyl acetate, the extract was washed with water and was dried with anhydrous sodium sulfate. After removal of ethyl acetate by distillation, the residue was crystallized by adding ether, reprecipitated from ethyl acetate-ether to obtain 3.75 g of Z-Ser-Ser-OMe.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:15]>Cl.O1CCCC1>[ClH:1].[C:8]([O:9][CH2:10][C:11]([NH2:12])([CH3:14])[CH3:13])(=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CC1(C)COC(c2ccccc2)=N1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(N)COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To 8.7 g (0.041 mol) 2-phenyl-4,4-dimethyl-1,3-oxazoline hydrochloride suspended in 120 ml anhydrous hydrogen chloride in tetrahydrofuran (1M) was added 3.6 ml (0.20 mol) water. The mixture was warmed to cause solution and heated under reflux with stirring for 1 hour. The tetrahydrofuran was removed under reduced pressure to afford a nearly colorless oil which crystallized at 0° following the addition of anhydrous ether. The solid was triturated with anhydrous ether overnight and isolated by filtration under a nitrogen atmosphere. After drying in vacuo over calcium sulfate, 6.9 g (0.30 mol), 73%, 2-amino-2-methyl-1-propyl benzoate hydrochloride was obtained as a white solid, mp 225°-228° (dec.) acetone:hexane, ir (KBr) 1725 (c=o) cm-1, pmr (D2O) δ 1.50 (s, 6H), 4.4 (s, 2H) and 7.0 - 8.3 (m, 5H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:20]([C:30]([O:32][CH2:33][CH2:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:31])=[C:19]([CH3:48])[NH:18][C:17]=2[CH3:49])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C([O-])=O>ClCCl>[C:42]1([CH:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:34][CH2:33][O:32][C:30](=[O:31])[C:20]2[C:21]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)=[C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[C:17]([CH3:49])=[N:18][C:19]=2[CH3:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2cc(Cl)cc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N2CCNCC2)c(-c2cc(Cl)cc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
419 mg (0.595 mmol) of 4-[4-(3,5-dichlorophenyl)-5-(3,3-diphenylpropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester was dissolved in 15 ml of dichloromethane. After adding 7 ml of trifluoroacetate under cooling with ice, the reaction mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane) to obtain the title compound.
Reaction SMILES: Cl.[N:2]1[CH:3]=[C:4]2[N:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=13)[S:7][C:6]([C:14]([OH:16])=O)=[CH:5]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:39][CH2:40][C:41]1[CH:60]=[CH:59][C:44]([CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[CH:43][CH:42]=1>C(#N)C.C(N(CC)CC)C>[CH2:52]([CH:49]1[CH2:50][CH2:51][N:46]([CH2:45][C:44]2[CH:43]=[CH:42][C:41]([CH2:40][NH:39][C:14]([C:6]3[S:7][C:8]4[N:13]5[C:4](=[CH:3][N:2]=[C:12]5[CH:11]=[CH:10][CH:9]=4)[CH:5]=3)=[O:16])=[CH:60][CH:59]=2)[CH2:47][CH2:48]1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid hydrochloride and 0.90 g (7.82 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.51 g (7.88 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature, and the mixture was stirred for 2 hours. To this reaction mixture was added a solution of 1.88 g (5.12 mM) of 1-[4-(aminomethyl)benzyl]-4-benzylpiperidine dihydrochloride and 0.55 ml (3.95 mM) of triethylamine in acetonitrile (20 ml) and the mixture was further stirred for 4 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (a small amount of ethanol was additionally used). The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 20%) to provide the title compound as red amorphous substance.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:41]=[CH:40][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:42]1([OH:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH:42]1([O:48][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[CH:28][C:29]([N:32]6[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]6)=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:40][CH:41]=3)=[CH:4][CH:3]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nc4)cc3)cc2)S(=O)(=O)N1
Reactant: OC1CCCCC1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OC5CCCCC5)nc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-[4-(6-Chloro-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (63 mg, 0.1 mmol) was treated as described in general procedure L using cyclohexanol (20 mg, 0.2 mmol) to give 5-{4-[2[4-(6-cyclohexyloxy-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=O)[O:11][C:12](=[O:14])[CH:13]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(CC#[N:28])=CC=1.O.C(O)(=O)C=O.C(=O)([O-])[O-].[K+:41].[K+]>CO>[K+:41].[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=1)=[CH:13][C:12]([O-:11])=[O:14])#[N:28]
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: O=C1C=C(c2ccc(C(F)(F)F)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: O=CC(=O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC(=CC(=O)[O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(4-Trifluoromethyl-phenyl)-furan-2,5-dione. A mixture of 4-(trifluoromethyl)phenylacetonitrile (9.26 g, 50 mmol), glyoxylic acid monohydrate (6.9 g, 75 mmol), and potassium carbonate (17 g, 125 mmol) in methanol (100 mL) was stirred at room temperature for 3-5 h. The resulting thick solid precipitate was filtered and washed with dichloromethane. This solid was suspended in 250 mL of water, stirred overnight, and filtered and air-dried to provide 3-cyano-3-(4-trifluoromethyl-phenyl)-acrylic acid potassium salt. This was dissolved in 88% formic acid (ca. 200 mL) containing concentrated sulfuric acid (15 mL). This mixture was heated at reflux for 2-3 h and cooled and poured into ice water. The resulting precipitate was collected by filtration, washed with water, and air dried to provide the title compound. 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 7.97 (d, J=8.2 Hz, 2H), 8.24 (d, J=8.2 Hz, 2H).