Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][OH:20])=[CH:16][O:17][C:13]=2[CH:12]=1.CCN(C(C)C)C(C)C.[O:32](S(C)(=O)=O)[S:33]([CH3:36])(=O)=[O:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][O:20][S:33]([CH3:36])(=[O:34])=[O:32])=[CH:16][O:17][C:13]=2[CH:12]=1
Reactant: OCCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.5 %

Procedure:
To a solution of 2-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-yl]-ethanol (0.4 g, 1.3 mmol) in DCM (13 mL) was added 4-dimethylaminopyridine (16 mg, 0.13 mmol), DIEA (0.27 mL, 1.5 mmol) and Ms2O (0.27 g, 1.5 mmol) and the resulting solution was stirred (rt, 15 min). The reaction mixture was diluted with DCM (40 mL). The organic layer was washed with saturated NH4Cl (2×50 mL), brine (2×50 mL), dried, filtered and concentrated in vacuo to provide the title compound as a clear oil (0.52 g, 100%). MS (ESI): mass calcd. for C17H14N2O5S2, 390.4; m/z found, 391.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[C:4]([F:21])[CH:3]=1.C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.C(C1C=C(NC(=O)C2C=CC(N3CCNCC3)=C(F)C=2)C=CC=1)(C)(C)C>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:3][C:4]=2[F:21])[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)cc2F)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2F)c1

Procedure:
N-(3-tert-Butyl-phenyl)-2-fluoro-4-piperazin-1-yl-benzamide was synthesized from 4-bromo-N-(3-tert-butyl-phenyl)-2-fluoro-benzamide and piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide above. LCMS calcd for C21H26FN3O (m/e) 355, obsd 356 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH:17]([OH:20])([CH3:19])[CH3:18].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:20][CH:17]([CH3:19])[CH3:18])[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CC(C)O
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)Oc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, isopropanol and DBU in THF. ES-MS m/e (%): 346 (M+H+, 100).
Reaction SMILES: [C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH2:23])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2].[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](O)=[O:29]>>[C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:28](=[O:29])[C:27]([Cl:32])([Cl:31])[Cl:26])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2]
Reactant: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: O=C(O)C(Cl)(Cl)Cl
Product: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CNC(=O)C(Cl)(Cl)Cl)OC3=O)cc2F)CC1
Yield: 45 %

Procedure:
The title compound was prepared by following the procedure of Example 29 and by using (S)-N-{3-[4-(4-(1-cyanoethylidene)-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and trichloroacetic acid in 45% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][CH3:30])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH2:29]([C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[N:13][CH:12]=3)=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=1)[CH3:30]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3)CC2)c(C)c1
Yield: 55.9 %

Procedure:
Using pyrrolidin-2-one (49 mg) and (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 145 and by the reaction and treatment in the same manner as in Example 1, the title compound (113 mg) was obtained.
Reaction SMILES: CC(S([NH:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[NH:16][C:12]=2[CH:11]=1)[CH3:9])=O)(C)C.[ClH:20]>CO>[ClH:20].[NH2:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[NH:16][C:12]=2[CH:11]=1)[CH3:9]
Reactant: CC(NS(=O)C(C)(C)C)c1ccc2[nH]c(=O)[nH]c2c1
Agent: Cl
Solvent: CO
Product: CC(N)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A mixture of 2-methyl-N-[1-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)ethyl]propane-2-sulfinamide (430 mg, 1.53 mmol) and 10% hydrochloride in MeOH (10 ml) was stirred at room temperature for 4 hours. The mixture was concentrated, triturated with MeOH to give 265 mg (81%) of the title compound as a pale brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.50 (3H, d, J=6.6 Hz), 4.40-4.31 (1H, m), 6.94 (1H, d, J=7.3 Hz), 7.06 (1H, d, J=8.1 Hz), 7.10 (1H, s), 8.38 (2H, br.s), 10.74 (1H, br.s), 10.83 (1H, bs). MS (ESI) m/z 178 (M+H)+, 176 (M−H)−.
Reaction SMILES: C(Cl)CCl.[CH3:5][N:6]1[C:10](=[O:11])[CH:9]=[CH:8][S:7]1=[O:12].[CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]=1>>[CH3:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:18]3[CH2:17][CH2:16][CH:15]([CH:8]2[S:7]1=[O:12])[CH:14]=[CH:13]3
Reactant: CN1C(=O)C=CS1=O
Reactant: C1=CCCC=C1
Solvent: ClCCCl
Product: CN1C(=O)C2C3C=CC(CC3)C2S1=O
Reaction time: 8 h
Yield: 93 %

Procedure:
A 30 ml solution of ethylene dichloride containing 3.3 g (0.025 mole) of 2-methyl-4-isothiazolin-3-one 1-oxide and 2.0 g (0.025 mole) of cyclohexadiene is heated at 52°-53° C. and stirred overnight. The solution is concentrated to give 4.9 g (93%) of a white solid, m.p. 118°-120° C. which can be recrystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([NH:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[CH2:42][CH2:43][CH2:44][C@H:37]12.[C:45](=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([N:18]([C:19]3[CH:20]=[N:21][C:22]([N:41]4[CH2:40][CH2:39][N:38]5[CH2:42][CH2:43][CH2:44][C@@H:37]5[CH2:36]4)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])[CH3:45])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1NC(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=C([O-])[O-]
Reactant: C1C[C@@H]2CNCCN2C1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@@H]3C2)ncc1N(C)C(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 150 °C
Yield: 60 %

Procedure:
The title compound was prepared starting from 100 mg (0.188 mmoles) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]cyclopropanecarboxamide (D2), 70 mg (0.554 mmol) of (8aR)-octahydropyrrolo[1,2-a]pyrazine, 52.2 mg (0.377 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 1:1, to ethyl acetate 100% and affording 70 mg of the title compound as pale yellow solid.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCCC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 3 h
Yield: 101 %

Procedure:
A mixture of tert-butyl 3-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate 153 (0.40 g, 0.82 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 154 (0.33 g, quantitative yield) as a white foam.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:17])[CH2:14][CH2:15]O>>[OH:7][CH2:6][CH2:5][CH2:4][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:15][CH2:14][CH2:13][OH:17])=[O:11])=[CH:3][CH:4]=1
Reactant: OCCCO
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: O=C(OCCCO)c1ccc(C(=O)OCCCO)cc1
Temperature: 245 °C
Reaction time: 3.5 h

Procedure:
50.6 kg of terephthalic acid (TPA) and 30.2 kg of 1,3-propanediol (PDO) were charged in an esterification vessel and stirred thoroughly at a stirring rate of 130 rpm in the presence of an esterification catalyst. Nitrogen was then introduced at a flow rate of 4 L/min, and the reaction pressure was maintained at 2 kg/cm2G. The internal temperature of the esterification vessel was increased to 245° C. During the esterification process, the byproducts water and 1,3-PDO were separated by using a separation tower such that 1,3-PDO was introduced to the esterification reaction system and that water was made to flow out from the top of the tower, which is then cooled and recovered. The total esterification reaction time was 3.5 hours. The esterified product BHPT was cooled and crushed, by which the saponification value can be determined, and the saponification value was then converted to have a calculated esterification conversion of 98.1%. The reaction conditions are summarized in Table 1.
Reaction SMILES: C(N[C:5]([C:7]([NH:9][C:10](=[O:12])[CH3:11])=O)=[O:6])(=O)C.[CH2:13]([CH2:15][NH2:16])[OH:14].C[OH:18]>>[OH:14][CH2:13][CH2:15][NH:16][C:11]([C:10]([NH:9][CH2:7][CH2:5][OH:6])=[O:12])=[O:18]
Reactant: CC(=O)NC(=O)C(=O)NC(C)=O
Reactant: NCCO
Reactant: CO
Product: O=C(NCCO)C(=O)NCCO
Reaction time: 2 h
Yield: 93 %

Procedure:
A suspension of N,N'-diacetyloxamide (10 g, 0.058 mol) in anhydrous methyl alcohol (50 ml) is charged into a four-necked flask equipped with a reflux condenser, an inlet tube for nitrogen, a dropping funnel, a thermometer, and a magnetic stirrer. A solution of monoethanolamine (8.2 g, 0.134 mol) in anhydrous methyl alcohol (20 ml) is gradually dripped in at 25° C. The reaction is exothermic and the temperature rises up to 60° C. The reaction is allowed to proceed at this temperature for 2 hours, then the reaction mixture is cooled and the precipitate is recovered by filtration. The compound of the title is thus obtained (9.5 g, 0.054 mol, 93% yield) with m.p. 166°-69° C.
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][NH:7][C:8]([CH3:15])([C:10]([NH:13][OH:14])([CH3:12])[CH3:11])[CH3:9].[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=O>O>[OH:6][N:7]1[C:8]([CH3:15])([CH3:9])[C:10]([CH3:12])([CH3:11])[N:13]([OH:14])[CH:16]1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(NO)C(C)(C)NO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)N(O)C(c2ccc(C(=O)O)cc2)N(O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
24.6 g of 2,3-bis-(hydroxyamino)-2,3-dimethylbutane sulfate was dissolved in 100 ml of water. After neutralized with 1M KHCO3 with cooling on ice, the solution was added with 15.0 g of p-formylbenzoic acid and was agitated overnight at room temperature. The precipitate was dried and 16.9 g of 1,3-dihydroxy-4,4,5,5-tetramethyl 2-(4-carboxyphenyl)imidazole (I) was obtained.
Reaction SMILES: [C:1]([S:9][CH2:10][CH2:11][C:12]([N:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH2:17][CH2:16][CH:15]1[C:26]([OH:28])=O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[C:37]([O:41][C:42](=[O:52])[C@H:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[NH2:44])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C>C1COCC1.C(Cl)(=O)OCC(C)C>[C:37]([O:41][C:42](=[O:52])[C@H:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[NH:44][C:26]([C@@H:15]1[CH2:16][CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[N:14]1[C:12](=[O:13])[CH2:11][CH2:10][S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(SCCC(=O)N1C(C(=O)O)CCC1c1ccccc1O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CCSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To the solution of 1.43 g of 1-(S-benzoyl-3-mercaptopropanoyl)-5-(2-hydroxyphenyl)-2-pyrrolidinecarboxylic acid (mp 89°-92° C. (dec.); [α]D25 +47.4° (c=1.0, methanol)) and 0.3 g of N-methylmorpholine dissolved in 30 ml of dry THF 0.41 g of isobutyl chlorocarbonate is added at a temperature of -15° to -10° C. After stirring it for 30 minutes, the solution of 0.77 g of L-phenylalanine t-butyl ester hydrochloride and 0.3 g of triethylamine dissolved in 10 ml of aqueous THF is added to it. After stirring the mixture under ice-cooling for 30 minutes and at room temperature for an additional 30 minutes, and then removing THF in vacuo, the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, in order, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 1.5 g (83%) of the titled compound.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([C:12]3[S:13][CH:14]=[CH:15][N:16]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1csc(N2CCC3(CC2)OCCO3)n1
Yield: 60.8 %

Procedure:
4-Piperidone ethylene ketal (2.0 ml, 16 mmol), 2-bromothiazole (2.68 g) and caesium carbonate (8.9 g) in DMF (20 ml) were heated at 90°-100° C. for 16 h . The cooled mixture was diluted with water, extracted twice with ether, the ether layers washed with water six times, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting with 50% ether/hexane to afford the title compound as a pale yellow oil (2.2 g), MS (+EI) 226 (M+), 1H NMR (CDCl3) 7.17 (1H, d, 3.6 Hz), 6.55 (1H, d, 3.6 Hz), 4.00 (4H, s), 3.65-3.61 (4H, m), 1.83-1.80 (4H, m).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:7].CO>O>[NH2:3][C:4]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Cl)cc1C(O)c1ccccc1F
Reaction time: 16 h

Procedure:
A solution of 18.5 g of sodium borohydride in 125 ml of water is added dropwise at 20° to 25° within 20 minutes to a solution of 124.8 g of 2-amino-5-chloro-2'-fluorobenzophenone. The mixture is stirred for a further 16 hours. 250 ml of methanol are then added thereto and the mixture is heated to boiling under reflux for 15 minutes. After evaporation of the organic solvent, the residue is diluted with water, whereupon the mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solutions are washed, dried, concentrated to 100 ml in vacuo and subsequently treated with 300 ml of petroleum ether. There is obtained crystalline 2-amino-5-chloro-2'-fluorobenzhydrol of melting point 97°-99°.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]2[N:14]=[C:15]([SH:17])[NH:16][C:10]=2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>ClCCl.CO>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]2[N:14]=[C:15]([S:17][CH3:19])[NH:16][C:10]=2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2[nH]c(S)nc2ccn1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CO
Solvent: ClCCl
Product: CSc1nc2ccn(Cc3ccccc3)c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.0 g (15.55 mmol) of 5-benzyl-2-mercapto-3,5-dihydro-imidazo[4,5-c]pyridin-4-one were suspended in a mixture of 100 ml of dichloromethane and 50 ml of methanol, then 2.15 g (15.55 mmol) of potassium carbonate and 0.97 ml (15.55 mmol) of iodomethane were added and the mixture was stirred for 1 hour at ambient temperature. Then it was filtered, the filtrate was evaporated down and the residue was further reacted in its crude form.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:19](=O)([O:28][CH2:29][CH:30]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:37][C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:20]N1C(=O)CCC1=O>O.O1CCOCC1>[CH:42]1[C:43]2[CH:30]([CH2:29][O:28][C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:20])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:37][C:38]=2[CH:39]=[CH:40][CH:41]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCC1c2ccccc2Oc2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a suspension of 0.467 g of L-phenylalanine and 0.6 g of sodium carbonate in 6 mL of water and 6 mL of dioxane was added dropwise at 0° C. a solution of 1.0 g of succinimidyl 9-xanthenylmethyl carbonate in 10 mL of dioxane over a period of 10 minutes. The mixture was stirred at room temperature for four hours, washed with ether (2×15 mL), and the ether layer was discarded. The aqueous layer was acidified with 10% HCl (Congo Red) and extracted with EtOAc (3×15 ml). The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to give 1.02 g (89.43%) of the crude Xmoc-Phe-OH as a colorless oil. Crystallization from Skelly B -EtOAc (3:1) gave 0.77 g (67.51%) of the pure Xmoc-Phe-OH as white crystals, m.p. 143°-145° C.; IR KBr: 3420 (NH and OH), 1720 (C=O)cm-1 ; 1H NMR (CDCl3): δ 2.90-3.30 (m, 2H, CH2Ar), 4.40-4.45 (m, 3H, CH--CH2O), 4.65 (m, 1H, NCH), 5.18 (b, 1H, NH), 6.85-7.60 (m, 13H, aryl); [α]23D -3.1 (c=1, EtOAc), [α]23 546 -3.4 (c=1, EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: O=Cc1ccccc1O
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccccc1O
Yield: 76 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with salicylaldehyde as described in Example 11. 1-Nitro-5-(o-hydroxyphenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is obtained with a yield of 76%. M.p.: 235°-237° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27](O)[CH3:28])[CH2:22][CH2:21]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([O:15][CH:27]([CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1)[CH3:28])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(O)CN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CSCCC(NC(=O)OCc1ccccc1)C(=O)OC(C)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyric acid (1.13 g; 2.76 mmol), 1-(morpholino)propan-2-ol (0.57 ml; 4 mmol), EDC (0.768 g; 4 mmol), DMAP (0.488 g; 4 mmol) in dichloromethane (5 ml) was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give 1-(morpholinoprop-2-yl 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyrate as a foam. Yield=55%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-fluorobenzyl bromide (15 g, 79 mmol) and 2-piperidinone (8.4 g, 85 mmol) in DMF (150 mL) was added sodium hydride (3.6 g of a 60% suspension in mineral oil, 90 mmol) in portions over a period of 20 min. The mixture was stirred at ambient temperature for 18 hours. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residual oil was purified using silica gel column chromatography eluting with 50%-70% ethyl acetate in hexanes. The appropriate fractions were combined and concentrated to afford the title compound as white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=8.7; 5.4 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 4.56 (s, 2H), 3.18 (t, J=6 Hz, 2H), 2.46 (t, J=6 Hz, 2H), 1.79 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCC(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(C)c1ccc(N)cc1
Yield: 84.7 %

Procedure:
A mixture of 114 g of ethyl 4-(4-nitrophenyl)pentanoate, 170 ml of absolute ethanol and 2 g of 10% palladium-on-charcoal, was hydrogenated (Paar shaker) until consumption of hydrogen ceased. The catalyst was filtered and the ethanol evaporated. The residue was partitioned between water and ether. The ether extract was washed with 5% sodium bicarbonate and water. The ether extract was dried over anhydrous sodium sulfate, filtered and evaporated to give an oil. The oil was distilled 0.55-0.60 mm to give 85 g (86%) of product, b.p. 118°-122° C.