Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:19][C:10]3=[N:11][CH:12]=[C:13]4[C:17]([NH2:18])=[N:16][NH:15][C:14]4=[C:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2[O:19][C:10]3=[N:11][CH:12]=[C:13]4[C:17]([NH:18][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[N:16][NH:15][C:14]4=[C:9]3[C:8]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN=C=O
Reactant: Nc1n[nH]c2c1cnc1oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1n[nH]c2c1cnc1oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 50 °C

Procedure:
To a solution of 11 (22 mg, 0.068 mmol, 1.0 equiv) in THF (2 mL) was added 4-(Dimethylamino)pyridine (1 mg, 0.008 mmol, 0.1 equiv) and ethyl isocyanate (53 μL, 0.675 mmol, 10.0 equiv). After heating at 50° C. for 2 hrs, the solvent was removed in vacuo. The resulting yellow residue was purified by silica gel chromatography (5% MeOH:CH2Cl2) to afford urea 12a. MS (MH+) 398.4; Calculated 397.2 for C23H19N5O2.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[CH:12]2)=[N:9][CH:10]=1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([Br:1])[CH2:12]2)=[N:9][CH:10]=1
Reactant: BrBr
Reactant: O=c1cc(C(F)(F)F)ncn1-c1ccc(C(F)(F)F)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=C(C(F)(F)F)N(Br)CN1c1ccc(C(F)(F)F)cn1
Reaction time: 16 h

Procedure:
Bromine (0.15 ml) was added in one portion to a suspension of 1-(5-trifluoromethyl-2-pyridyl)-4-trifluoromethylpyrimidin-6-one (compound No. 2 in Table I) (0.5 g) and sodium acetate trihydrate (1.1 g) in acetic acid (4.8 ml). After stirring for 16 hours, the solvent, was removed under reduced pressure, and the residue was poured into water and aqueous sodium bicarbonate solution. Rigourous extraction into diethylether followed by drying over magnesium sulphate and removal of the solvent under reduced pressure, gave 1-(5-trifluoromethyl-2-pyridyl)-3-bromo-4-trifluoromethylpyrimidin-6-one as a pale yellow solid (m.p. 142-143° C.). The compound showed (CDC13) 8.90 (1H,s), 8.80 (1H,s), 8.2 (1H,dg), 8.16 (1H,d).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14](OC)=[O:15])[C:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:7]2[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])[CH2:31][CH2:30]1)=[O:28].Cl.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][OH:15])[C:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[C:7]2[CH2:25][CH2:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])[CH2:33][CH2:34]1)=[O:28]
Reactant: COC(=O)Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(c3ccccc3OC)CC2)c2cc(Cl)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(CCO)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
Lithium borohydride (5 mg) was added in one portion to a solution of methyl 5-chloro-2-(4-chlorophenyl)-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]-3-oxoprop-1-yl}-1H-indole-1-acetate (Example 140, 43 mg) in THF (2 mL) and toluene (1 mL) and the mixture was stirred at room temperature for 15 min., then at 60° C. for 45 min. The mixture was cooled, hydrochloric acid (1M, 2 mL) was added and the mixture was stirred at room temperature for 10 min. Potassium carbonate and ethyl acetate (30 mL) were added and the layers were separated. The organic phase was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was recrystallised from ethyl acetate and the solid was collected and dried in vacuo to give the title compound as a colorless solid (21 mg). m/z (ES+) 552, 554 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[Cl:22][C:23]1[C:24]([O:8][C:6]2[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[N:11][CH:10]=3)=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[C:2]([Cl:1])[CH:7]=2)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: Oc1cc(Cl)c(-c2cccc(F)c2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4cccc(F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
2-Chloro-3′-fluoro-5-(pyridazin-4-yl)biphenyl-4-ol (Preparation 67, 98 mg, 0.33 mmol) was dissolved in dimethylsulfoxide (2 mL) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 181 mg, 0.39 mmol) and potassium carbonate (135 mg, 0.98 mmol) were added. The reaction was stirred at room temperature for 18 hours. Water (10 mL) and ethyl acetate (15 mL) were added and the two layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% heptane in ethyl acetate) to give the title compound (165 mg, 67%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.Cl.Cl.Cl.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C@H:36]2[CH2:39][C@@H:38]([NH2:40])[CH2:37]2)=[N:33][CH:34]=1.CC(C)([O-])C.[Na+]>ClCCCl.C1COCC1.O>[CH3:12][C:8]1([CH3:13])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:40]([C@H:38]2[CH2:37][C@@H:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]=3)[CH2:39]2)[C:9]1=[O:11]
Reactant: Cc1ccc(N[C@H]2C[C@@H](N)C2)nc1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N[C@H]2C[C@@H](N3C(=O)C(C)(C)c4nccnc43)C2)nc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (0.200 g, 0.997 mmol), (INTERMEDIATE 29), in DCE (2 mL) was treated with thionyl chloride (2 ml, 27.4 mmol) at room temperature and the resulting solution heated to 60° C. for 1 h and concentrated. The residue obtained was dissolved in THF (5 mL) and triethylamine (0.416 ml, 2.99 mmol) and cis-N1-(5-methylpyridin-2-yl)cyclobutane-1,3-diamine trihydrochloride (INTERMEDIATE 61) (0.314 g, 1.097 mmol) were added. After stirring at room temperature for 30 minutes, sodium tert-butoxide (0.610 ml, 4.98 mmol) was added. The reaction mixture was stirred at room temperature for another 1 h, then diluted with water and extracted with EtOAc. EtOAc was concentrated and residue purified with ISCO eluting with 0-80% EtOAc/hexanes to afford the title compound 7,7-dimethyl-5-(cis-3-((5-methylpyridin-2-yl)amino)cyclobutyl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.192 g, 0.594 mmol, 59.6% yield). m/z: 324.2 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ; ppm 8.02-8.16 (m, 2 H), 7.93 (d, J=0.78 Hz, 1 H), 7.25-7.31 (m, 2 H), 6.37 (d, J=8.41 Hz, 1 H), 4.99 (d, J=8.41 Hz, 1 H), 4.79 (quin, J=8.71 Hz, 1 H), 4.02-4.26 (m, 1 H), 2.92-3.06 (m, 3 H), 2.74-2.90 (m, 3 H), 2.18 (s, 4 H), 1.44 (s, 8 H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=3)[C:4]=2[CH:3]=1.B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=3)[C:4]=2[CH:3]=1
Reactant: CCC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 38.3 %

Procedure:
The title compound was prepared from 2-bromo-6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (0.61 g, 1.3 mmol), tetrabutylammonium iodide (1.1 g, 3.1 mmol), and 1 M boron trichloride in dichloromethane (9.0 mL, 9.0 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (3:7 to 1:1 gradient), followed by trituration from a mixture of ethyl acetate-hexane to yield 4-[(2-bromo-6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.23 g, 38%), m.p. 220-221° C.;
Reaction SMILES: [OH-:1].[Mg+2:2].[OH-].[Si:4]([OH:8])([OH:7])([OH:6])[OH:5]>>[Si:4]([O-:8])([O-:7])([O-:6])[O-:5].[Mg+2:2].[Mg+2:2].[OH-:1].[Mg+2:2].[OH-:5]
Reactant: O[Si](O)(O)O
Agent: [Mg+2]
Agent: [OH-]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
Patent document 1 discloses a method of manufacturing a magnesium hydroxide particle having a large specific surface area by heating magnesium hydroxide and amorphous silicic acid in an aqueous medium to form magnesium silicate on the surface of a magnesium hydroxide particle. However, the reason that the specific surface area of the magnesium hydroxide particle obtained by this manufacturing method is large is assumed to be the influence of both magnesium silicate formed only on the surface and amorphous silicic acid which seems to remain unreacted partially. It is hard to say that the specific surface area of the magnesium hydroxide particle becomes large.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCCO)C>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 180 mg (0.96 mmol) of 4-phenoxyaniline in 5 mL of 2-ethoxyethanol is heated at reflux temperature for 3 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with saturated sodium bicarbonate, followed by brine, then dried over sodium sulfate and filtered through a pad of diatomaceous earth. Concentration in vacuo yields 115 mg (35%) of a beige solid, mp 175-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:31])[C:8]4[CH:20]=[C:19]([Br:21])[C:18]([O:22][CH2:23][C@H:24]5[CH2:28][O:27]C(C)(C)[O:25]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl>CO>[Br:21][C:19]1[C:18]([O:22][CH2:23][C@H:24]([OH:25])[CH2:28][OH:27])=[CH:17][C:9]2[C:10]([CH3:15])([CH3:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:31])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:14]=4
Reactant: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Agent: Cl
Solvent: CO
Product: CC1(C)c2cc(OC[C@H](O)CO)c(Br)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-1, 56 mg, 0.11 mmol) was dissolved in methanol (5 mL), added with 1 N hydrochloric acid (0.2 ml), and stirred at 50° C. for 2 hr. After cooling, the reaction solution was concentrated under reduced pressure and the resulting residues were added with methanol to obtain a precipitated solid, which was then filtered to obtain the title compound (white powder, 26 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].CC(C)([O-])C.[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CBr
Reactant: OCCOCCOCCOCCOCCOCCOCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCOCCOCCOCCOCCOCCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
To a stirred solution of the product of step (d) (1.5 g) in toluene (30 mL) was added potassium tert-butoxide (0.69 g) and the resulting mixture was stirred at room temperature for 3 hours. Ethyl bromoacetate (1.38 g) was added and the reaction was stirred at 130° C. for 48 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (500 mL) and washed with water (2×400 mL). The organic layer was washed with brine (300 mL), dried and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (Biotage), eluting with 65–75% ethyl acetate in cyclohexane to give the title compound as a brown oil (0.40 g). LC retention time 2.77 min. Mass spectrum m/z 468 [MNH4+]
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.N.[CH3:23]O>>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([O:17][CH3:23])=[O:16])=[CH:11][CH:12]=1
Reactant: CO
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: N
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 0 °C

Procedure:
6 g of sulfuric acid in 12 ml of methanol was added to 3.2 g of 2-(4-methylphenyl)benzoic acid [see A. I. Meyers et al., J. Org. Chem., 43, 1372 (1978)], and the mixture was heated under reflux for 8 hr. The refluxed solution was cooled, poured into ice water, weakly alkalified with aqueous ammonia and extracted with ether. The extract was dried over anhydrous magnesium sulfate. The dried extract was concentrated, and the residue was recrystallized from n-hexane to prepare 2.4 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCc1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(CC)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-2-(4-ethyl-phenyl)-5-methyl-oxazole (example 122 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as light yellow solid.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([F:40])[CH:19]=1>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:19][C:20]=2[F:40])=[O:25])[CH2:31][CH2:30]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 60.5 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (4-bromo-2-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (869 mg) described in Preparation Example 116 and by the reaction and treatment in the same manner as in Example 32, the title compound (620 mg) was obtained.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:47]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (Example 7) gave 317. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.30 (td, J=7.9, 1.8 Hz, 1H), 7.87 (s, 1H), 7.48-7.26 (m, 5H), 7.02-6.56 (m, 1H), 4.84 (dd, J=10.6, 3.5 Hz, 1H), 4.58-4.39 (m, 1H), 4.36-4.22 (m, 1H), 4.20-3.98 (m, 1H), 3.76 (s, 3H), 2.09-1.91 (m, 2H), 1.87-1.67 (m, 3H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[N:16](C(OC(C)(C)C)=O)[C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1.Cl>CCOC(C)=O.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[NH:16][C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](Nc1cnc(C(F)(F)F)cn1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2N3)cn1
Reaction time: 2 h

Procedure:
To the title compound of step A (200 mg, 0.6 mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (3 mL). After 2 h, the reaction was concentrated, neutralized with 5% Na2CO3 (aq) and extracted with DCM (2×). The combined organics were dried (Na2SO4) to give the title compound of step B that was used without further purification. MS (ESI) mass calcd. for C11H13F3N4, 258.1; m/z found 259.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+:39]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([O-:32])=[O:31])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:33][CH:34]=1.[Na+:39]
Reactant: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)[O-])cc1

Procedure:
To a solution of 0.9 g of N-(4-methoxybenzoyl)-phenylalanyltyrosine and 10 ml of ethanol, 10 ml of water was added. The mixture was adjusted to a pH of 8 with 1N sodium hydroxide and concentrated to dryness. Sodium N-(4-methoxybenzoyl)-phenylalanyltyrosinate in the form of a powder was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:30])=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]4)[N:17]=3)[C:12](=[O:26])[C:11]([C:27]([OH:29])=[O:28])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:31](O)=O.[CH2:34](O)[CH3:35]>>[CH:34]([O:26][CH:12]([CH3:11])[CH3:13])([CH3:35])[CH3:31].[CH:27]([OH:29])=[O:28].[NH2:1][C:2]1[C:3]([F:30])=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]4)[N:17]=3)[C:12](=[O:26])[C:11]([C:27]([OH:29])=[O:28])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCO
Agent: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)nc32)c1F
Solvent: O=CO
Product: CC(C)OC(C)C
Reaction time: 0.02 h

Procedure:
A mixture of 200 mg of 1-(3-amino-2,4-difluorophenyl)-7-[(3S)-3-aminopyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 200 mg of formic acid was stirred for about one minute, combined with 200 mg of ethanol and stirred at 90° C. for one minute. The solution was combined with 2 ml of ethanol, stirred at the same temperature for a further 2 minutes, and allowed to stand. The precipitate was collected by filtration and washed with ethanol and then with diisopropyl ether to give 154 mg of the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.Cl.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[OH-].[Na+]>C(O)(=O)C.C(O)(C)C>[CH3:22][C:21]([NH:13][CH2:12][CH2:11][C:8]1[C:4]2[CH:5]=[C:6]([OH:7])[CH:1]=[CH:2][C:3]=2[NH:10][CH:9]=1)=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 23.4 %

Procedure:
N-acetyl serotonin was synthesized as follows. 100 mg (0.47 mmol) serotonin hydrochloride and 10 mL of pyridine were mixed in a 100 mL round-bottomed flask, and the solution was cooled to 0° C. under argon. Acetic anhydride (2.84 g, 28.4 mmol) was added slowly over 1 hr. After stirring at 0° C. for 20 hr the reaction was terminated by removing the volatile reagents under high vacuum. The remaining syrup was dissolved into 25 mL of methylene chloride and washed with 0.1 M HCl until the pH of the aqueous phase was less than 3. The organic phase was dried under anhydrous sodium sulfate, filtered and concentrated to yield a syrup. To this syrup was added 25 mL of aqueous isopropyl alcohol (50 wt%) and the solution was cooled to 0° C. Sodium hydroxide (1 mL of a 1.0 mM solution) was added and stirred at 0° C. for 4 hr. The solution was neutralized with acetic acid, concentrated and filtered through a short plug of silica gel with ether, concentrated and recrystallized from benzene/chloroform to yield 27 mg (0.11 mmol) of N-acetyl serotonin.