Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[NH2:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h

Procedure:
All the obtained oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysine and L-proline benzylester hydrochloride (4.3 g, 17.8 m mole) were dissolved in methylene dichloride and WSC (3.3 ml, 17.8 m mole) was added thereto while cooling to -15° C. The mixture was stirred overnight and the methylene dichloride solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain an oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysyl-L-proline benzylester.
Reaction SMILES: FC(F)[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][SiH:9](Br)[CH2:8][CH2:7]1.[Mg].Cl[SiH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>C1COCC1>[CH2:5]([CH:6]1[CH2:11][CH2:10][SiH:9]([SiH:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:8][CH2:7]1)[CH2:4][CH3:3]
Reactant: FC(F)(F)c1ccc(C2CC[SiH](Cl)CC2)cc1
Reactant: FC(F)CCCC1CC[SiH](Br)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1CC[SiH]([SiH]2CCC(c3ccc(C(F)(F)F)cc3)CC2)CC1
Yield: 85 %

Procedure:
5.4 g (9.0 mmol) of 4-(4,4-difluorobutyl) silacyclohexyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 5.6 g (20 mmol) of 4-(4-chloro-4-silacyclohexyl)-1-trifluoromethylbenzene to obtain 4-(4-(4-n-propylsilacyclohexyl)-4-silacyclohexyl)-1-trifluoromethylbenzene. This product was a mixture of trans isomers and cis isomers with regard to the silacyclohexane ring. They were separated by means of chromatography to obtain 4 g of the trans isomers (yield 85%).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.Cl.[NH:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>C(Cl)(Cl)Cl.C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C>[C:4]1(=[O:12])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([N:19]2[CH2:30][CH2:29][CH2:28][C@H:20]2[C:21]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:22])=[O:11])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12
Reactant: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C([C@@H]1CCCN1)N1CCCC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CCCN1C(=O)CCCN1C(=O)c2ccccc2C1=O)N1CCCC1
Yield: 57.2 %

Procedure:
To a solution prepared by dissolving 1,17 g (5,0 mM) 4-phtalimido-butyric acid and 0,56 g (5,5 mM) triethylamin in 20 ml chloroform 0,61 g (5,0 mm) pivaloylchlorid were dropped at −15° C. under stirring. The reaction mixture was stirred for 1 hour at the above temperature and then a solution prepared by dissolving 1,03 g (5,0 mM) L-prolyl-pyrrolidin-hydrochloric acid salt in a mixture of 5 ml chloroform and 1,5 ml (1,1 g, 11,0 mM) triethylamine were dropwise added to it. Reaction mixture was stirred at room temperature for 4 hours, then it was washed successively with water, 30% cc. citric acid solution, saturated aqueous sodium bicarbonate solution, water and with saturated sodium chloride solution. The organic phase was dried on calcinated magnesium sulfate and it was evaporated. Crystallisation of the residue from a mixture of 5 ml chloroform and 10 ml petrolether yielded 1,1 g (53%) N-(4-phtalimido-butanoyl)-L-prolyl-pyrrolidin which melted at 148-149° C. The compounds of the general formula I were synthetised by the method as explained above starting from the corresponding compounds having general Formulas (II) and (III).
Reaction SMILES: C([NH:4][C:5]1[C:6]2[N:7]([C:11]([CH3:26])=[C:12]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]4[N:20]=[C:21]([NH2:23])[O:22][C:18]=4[CH:17]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:23][C:21]1[O:22][C:18]2[CH:17]=[C:16]([CH2:15][CH2:14][C:12]3[N:13]=[C:6]4[C:5]([NH2:4])=[CH:10][CH:9]=[CH:8][N:7]4[C:11]=3[CH3:26])[CH:25]=[CH:24][C:19]=2[N:20]=1
Reactant: CC(=O)Nc1cccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2c(N)cccn12
Yield: 85.3 %

Procedure:
A mixture of 6-[2-(8-acetylamino-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzoxazole (0.6 g) and conc. hydrochloric acid (0.76 ml) in ethanol (12 ml) was refluxed for 7 hours. To the reaction mixture was added ethyl acetate (18 ml) and the resulting precipitate was collected by filtration. A solution of resulting precipitate in water was adjusted to pH 9.0 with 20% aqueous potassium carbonate solution and the precipitate was collected by filtration and dried to give 2-amino-6-[2-(8-amino-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.45 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:20](O)[CH2:21][CH2:22][Cl:23]>C(O)C>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12]
Reactant: OC(Br)CCCl
Reactant: O=C1NCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1NCCc2c(OCCCCl)cccc21
Reaction time: 5 h
Yield: 84.4 %

Procedure:
A mixture of 3.0 g (22.0 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone and 6.7 g (48.5 mmol) of potassium carbonate in 100 ml of ethanol was refluxed for one hour. Then 10.9 ml (100 mmol) of 1-bromo-3-chloropropanol was added and refluxing continued for five hours. The solution was cooled and concentrated. The residue was dissolved in chloroform, filtered and concentrated to provide 4.45 g (85%) of 5-(3-chloropropoxy)-3,4-dihydro-1(2H)-isoquinolinone; mp 131.5°-133°.
Reaction SMILES: [C:1]1([CH3:12])[C:2]([CH3:11])=[CH:3][C:4](S([O-])(=O)=O)=[CH:5][CH:6]=1.[Na+].[NH2-:14].[Na+].N>>[NH2:14][C:4]1[CH:5]=[CH:6][C:1]([CH3:12])=[C:2]([CH3:11])[CH:3]=1
Reactant: [NH2-]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1C
Agent: N
Agent: [Na+]
Product: Cc1ccc(N)cc1C
Yield: 88.1 %

Procedure:
In a 200-ml autoclave were placed 35 grams (0.163 moles) of anhydrous sodium 4-o-xylene sulfonate, 14 grams (0.35 mole) of sodium amide and 120 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 120° to 125° C for 15 hours. The reaction pressure in the autoclave was 90 to 100 atm. during the reaction. After the ammonia was removed, 15 ml of methanol was added to the reaction mixture for solvolysis. Thereafter 500 ml of water was added to the product and the mixture was treated in the same manner as in Example 1, whereby 17.4 grams of 3,4-xylidine boiling at 112° C/22 mm Hg was obtained. Yield was 88.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][N:13]1[C:17]([C:18](=[O:20])[NH2:19])=[CH:16][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:14]1>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[NH:19][C:18](=[O:20])[C:17]3=[CH:16][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:14][N:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(C(N)=O)n(N)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: COC(=O)c1cc2c(=O)[nH]c(-c3ccc([N+](=O)[O-])cc3)nn2c1
Yield: 72 %

Procedure:
According to the general preparation method described in example 5 above, p-nitrobenzaldehyde reacts with compound 3 to give compound Ma as light yellow solid in 72.0% yield. m.p.>300° C. 1H NMR (300 MHz, DMSO-d6): δ 12.52 (s, 1H), 8.38 (d, J=8.5 Hz, 2H), 8.22 (s, 1H), 8.21 (d, J=8.5 Hz, 2H), 7.26 (s, 1H), 3.80 (s, 3H). LRMS (EI) m/z (%): 314 (M+, 85), 283 (100). HRMS calcd. C14H10N4O5: 314.0651. found: 314.0659.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.Cl[C:12]1[N:17]2[N:18]=[CH:19][CH:20]=[C:16]2[N:15]=[C:14]([S:21][CH3:22])[N:13]=1.O>O1CCOCC1>[CH2:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:12]2[N:17]3[N:18]=[CH:19][CH:20]=[C:16]3[N:15]=[C:14]([S:21][CH3:22])[N:13]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CCOc1ccc(N)cc1
Reactant: CSc1nc(Cl)n2nccc2n1
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(Nc2nc(SC)nc3ccnn23)cc1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
p-Phenetidine (3.09 g, 22.51 mmol) was added to a mixture of 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (300 mg, 1.5 mmol) from 1d in 1,4-dioxane (6 mL). The mixture was heated to 100° C. for ½ hour. Water (15 mL) was then added to the reaction mixture and the resulting precipitate was collected by vacuum filtration, washed with cold water and hexane, and then air dried to give 360 mg (80%) of N-(4-ethoxyphenyl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1>Cl>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c(N)c2c1=O
Agent: Cl
Product: Nc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A suspension of 17.2 g (50.2 mmol) of ethyl 5-amino-8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 100 ml of 6 M hydrochloric acid was refluxed for three hours. The mixture was cooled to room temperature, and the solids were filtered, washed with water and ether, and dried to give 14.2 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[CH2:21][O:22]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[CH2:21][O:22][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[Cl:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1COS(C)(=O)=O
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1COc1ccccc1Cl

Procedure:
12.5 Reaction of 1.5 g of 1-tert-butyloxycarbonyl-(2R,4S)-2-(methylsulfonyloxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine with 560 μl of 2-chlorophenol and 1.19 g of caesium carbonate in 15 ml of DMF under standard conditions gives 751 mg of (2R,4S)-1-tert-butyloxycarbonyl-2-(2-chlorophenoxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine. 223 mg of the silyl-eliminated product (2R,4S)-1-tert-butyloxycarbonyl-2-(2-chlorophenoxymethyl)-4-hydroxypyrrolidine are formed as by-product.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:8](=[O:21])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:10]=[CH:11][C:12]=2Cl)=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>>[N:24]([C:12]1[CH:11]=[N:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8](=[O:21])[C:7]=1[O:6][C:5]1[CH:22]=[CH:23][C:2]([Br:1])=[CH:3][CH:4]=1)=[N+:25]=[N-:26]
Reactant: O=c1c(Oc2ccc(Br)cc2)c(Cl)cnn1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1cnn(-c2ccc(Cl)cc2)c(=O)c1Oc1ccc(Br)cc1

Procedure:
Obtainable by general method 13 from 7.55 g (18.3 mmol) of the compound from Example 10A with 5.96 g (91.6 mmol) of sodium azide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+].[Cl-].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 57.5 °C
Reaction time: 10 h
Yield: 97.9 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), 1.02 g (13.7 mmol) of potassium chloride, and 10 mL of acetone. The resulting mixture was refluxed under stirring at 55-60° C. in an argon gas atmosphere for 10 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.39 g (reaction yield: 98.2%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
A solution of 3-chloro-2-(bromoacetamido)benzoic acid from Example 39 (7.5 g, 0.026 mol), aniline (5.8 mL, 250 mol %) and anhydrous DMF (60 mL) was heated at 95-100° C. for 20 h, cooled and stirred at rt for 4 h. The reaction mixture was poured into ice-water (400 mL) and the precipitated product was solubilized by adding aqueous 5% KOH (60 mL). The resulting milky homogenous solution was extracted with CH2Cl2 (3×70 mL). The combined CH2Cl2 extracts were set aside and the aqueous layer was acidified to pH=3 with aqueous 5% HBr. The resulting oil was extracted into EtOAc (3×100 mL) and the combined extract was washed with brine, dried, filtered and concentrated. Recrystallization of the resulting solid from diethyl ether afforded 3 g (38%) of the title compound as a white crystals, mp 184-185° C.; 1H NMR (CD3OD) δ 7.85 (dd, 1H, J=1.6, J=6), 7.66 (dd, 1H, J=1.6, J=6.4), 7.33 (t, 1H, J=8), 7.16 (t, 2H, J=7.2), 6.72 (dd, 3H, J=2, J=5.6), 3.91 (s, 2H); 13C NMR (CD3OD): 203.86, 196.95, 173.19, 173.17, 168.69, 149.44, 134.30, 130.41, 130.09, 128.42, 119.31, 114.44; MS (EI, m/z) 304 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)[CH:4]=1
Reactant: Fc1cccc(CCl)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(O)c(Cc2cccc(F)c2)c1

Procedure:
Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3′-fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the procedure similar to that in Example 18 method B.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:17])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2].B.[Na]>CO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH:13]([OH:17])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c1O)C(=O)CCC2
Agent: B
Agent: [Na]
Solvent: CO
Product: CCOC(=O)c1cnc2c(c1O)C(O)CCC2
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
4-Hydroxy-5,6,7,8-tetrahydro-5-oxo-3-quinolinecarboxylic acid ethyl ester (11.5 g) was suspended in 600 ml of methyl alcohol, and 1.1 g of sodium boron hydride (NaBH4) was added to the suspension with its internal temperature kept at 20°-25° C. After completion of the reaction, the methyl alcohol was distilled off under reduced pressure and 200 ml of water was added to the residue. The resulting solution was adjusted to pH 2.4 with dilute hydrochloric acid and stirred for 30 minutes. Then, under cooling, the solution was adjusted to pH 6.5 with dilute aqueous sodium hydroxide and stirred for 30 minutes. The precipitate so formed was separated by filtration to obtain a yield of 10.4 g of the desired compound. This compound melted at 182°-183° C. (uncorrected values). Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3440, 3160, 2960, 1730, 1655, 1540, 1305, and 1190 cm-1, and its n.m.r. spectrum (CF3COOH, 60Mc, TMS) had signals at δ values of 1.52 (3H, t, J=6.8 Hz), 1.9-2.4 (4H, m), 2.9-3.3 (2H, m), 4.64 (2H, q, J=6.8 Hz), 5.48 (1H, bs), and 8.95 (1H, d, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH2:14])=[CH:12][N:11]([CH3:15])[N:10]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33](Cl)=[O:34])=[C:26]2[N:25]=1>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]2[N:30]=[CH:31][C:32]([C:33]([NH:14][C:13]3[C:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10][N:11]([CH3:15])[CH:12]=3)=[O:34])=[C:26]2[N:25]=1
Reactant: Cn1cc(N)c(-c2cc(Cl)ccc2Cl)n1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cc(Cl)ccc2Cl)n1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To an ice-cooled solution of 3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-amine (121 mg, 0.50 mmol) and triethylamine (101 mg, 1.00 mmol) in dichloromethane (15 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (162 mg, 1.5 mmol). The reaction mixture was warmed to room temperature for 3 hours. The mixture was then washed with saturated aqueous sodium chloride solution. The collected organics were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded 5-chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a solid (110 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): 9.34 (d, J=7.6 Hz, 1H), 9.21 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.36 (d, J=6.8 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH:28]4[CH2:30][CH2:29]4)=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[O:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[CH:28]1([C:24]2[CH:25]=[C:26]([CH3:27])[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:13]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[CH2:34][CH2:35][O:31][C:32]5=[O:36])=[CH:7][C:6]=4[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]3)=[N:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2NS(C)(=O)=O)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2NS(C)(=O)=O)CC1
Yield: 32.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using N-{5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (247 mg) described in Preparation Example 124 and oxazolidin-2-one (43.5 mg), the title compound (80.1 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Clc1nc2ccccc2s1
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1Nc1nc2ccccc2s1
Temperature: 130 °C
Yield: 99.9 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (1.00 g, 5.26 mmol) in toluene (25 mL) was added 2-chlorobenzothiazole (0.75 mL, 5.79 mmol). The purple solution was heated at 110-150° C. in a resealable tube for 66 hand then cooled to room temperature. The resulting brown solution was concentrated to give a purple solid which was triturated with heptane to afford N2-(4-bromo-2-fluorophenyl)-1,3-benzothiazol-2-amine (1.699 g, 99%) as a light purple powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=13.82 min, 95%; m/z 325 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:8]=2)([O-:3])=[O:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc([N+](=O)[O-])cnc2c1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
In DMF (9 mL) was dissolved 3-nitro-7-hydroxyquinoline (800 mg, 4.24 mmol.). Sodium hydride (168 mg, 4.24 mmol.) and 4-chloromethyl-5-methyl-2-phenyloxazole (880 mg, 4.24 mmol.) were added to the resulting solution under chilling with ice. The mixture was stirred overnight at 50°-60° C. After the completion of reaction was confirmed, ethyl acetate and aqueous sodium sulfate were added. The ethyl acetate portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give 740 mg of the desired compound as a yellow-white crystalline product (yield 48%).
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1([OH:22])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH3:3].C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH2:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][CH3:3]
Reactant: CCCc1ccsc1C1(O)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccsc1C1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-(3-propylthien-2-yl)-9H-fluoren-9-ol and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;