Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=1.[C:14]([O:21][CH3:22])(=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].[H-].[Na+]>CN(C=O)C>[CH3:19][O:18][C:16](=[O:17])[CH:15]([C:2]1[C:7]([S:8][CH3:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=1)[C:14]([O:21][CH3:22])=[O:20]
Reactant: COc1nc(Cl)c(SC)c(OC)n1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1nc(OC)nc(OC)c1SC
Temperature: 100 °C
Reaction time: 10 h

Procedure:
A mixture of 4-chloro-2,6-dimethoxy-5-methylsulfanyl-pyrimidine (3.30 g, 15.0 mmol.) and dimethyl malonate (11.88 g, 90.0 mmol, 6.0 eq.) was added dropwise to slurry of sodium hydride (60% w/w) (3.67 g, 90.0 mmol, 6.0 eq) in DMF (80 ml) in ice bath at 0° C., then the reaction mixture was stirred at 100° C. for 10 hrs and dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and 0.1 N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 6:1) to give a pale yellow oil product of 2.85 g (60.2%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1([CH3:29])[CH2:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH2:25][CH2:26][CH3:27])[C:16]=2[O:15]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].Cl>CCOCC.O.CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][O:28][C:23]1[CH:22]=[CH:21][C:17]2[C:18](=[O:20])[CH2:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)([CH3:29])[O:15][C:16]=2[C:24]=1[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)CBr
Reactant: CCCc1c(O)ccc2c1OC(C)(CCCCCCOC1CCCCO1)CC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCCc1c(OCC(=O)OC)ccc2c1OC(C)(CCCCCCOC1CCCCO1)CC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of 0.706 g of rac.-2,3-dihydro-2-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]-7-hydroxy-2-methyl-8-propyl-4H-1-benzopyran-4-one, 16 ml of N,N-dimethylformamide, and 0.477 g of anhydrous potassium carbonate was stirred at room temperature for 2 hours. A 0.33 ml (0.53 g) portion of methyl bromoacetate was added and stirring was continued for 17.5 hours at room temperature. The mixture was poured into water and the pH was adjusted to 7 with 0.5N hydrochloric acid. The organic product was isolated by extraction with 3 portions of ether. The ether extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate filtered and concentrated in vacuo to give a yellow oil. This material was purified by high pressure liquid chromatography (HPLC) (silica gel, 2:1 hexane-ethyl acetate) yielding 0.589 g (70.8%) of rac.-[[3,4-dihydro-2-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid methyl ester as a pale-yellow oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:19][C:18]3[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[CH:22]=[CH:23][C:17]=3[O:16]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.ClCCl>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:22]=[CH:23][C:17]3[O:16][CH:15]([CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)[CH2:19][C:18]=3[CH:20]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32].[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of HCl in dioxane (4 N, 5.0 mL) is added to 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (750 mg) in dichloromethane (1 mL) and the resulting mixture is stirred for 5 min at room temperature. The solvents are evaporated in vacuo to give the title compound as its hydrochloric acid salt. Mass spectrum (ESI+): m/z=358 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[C:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1.BrC1C2C[C@H](C)OC=2C(N)=CC=1C>>[CH3:1][C@H:2]1[CH2:6][C:5]2[C:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1
Reactant: Cc1cc(N)c2c(c1-c1ccncc1)C[C@@H](C)O2
Agent: Cc1cc(N)c2c(c1Br)C[C@H](C)O2
Product: Cc1cc(N)c2c(c1-c1ccncc1)C[C@H](C)O2

Procedure:
The title compound 5g was prepared according to the method for preparation of compound 3h of Example 3 by replacing 3g with 5f. MS-ESI (m/z): 241 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10](Cl)[C:9]=1[Cl:16]>CS(C)=O>[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([O:4][CH2:3][CH2:2][NH2:1])[C:9]=1[Cl:16]
Reactant: Nc1c(Cl)cnc(Cl)c1Cl
Reactant: NCCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NCCOc1ncc(Cl)c(N)c1Cl
Temperature: 150 °C

Procedure:
A mixture containing 21.4 grams (0.35 mole) of 2-aminoethanol, 50 milliliters of dimethylsulfoxide and 20 grams (0.36 mole) of potassium hydroxide was heated at 110° C. until all of the potassium hydroxide was reacted. The solution was added to a mixture containing 69 grams (0.35 mole) of 4-amino-2,3,5-trichloropyridine dissolved in 200 milliliters of dimethylsulfoxide. The mixture was heated for 11/2 hours at 138° C. to 150° C. under agitation and thereafter quenched by pouring into ice water. The solid which precipitated was recovered by filtration under reduced pressure, dried and recrystallized from a mixture of hexane and chloroform. The solid was dissolved in 100 milliliters of dimethylsulfoxide and mixed with a solution composed of 21.4 grams (0.35 mole) of 2-aminoethanol and 20 grams (0.36 mole) of potassium hydroxide dissolved in 50 milliliters of dimethylsulfoxide. This mixture was heated for 2 hours at 150° C., cooled by quenching with ice water to precipitate the product as a solid which was recovered by filtration under reduced pressure. This product was distilled under azeotropic conditions with benzene to remove water from the 4-amino-2-(2-aminoethoxy)-3,5-dichloropyridine product which has a melting point of 115°-116.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[S:11]([CH3:14])(=[O:13])=[O:12].Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N:18]([CH3:19])[CH3:17])[CH:7]=[CH:6][C:5]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CNC
Reactant: COC(=O)c1cc(F)ccc1S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1S(C)(=O)=O
Temperature: 60 °C
Reaction time: 7 h
Yield: 56 %

Procedure:
To a stirred solution of 5.23 g (22.5 mmol) 5-Fluoro-2-methanesulfonyl-benzoic acid methyl ester (J. Med. Chem.; 40; 13; 1997; 2017-2034) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 7 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 17a was obtained in 56% yield (3.24 g, 12.6 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccn(-c5ccc(F)c(F)c5)n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccn(-c2ccc(F)c(F)c2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 16 h
Yield: 61.3 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(1-(3,4-difluorophenyl)-1H-pyrazol-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.067 g, 0.121 mmol) in 3:1 THF/MeOH (1 ml) was added 1M sodium hydroxide (0.133 ml, 0.133 mmol), and the reaction was allowed to stir for 16 hours. The reaction was concentrated, acidified with dilute HCl, and extracted twice with EtOAc. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired product (0.039 g, 0.0742 mmol, 61.3% yield). MS (apci): m/z=526.1 (M+H).
Reaction SMILES: [NH:1]([CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6](OCC)=[O:7])[C:2]([NH2:4])=[O:3].C1(C2CCCCCCCC=2)CCCCCCNN=1.C(Cl)(Cl)Cl.Cl>CCOCC>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:5]1[NH:1][C:2](=[O:3])[NH:4][C:6]1=[O:7])=[O:18])[CH3:21]
Reactant: CCOC(=O)CCCCCCC(NC(N)=O)C(=O)OCC
Agent: C1=C(C2=NNCCCCCC2)CCCCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCCC1NC(=O)NC1=O

Procedure:
A mixture of diethyl 2-ureidononanedioate (8 g) with diazabicyclononene (DBN) (1.28 g) was heated in a bath at 100° for 1 hour and the reaction mixture was shaken with chloroform and a slight excess of dilute hydrochloric acid. The chloroform phase was separated, washed with water and dried (MgSO4), and the chloroform was evaporated, to give a crystalline residue. The crystals were suspended in ether and collected, to give 5-(6-ethoxycarbonylhexyl) hydantoin, m.p. 110°-110.5° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:12](OCC)=[O:13].[Na]>CCCCCC.C(O)C>[CH:12]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]#[N:11])=[O:13]
Reactant: CCOC=O
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCC
Solvent: CCO
Product: N#CC(C=O)c1ccccc1

Procedure:
A 20.0 g. amount of sodium hydride (50% in oil) is added portionwise with stirring to a solution of 20.0 g. of phenylacetonitrile and 40.0 ml. of ethyl formate in 200 ml. of sodium dried benzene. The mixture is heated on a steam bath to start the reaction and after the vigorous reaction has subsided, the mixture is heated on the steam bath for 2 hours with stirring. Ethanol is then added dropwise to decompose the excess sodium hydride. The mixture is then swamped with n-hexane and the precipitate is collected and washed with n-hexane. The precipitate is suspended in water then an excess of dilute hydrochloric acid is added and the product is extracted with ether. The ether extracts are dried and evaporated. The residue is crystallized from acetone-n-hexane to give 12.0 g. of the product of the Example m.p. 161°-163° C. Reference: D. J. Brown and T. C. Lee, J. Chem. Soc. (C), 214 (1970).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C.[Cl:56][C:57]1[C:58]([F:100])=[C:59]([C@@H:63]2[C@:67]([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][C:71]=3[F:77])([C:68]#[N:69])[C@H:66]([CH2:78][C:79]([CH3:82])([CH3:81])[CH3:80])[NH:65][C@H:64]2[C:83]([NH:85][C:86]2[CH:97]=[CH:96][C:89]([C:90]([O:92][CH2:93][CH2:94]O)=[O:91])=[CH:88][C:87]=2[O:98][CH3:99])=[O:84])[CH:60]=[CH:61][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([O:12][CH2:94][CH2:93][O:92][C:90](=[O:91])[C:89]1[CH:96]=[CH:97][C:86]([NH:85][C:83]([C@H:64]2[C@H:63]([C:59]3[CH:60]=[CH:61][CH:62]=[C:57]([Cl:56])[C:58]=3[F:100])[C@:67]([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][C:71]=3[F:77])([C:68]#[N:69])[C@H:66]([CH2:78][C:79]([CH3:80])([CH3:81])[CH3:82])[NH:65]2)=[O:84])=[C:87]([O:98][CH3:99])[CH:88]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of (S)-L-(2-(tert-butoxycarbonylamino)propanoic acid (Chem-Impex, 13.6 mg, 0.072 mmol), HATU (Bachem, 27.3 mg, 0.072 mmol), N,N-diisopropylethylamine (18.6 mg, 0.025 mL, 0.144 mmol) and dimethylaminopyridine (Aldrich, 2.2 mg, 0.018 mmol) in dimethyl formamide (8 mL) was stirred for 10 min before 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 1, 19 mg, 0.028 mmol) in dimethyl formamide (1 mL) was added. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed successively with aqueous sodium bicarbonate solution, water (3×15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (hexane/ethyl acetate, 95/5 to 65/35) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((S)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester as a white solid (17 mg, 71% yield). MS (ES+) m/z calcd. for C41H47Cl2F2N4O8 [(M+H)+]: 831. found: 831.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:10]
Reactant: C1CCNC1
Reactant: CC(=O)c1ccc(F)cc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(c1ccc(F)cc1F)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.6 %

Procedure:
To a solution of 1-(2,4-difluorophenyl)ethanone (10.0 g, 64.0 mmol) and pyrrolidine (32.1 mL, 384 mmol) in hexane (150 mL) was added titanium tetrachloride (3.86 mL, 35.2 mmol) dropwise at 0° C. over 15 minutes. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated in vacuo to give pale yellow oil, which was distilled under reduced pressure (0.3 mmHg, 90-120° C.) to give the title compound as a pale yellow oil (4.90 g, 36%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][C:5]1=[O:11].S(Cl)([Cl:14])=O>>[Cl:14][CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][C:5]1=[O:11]
Reactant: Nc1ccn(CCO)c(=O)n1
Reactant: O=S(Cl)Cl
Product: Nc1ccn(CCCl)c(=O)n1

Procedure:
B] 1-(2-Chloroethyl)-4-amino-2-1H-pyrimidinone was prepared according to example 14C from 3.8 g 1-(2-hydroxyethyl)-4-amino-2-1H-pyrimidinone and 60 ml thionyl chloride. 3.2 g (97%) of crude product were obtained and used without further purification. Recrystallization was omitted in this case due to decomposition. Rf: 0.51 (ethyl acetate/acetone/acetic acid/H2O 6:2:1:1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[CH2:8][OH:9]>O1CCCC1.[O-2].[Mn+4].[O-2]>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[CH:8]=[O:9]
Reactant: Cc1nnc(CO)n1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1nnc(C=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of (4,5-dimethyl-4H-1,2,4-triazol-3-yl)methanol (2.48 g, 19.5 mmol) and manganese (IV) oxide (17.8 g, 204.8 mmol) in dry tetrahydrofuran (72 mL) was stirred at room temperature overnight. The mixture was filtered, and the cake washed with dichloromethane (100 mL×3). The combined filtrate was concentrated to give the title compound (1.6 g, yield 66%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.54 (s, 3H), 3.89 (s, 3H), 10.06 (s, 2H). LC-MS (ESI) m/z: 126 (M+1)+.
Reaction SMILES: [H-].[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].Cl>C1C=CC=CC=1.C(=S)=S.O>[CH3:18][CH:17]([CH3:19])[CH2:16][C:15]([C:9]1[C:7]([CH3:8])=[CH:6][C:4]([OH:5])=[CH:3][C:2]=1[OH:10])=[O:20]
Reactant: Cc1cc(O)cc(O)c1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: S=C=S
Solvent: O
Product: Cc1cc(O)cc(O)c1C(=O)CC(C)C

Procedure:
Orcinol monohydride, 14.20 g (100.0 mmol), in 160 ml of benzene was heated to distill benzene. This step was carried out twice by way of an operation of dehydration. The product of dehydration was dissolved in 45 ml of nitrobenzene and 45 ml of carbon disulfide, and 26.7 g (200 mmol, 2.00 equivalents) of aluminum chloride was added piecemeal while cooled with cold water and stirred, with a calcium chloride tube attached. Then, 12.1 g (100 mmol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise and stirred at room temperature for 14 hours. After the stop of the evolution of an acidic gas was confirmed, the resultant reaction mixture was poured into dilute hydrochloric acid (prepared from 100 ml of concentrated hydrochloric acid and 400 ml of cold water), stirred, and then extracted by ether. The ether layer was washed with saturated brine and the ether was removed under a reduced pressure. The residue was combined with water added piecemeal and meanwhile distilled under a reduced pressure to remove nitrobenzene by steam distillation. The residue was extracted by ether, washed with saturated brine, dried over sodium sulfate, and distilled off the solvent and obtain 18.53 g of a crude product in the form of brown viscous oily substance. The crude product was subjected to silica gel column chromatography (220 g of Wako Gel C-200, eluted with hexane:ethyl acetate=9:1) to obtain 5.681 g of (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:21]2)=[CH:38][CH:39]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (671 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (495 mg, yield: 78%). This was recrystallized from ethyl acetate-hexane. Melting point: 157–158° C.
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[C:35]([CH3:36])=[C:34]2[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]2[C@@H:37]2[CH2:39][C@@H:38]2[F:40])=[CH:28][CH:27]=1>CS(C)=O>[F:40][C@H:38]1[CH2:39][C@H:37]1[N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([N:15]3[CH2:16][CH2:17][C@@H:13]([C:10]4([NH:8][CH3:9])[CH2:11][CH2:12]4)[CH2:14]3)[C:35]=2[CH3:36])[C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3C)C2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (118 mg, 436 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml, 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (122 mg, 436 μmol) was added thereto and heated under reflux in an oil bath of 100° C. for 18 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (2 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by a preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 72.8 mg (42%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(O)c1
Reactant: Brc1nccs1
Solvent: CN(C)C=O
Product: COc1cccc(Oc2nccs2)c1
Yield: 60.6 %

Procedure:
3-Methoxyphenol (2.48 g, 20 mmol), 2-bromothiazole (3.28 g, 20 mmol) and Me4N+OH-.5H2O (3.62 g, 20 mmol) were heated in dry DMF (30 mL) under N2 (g) for 16 hours. The mixture was filtered and the filtrate was partitioned between H2O and EtOAc. Organic extracts were pooled, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica (CHCl3) to yield 2.51 g of 2[(3-methoxyphenyl)oxy]thiazole (GC-MS m/z 207 (M+)). A portion (2.42 g, 11.7 mmol) of this material was dissolved in dry CH2Cl2 (40 mL), and BBr3 (2.2 eq.) was added dropwise at about -10° C. under N2 (g). The mixture was allowed to warm to about 20° C., stirred 3 hours, and then poured into ice/H2O and extracted with CH2Cl2. Organic extracts were washed with 5% NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to yield 3-[(thiazol-2-yl)oxy]phenol as an oil (1.3 g) which was used without further purification (GC-MS m/z 193 (M+)).