Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].N1CCCCC1.[Br-:13].[NH2:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[Br-:13].[Cl:1][CH2:2][CH2:3][C:4]([NH:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C(CCCl)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
3-Chioropropionyl chloride (3.0 ml, 32 mmol) and piperidine (3.5 ml, 43.5 mmol) were added to a suspension of 2-aminobenzyltriphenylphosphonium bromide (13.0 g, 29 mmol) (synthesised using the procedure of Capuano et al, Chem. Ber., 1986, 119, 2069-2074) in dichloromethane (60 ml) under a nitrogen atmosphere. The mixture was heated at reflux for 30 min. and then cooled to room temperature. Dichloromethane (60 ml) and hydrochloric acid (1N, 50 ml) were added and the precipitated solid was collected by filtration, washed with dichloromethane and dried in vacuo to give 2-(3-chloropropionylamino)benzyltriphenylphosphonium bromide (7.5 g, 48%). The filtrate was diluted with dichloromethane (300 ml) and washed with sodium carbonate (satd., 150 ml). Evaporation of the dichloromethane gave a residue which was triturated with ether (200 ml) and the white solid collected to afford a second crop of product (5.0 g, 32%).
Reaction SMILES: C(O[C:5]1[C:8](=[O:9])[C:7](=[O:10])[C:6]=1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[O:14][C:13]([CH3:24])([CH3:23])[CH:12]=1)(C)C.[CH3:25][NH2:26]>CC#N.CCO>[CH3:24][C:13]1([CH3:23])[CH:12]=[C:11]([C:6]2[C:7](=[O:10])[C:8](=[O:9])[C:5]=2[NH:26][CH3:25])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[O:14]1
Reactant: CN
Reactant: CC(C)Oc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Solvent: CC#N
Solvent: CCO
Product: CNc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 437 mg (1.35 mmol) of 4-(2-isopropoxy-3,4-dioxo-cyclobut-1-enyl)-2,2-dimethyl-2H-chromene-6-carbonitrile in CH3CN 14 mL) was added dropwise 8.03M methylamine in EtOH. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with H2O (50 mL) and then was extracted into 20% THF-CH2Cl2. The combined organic extracts were dried (Na2SO4) and purified by flash chromatography (4% MeOH--CHCl3) and crystallization from CH2Cl2 -petroleum ether to give 210 mg (53% yield) of the title compound, mp 193°-194° C., as a white solid: 1H-NMR (DMSO-d6 ; 400 MHz; major rotamer) δ8.7-8.8 (br q, 1H), 7.78 (d, 1H), 7.67 (dd, 1H), 7.01 (d, 1H), 6.22 (s, 1H), 3.25 (d, 3H), and 1.46 ppm (s, 3H); IR (KBr) 2220, 1775, 1735, 1620 cm-1 ; mass spectrum (DCI+), m/e 2.95.
Reaction SMILES: [CH2:1]([C@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4](O)=[O:5])[CH3:2].C([N:15](CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([C@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4]([NH2:15])=[O:5])[CH3:2]
Reactant: CC[C@@H](C(=O)O)N1CCCC1=O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A suspension of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (45 g, 0.26 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (53 g, 0.53 mol) and methanesulfonyl chloride (39 g, 0.34 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was crystallized from methyl isobutyl ketone to give 36 g (80%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][N:13](CC(C)CC)[CH2:12][C@H:11]2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[Cl:34]C(OC(Cl)C)=O.Cl.C1OC2C=CC(OC[C@H]3[C@H](C4C=CC([N+]([O-])=O)=CC=4)CCNC3)=CC=2O1>ClCCCl>[ClH:34].[CH3:2][N:3]([CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[CH:6][CH:5]=1
Reactant: CCC(C)CN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: O=[N+]([O-])c1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Solvent: ClCCCl
Product: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Yield: 62 %

Procedure:
Was prepared from compound (13) (3 g) and 1-chloroethyl chloroformate (1 g) in dry 1,2-dichloroethane (50 ml) as described for compound (6 ). Yield 62%. M.p. 195.5°-199.6° C. (d).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([C:47]([F:50])([F:49])[F:48])[N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:46])[CH2:26][C@H:27]([NH:38]C(OC(C)(C)C)=O)[CH2:28][C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:21][C:20]=23)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:51]>CO>[ClH:51].[ClH:51].[NH2:38][C@H:27]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH2:26][C:25]([N:22]1[CH2:23][CH2:24][N:19]2[C:18]([C:47]([F:48])([F:50])[F:49])=[N:17][C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])=[C:20]2[CH2:21]1)=[O:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCNCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
(R)-4-{7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester 13a (0.12 g, 0.199 mmol) was added into the reaction flask. A solution of 2.3 N hydrochloric acid in 5 mL of methanol was then added to the flask. The reaction mixture was reacted at room temperature overnight, and then was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-[1-(piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one dihydrochloride 13 (0.10 g, yield 94%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:14](=[O:17])(=[O:16])[NH2:15])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([N:28](C2C=CC=CC=2)[C:29](=O)[O-:30])[N:21]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:14]([NH:15][C:29]([NH:28][C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[C:24]([O:26][CH3:27])[N:23]=2)=[O:30])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1cc(Br)cc2c1OS(=O)(=O)C=C2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(Br)cc3c2OS(=O)(=O)C=C3)n1
Reaction time: 2 h
Yield: 65.3 %

Procedure:
0.3 g of 6-bromo-8-sulfamoyl-2,2-dioxo-1,2-benzoxathiine are dissolved in 10 ml of acetonitrile. To this solution are added 0.25 g of N-(4,6-dimethoxypyrimidin-2-yl)phenylcarbamate and 0.15 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and the mixture is stirred for 2 hours at 20°-25° C. The mixture is then acidified with 5% hydrochloric acid and diluted with water. The precipitated oil is extracted with ethyl acetate and the combined organic phases are washed with water, dried and concentrated. The oily residue is crystallised from ether, affording 0.3 g of N-(6-bromo-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4,6-dimethoxypyrimidin-2-yl)urea of m.p. 204°-209° C. (decompos.).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[N:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F.CCOCC>CCOCC.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([NH2:12])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OCCC#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCC1(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)propanenitrile (11.1 g, 60 mmol) in Et2O (400 mL) was added titanium tetraisopropanolate (28.9 g, 102 mmol) under N2 atmosphere. Ethylmagnesium bromide (3M in Et2O, 50 mL) was slowly added drop-wise at 0° C. The mixture was stirred at rt for 1 hr. Boron trifluoride etherate (17.0 g, 120 mmol) was slowly added at 0° C. The mixture was stirred at rt for 1 hr. The mixture was quenched with 10% aq. NaOH (300 mL) and then extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 5˜50% EtOAc/petroleum ether) to afford 1-(2-(tert-butyldim ethylsilyloxy)ethyl)cyclopropanamine (3.9 g, 30%) as a colorless oil. ESI-MS (EI+, m/z): 216.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:13]\[OH:14])/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[C:21](OC(=O)C)(=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>CCOCC>[C:21]([O:14]/[N:13]=[C:5](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])\[C:4]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([Cl:1])[C:3]=1[OH:20])(=[O:23])[CH3:22]
Reactant: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(/C(=N\OC(C)=O)c2ccccc2F)c(O)c1Cl

Procedure:
E-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone oxime (18.1 g) is warmed at 60° C. for 30 minutes with 9 ml of acetic anhydride. The reaction mixture is distributed between ether and 10% NaHCO3 and washed with 10% NaHCO3 until the washes remained basic. Drying, evaporation and trituration with hexane gives E-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 125°-128° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[SH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1S
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Product: O=C(O)c1ccccc1SSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 87.1 %

Procedure:
61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride are reacted with 32 g of 2-mercaptobenzoic acid by a method similar to that of Example 1. 74 g (87% of theory) of o-(4-nitro-2-trichloromethylphenyldithio)-benzoic acid of melting point 224° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([N:13]([CH2:22][CH2:23][CH3:24])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>CCOCC>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([N:10]2[CH2:11][CH:12]([N:13]([CH2:22][CH2:23][CH3:24])[C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:21])[Cl:20])=[O:15])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[O:35])=[CH:31][CH:32]=1
Reactant: CCCN(C(=O)OCC(Cl)(Cl)Cl)C1CNN=C1c1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Product: CCCN(C(=O)OCC(Cl)(Cl)Cl)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To half of the ether solution of 3-(4-chlorophenyl)-4-(N-propyl-N-(2,2,2-trichloroethoxycarbonyl)-amino)-4,5-dihydro-1H-pyrazole (Example 349c) (≤149 mmole) was added 18.7 g (100 mmole) of 4-trifluoromethylphenyl isocyanate. After stirring for 30 minutes, the mixture was concentrated in vacuo and dissolved in 200 ml of 50/50 diethyl ether/hexanes and cooled to -20° C. Crystals of the desired compound formed and were filtered yielding 30 g of the desired compound, mp 172°-173° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH3:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:30]1(N=C=NC2CCCCC2)CCCC[CH2:31]1.C(O)(=O)CCCCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][CH2:28][CH2:30][CH3:31])[CH3:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(C)OC(=O)CCC)cc2)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC(=O)O
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)OC(=O)CCCCC)cc2)cc1
Reaction time: 6 h
Yield: 76.3 %

Procedure:
Seven grammes (21 mmol) of (-)-1-(4-octyloxybiphenyl-4'-yl)ethanol prepared in Example 2, 7.5 g (36 mmol) of N,N'-dicyclohexylcarbodiimide and 1.0 g of 4-dimethylaminopyridine were dissolved in 200 ml of dichloromethane. To the solution, 3.4 g (29 mmol) of caproic acid was added and the mixture was stirred for six hours at room temperatre. The deposit crystals were filtered, 200 ml of water was added to the filtrate, and the organic layer was separated. 6N hydrochloric acid was added to the organic solution, and then the solution was neutralized with the aqueous solution of 2N sodium hydroxide. The neutralized solution was washed with water until the washed water became neutral. The solvent and low-boiling fractions were distilled off from the obtained solution. The residue was recrystallized from ethanol and the desired (-)-4-octyloxy-4'-(1-hexanoyloxyethyl)biphenyl 6.8 g was obtained. m.p. 60.8° C., [α]D -78.4° (c 0.88, C2H5OH).
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.S(=O)(=O)(O)O.C([O-])([O-])OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 0.3 ml of concentrated sulfuric acid, 1.96 g of ferric chloride and 1.15 ml of methyl orthoformate. The mixture was heated at 30° C. for 5 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain a desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.75 g. The yield of the desired product was 59%.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([O:16][CH3:21])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2

Procedure:
4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid, 25.5 g, synthesized according to the method of D.E. Aultz, et al. [J. Med. Chem., 20, 456 (1977)] and 0.9 g of p-toluenesulfonic acid monohydrate were heated under reflux for 3 hours in 600 ml of methanol. The solvent was distilled off under reduced pressure and the resulting residue was extracted with 500 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate= 3:1) to give 24.9 g of methyl 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate as light yellow solids.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[N:18]=[C:19]=[O:20]>CN(C)C=O>[CH3:1][N:2]1[C:3]2[NH:18][C:19](=[O:20])[C:17]3[C:12]([C:4]=2[C:5]2[CH:6]=[C:7]([Cl:11])[CH:8]=[CH:9][C:10]1=2)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: Cn1c(N=C=O)c(-c2ccccc2)c2cc(Cl)ccc21
Solvent: CN(C)C=O
Product: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Yield: 83.3 %

Procedure:
1-Methyl-2-isocyanato-3-phenyl-5-chloroindole (3.0 g) in 10 ml of dimethylformamide is heated with stirring at reflux temperature for 1 hour. After cooling, precipitates are separated by filtration to give 2.5 g of 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, melting point>300° C.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([S:26]([O-:29])(=[O:28])=[O:27])[C:16]2=[O:30])=[O:13])[N:10]=1)=O.[Na+:34].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:31][O:32][CH3:33])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([S:26]([O-:29])(=[O:28])=[O:27])[C:16]2=[O:30])=[O:13])[N:10]=1.[Na+:34]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1Sc1ccccc1)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1Sc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
To a solution of 0.15 g of the above sodium (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-phenylthio-2-oxoazetidine-1-sulfonate in 4 ml of water is added under ice-cooling 0.039 g of sodium monomethyldithiocarbamate, and the mixture is stirred for 1.5 hours at room temperature. The procedure as Example 3B yields 0.064 g of sodium (3R,4S)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-phenylthio-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:7]([NH:11][CH:12]3[CH2:14][CH2:13]3)=[N:6][C:5]3=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:19]=4)=[N:17][N:4]3[C:3]1=2>C1COCC1.CO>[CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:7]([NH:11][CH:12]3[CH2:14][CH2:13]3)=[N:6][C:5]3=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:19]=4)=[N:17][N:4]3[C:3]1=2
Reactant: COC(=O)CCc1cc(-c2cc3nc(NC4CC4)c4ncn(C)c4n3n2)ccc1F
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cnc2c(NC3CC3)nc3cc(-c4ccc(F)c(CCC(=O)O)c4)nn3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
A mixture of 1-methyl-4-cyclopropylamino-7-(4′-fluoro-3′-methoxycarbonylethylphenyl)-pyrazolo[5,1-b]purine (57.4 mg, 0.141 mmol) in THF/MeOH/1.0 N NaOH (3.5 mL, 4:2:1) was stirred at room temperature. After 3 days, neutralization with 1.0 N HCl precipitated a white solid. Filtration followed by wash with H2O and acetone furnished the title compound (26.9 mg, 49%) as a white solid. 1H NMR (d-MeOD, 400 MHz): 7.88 (d, J=7.34 Hz, 1H), 7.83 (s, 1H), 7.86-7.80 (m, 1H), 7.12 (t, J=9.78 Hz, 1H), 6.58 (s, 1H), 4.32 (s, 3H), 3.01 (t, J=7.83 Hz, 2H), 2.90 (m, 1H), 2.65 (t, J=7.82 Hz, 2H), 0.93 (m, 2H), 0.70 (m, 2H).
Reaction SMILES: [OH-].[Na+].[OH:3][C@@H:4]([CH2:38][OH:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:18][CH2:17][N:16](C(=O)C)[CH2:15][CH2:14]2)=[CH:9][C:8]=1[CH3:37].Cl>CO>[OH:35][CH:30]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:13]2([C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C@@H:4]([OH:3])[CH2:38][OH:39])=[C:8]([CH3:37])[CH:9]=3)[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:23][C:24]=1[CH3:36]
Reactant: CC(=O)N1CCC(c2ccc(OCC(O)C(C)(C)C)c(C)c2)(c2ccc(OC[C@@H](O)CO)c(C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2(c3ccc(OC[C@@H](O)CO)c(C)c3)CCNCC2)ccc1OCC(O)C(C)(C)C
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 1N NaOH (8 mL) in MeOH (2 mL) was added 1-(4-{4-[2(S),3-dihydroxy-propoxy]-3-methylphenyl}-4-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]piperidin-1-yl)ethanone (30 mg, 0.058 mmol). The reaction mixture was heated at 80° C. for 16 h, cooled, acidified with 1N HCl (8-9 mL), and washed with EtOAc. The aqueous layer was lyophilized and the crude material was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to provide the title compound (8.2 mg, 24%) as its TFA salt: 1H-NMR (DMSO-d6) δ 8.31 (2H, br s), 7.00 (4H, m), 6.78 (2H, app t), 4.70-4.90 (2H, m), 4.56-4.66 (1H, m), 3.88-4.04 (2H, m), 3.70-3.86 (3H, m), 3.00 (4H, br s), 2.47 (4H, br s), 2.12 (3H, s), 2.11 (3H, s), 2.09 (1H, br s), 0.91 (9H, s); MS(ESI): 472 (MH+).
Reaction SMILES: ClC1C(F)=NC=C(OCCC2OCCO2)C=1.CC(C)([O-])C.[K+].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37](O)[CH:38]=3)[N:33]=[CH:32][N:31]=2)=[N:25]1.[Cl-].[NH4+]>CN(C)C(=O)C>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)=[N:25]1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: Fc1ncc(OCCC2OCCO2)cc1Cl
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: Cn1ccc(Nc2ncnc3ccccc23)n1
Temperature: 25 °C
Yield: 151.2 %

Procedure:
3-Chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine (4.6 g, 18.4 mmol) and potassium tert-butoxide (2.6 g, 23 mmol) were added to an N,N-dimethylacetamide suspension (5 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (2.2 g, 9.1 mmol), and reacted at 200° C. for 2 hours, using microwaves. The reaction solution was cooled to room temperature, aqueous saturated ammonium chloride solution was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to obtain 6-03-chloro-5-{[2-(1,3-dioxolan-2-yl)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (3.1 g, yield: 73%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: Cc1nc2c(Br)cc(Cl)cc2[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(Br)cc(Cl)cc2n1C1CCCCO1
Temperature: 75 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A mixture of 4-bromo-6-chloro-2-methyl-1H-benzo[d]imidazole (3.5 g, 14.26 mmol), p-TsOH.H2O (272 mg, 1.43 mmol), and 3,4-dihydro-2H-pyran (5.9 g, 71.30 mmol) in THF (20 mL) was stirred at 75° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0 to 9% MeOH) to afford 4-bromo-6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a white solid (3.2 g, 69.6%). MS (ESI): m/z=329.0 [M+1]+.