Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)c(Br)c1
Yield: 96 %

Procedure:
A mixture of 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid (2.38 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (2.39 g, yield 96%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.60–2.71 (2H, m), 2.91–3.03 (2H, m), 3.69 (3H, s), 7.18–7.32 (1H, m), 7.60–7.70 (1H, m), 7.94 (1H, dd, J=2.2, 6.2 Hz), 8.23 (1H, s).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:32]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)(=[O:31])[CH2:29][CH3:30]>>[C:28]([N:32]([C:33]1[CH:38]=[CH:37][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:35][CH:34]=1)[CH2:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])(=[O:31])[CH2:29][CH3:30]
Reactant: CCC(=O)N(CCCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: CCC(=O)N(CCCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-propionyl-N-(3-dimethylamino-propyl)-p-phenylenediamine
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:31]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:32])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4cccc5ccccc45)CC3)cccc2n1
Yield: 96 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 1-naphthoyl chloride (70.5 mg; 0.37 mmol) via Method AA to yield 152 mg. (96% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.99 (m, 2H), 7.82 (m, 1H), 7.56 (m, 2H), 7.41 (m, 1H), 7.34 (m, 2H), 7.12 (br s, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.74 (t, J=12.0 Hz, 1H), 4.04 (d, J=6.0 Hz, 2H), 3.25 (br d, J=12.4 Hz, 1H), 3.00 (m, 2H), 2.22 (s, 1H), 1.97 (m, 1H), 1.63 (m, 1H), 1.44 (m, 1H), 1.3 (m, 1H). MS m/z (ESI) 428 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].N1C=CN=C1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:12]([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
A mixture of 3-fluoro-4-nitro-phenol (4.94 g, 31.4 mmol), triisopropylsilyl chloride (6.40 mL, 29.9 mmol), and imidazole (4.85 g, 70.7 mmol) in 70 mL of dichloromethane is stirred for 1.5 hours. Dichloromethane (100 mL) is added and the mixture is washed with water and brine, dried (MgSO4), and concentrated under reduced pressure. The residue is purified on silica gel (120 g) eluting with a gradient of ethyl acetate in heptane (0 to 80%) to provide the title compound (8.55 g, 87%) as an oil. ES/MS m/e 314.3.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
To a slurry of 46 g of the wet immobilized cells of Example 6 in 500 ml water at pH 8.0 and 37°C is added 5 g of potassium penicillin G. The pH of the slurry is maintained at 8.0 by the monitored addition of 1N NaOH, and the hydrolysis is complete after about 3 hours. The immobilized cells are filtered, washed with water and stored as a wet cake until further use. The filtrate is adjusted to pH 2 with 2N HCl and extracted with ethyl acetate. The resulting aqueous layer is adjusted to pH 4.3 with 2N NaOH, concentrated and cooled to give crystalline 6-amino-penicillanic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cnc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.186 g, 78%). MS (ISP) 476.1 [(M+H)+]; mp 244° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1COc2ccc(Br)cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1[nH]c1c3cc(Br)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 5-bromo-3(2H)-benzofuranone (3.10 g, 14.6 mmol) [Ellingboe, J. et al., J. Med. Chem. 1992,35 (7), 1176-1183] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (5.49 g, 29.1 mmol) in deionized water (200 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 3.65 g (72%) of the title compound as a brown solid: mp 195° C.(dec) which was used without further purification.
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>CCO>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:14]=2[CH2:13]1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CN1CCc2[nH]c3ccccc3c2C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Phenyl hydrazine hydrochloride (1 equiv.) and 1-methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is dissolved in EtOH and stirred at 80-90° C. overnight. The reaction is monitored by TLC. Upon completion, the reaction mixture is cooled to RT and the solvent is evaporated to dryness. The residue is dissolved in EtOAc and washed with a saturated sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[SH:24][CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C.Cl>COCCOCCOC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([S:24][CH2:25][C:26]([OH:28])=[O:27])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: O=C(O)CS
Agent: Cl
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: O=C(O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (0.40 g, 1.05 mmol), mercaptoacetic acid (0.11 mL, 1.60 mmol), triethylamine (0.59 mL, 4.2 mmol) in diglyme (2.5 mL) was heated with stirring at 130° C. under an atmosphere of nitrogen for 18 hours. The product mixture was treated with 1 M aq HCl at 0° C. The resulting yellow solid was filtered, washed with diethyl ether to provide the title acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[NH:10][CH2:9][CH2:8][S:7]1)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:15]2>ClCCl.CN(C)C=O>[CH3:2][O:3][C:4]([CH:6]1[N:10]([C:25](=[O:26])[CH2:24][NH:23][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=3)=[O:22])[CH2:9][CH2:8][S:7]1)=[O:5]
Reactant: COC(=O)C1NCCS1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1SCCN1C(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 79 %

Procedure:
(±)-Thiazolidine-2-carboxylic acid methyl ester hydro-chloride (1.02 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (1.02 mmol) were coupled according to Procedure A (1:1 dichloromethane-dimethylformamide solvent) and the crude product triturated with 1:1 ether-hexanes giving a light yellow solid. Yield 79%; HPLC (60/40) 4.47 minutes (95%); TSPMS 382/384 (MH+, 100%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:17]=[O:18])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)#[CH:2].Br[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:10]1([CH3:13])[CH2:9][CH2:8][C:7]([CH3:16])([CH3:15])[C:6]2[CH:5]=[C:4]([CH:17]=[O:18])[C:3]([C:1]#[C:2][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:12][C:11]1=2
Reactant: Brc1ncccn1
Reactant: C#Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(C#Cc3ncccn3)cc21
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of 0.400 g (1.66 mmol) of 3-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.278 g (1.75 mmol) of 2-bromopyrimidine, 0.053 g (0.075 mmol) of dichlorobis(triphenylphosphine)palladium(II), 0.026 g (0.14 mmol) of cuprous iodide, and 0.253 g (2.50 mmol) of triethylamine in 12 mL of dimethylformamide was heated to 45° C. for 3 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (25% ethyl acetate/hexane) to afford 0.372 g (70%) of 5,5,8,8-tetramethyl-3-pyrimidin-2-ylethynyl-5,6,7,8-tetrahydro-2-naphthaldehyde.(M+=318).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][CH2:16][CH2:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.BrBr.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][CH2:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2c(s1)CCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(s1)CCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Yield: 35.5 %

Procedure:
To a solution of 3.6 g of 2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in 30 ml of acetic acid is added 0.6 ml of bromine at 40° C. with stirring and the reaction mixture is stirred at 40-45° C. for 30 minutes. The mixture is poured into water and the resultant oil is collected by decantation. The crude product is subjected to column chromatography on silica gel and eluted with chloroform to give 1.27 g of 2-(4-chlorophenyl)-2,5,6,7-tetrahydro-9-methyl-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one, melting at 149.5°-151° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CCOCC>[CH:13]1([NH:19][C:20]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: S=C=NC1CCCCC1
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: S=C(NC1CCCCC1)N1CCN(c2cnccn2)CC1
Reaction time: 0.58 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added dropwise a solution of 4.2 g. of cyclohexyl isothiocyanate in 50 ml. of anhydrous ether over 5 minutes. The mixture isstirred for 35 minutes and the resulting solid is collected and recrystallized from 50 ml. of ethanol, giving 7.58 g. of the desired product, m.p. 176°-178° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[OH-].[K+].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCO>[C:5]([O:4][C:3]([NH:2][O:1][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCOC(=O)C(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)ONC(=O)OC(C)(C)C

Procedure:
To a solution of t-butyl hydroxycarbamate (530 mg, 3.98 mmol) and potassium hydroxide (223 mg, 3.98 mmol) in EtOH (10 mL) was added ethyl 2-bromopropanoate (600 mg, 3.31 mmol) slowly at rt. The reaction mixture was heated at reflux overnight. White precipitate was filtered off and the filtrate was concentrated. The resulting residue was dissolved in ether, washed with water and brine, and dried over Na2SO4. Solvent was evaporated to afford the title compound as a clear oil which was used in the next step without further purification (825 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.62 (s, 1H), 4.46 (q, 1H), 4.24 (q, 2H), 1.46 (d, 3H), 1.48 (s, 9H), 1.28 (t, 3H).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH3:30])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1)(=[O:27])=[O:26]>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:30]5[CH:31]=[N:32][CH:33]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cncc(S(C)(=O)=O)c3)cc1-2
Yield: 30 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 5-(methylsulfonyl)pyridin-3-ylboronic acid were reacted to give 237 (0.053 g, 30%). 1H NMR (400 MHz, DMSO) δ 9.28 (d, J=2.0, 1H), 9.07 (d, J=1.8, 1H), 8.82 (d, J=2.2, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J=8.4, 2.3, 1H), 7.27 (d, J=8.4, 1H), 5.87 (dt, J=13.0, 6.5, 1H), 4.45 (t, J=4.8, 2H), 3.50 (t, J=4.8, 2H), 3.41 (s, 3H), 1.59 (d, J=6.6, 6H). MS (ESI(+)): m/z 468.1 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH3:23][O:24][CH2:25][CH2:26][CH:27]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:27][CH2:26][CH2:25][O:24][CH3:23]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: COCCC=O
Product: COCCC=NOCCC1=C(C)/C(=C/c2ccncc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-methoxypropanal by the method of Example 1.
Reaction SMILES: C[C:2]1[C:3](C)=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[CH:8]=[C:7]([CH2:13][CH2:14][CH3:15])[C:6]=2[C:16]#[C:17]CO.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:9]1[CH:8]=[C:7]([CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[CH:17])=[C:5]2[C:10]=1[CH:11]=[CH:2][CH:3]=[N:4]2
Reactant: CCCc1cc(F)c2cc(C)c(C)nc2c1C#CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#Cc1c(CCC)cc(F)c2cccnc12
Temperature: 120 °C
Yield: 67.1 %

Procedure:
Dimethylhydroxymethyl-5-fluoro-7-propyl-8-quinolylacetylene (390 mg, 1.44 mmol) and NaOH (88.0 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 30 mL Schlenk tube equipped with a reflux condenser and the air inside the flask was replaced with Ar. 5.0 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 206 mg of 5-fluoro-7-propyl-8-quinolylethyne as a yellow solid (yield: 66.6%).
Reaction SMILES: CS([O:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)=O.O[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]3[CH:40]=[CH:39][C:30]4[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=4[CH:28]=3)[CH:20]=2)=[C:14]([CH3:41])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:6]1([O:5][C:12]2[CH:13]=[C:14]([CH3:41])[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]5[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=5[CH:28]=4)[CH:20]=3)=[C:16]([CH3:18])[CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Reactant: CS(=O)(=O)OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCCC5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Cyclopentyl methanesulfonate 10c (50 mg, 0.28 mmol), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (60 mg, 0.14 mmol), and cesium carbonate (100 mg, 0.30 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting mixture was mixed with 10 mL of water and extracted with ethyl acetate (20 mL×2). The organic phase was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL) successively, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under the reduced pressure and the residue was purified by elution system B to obtain the title compound (S)-methyl 2-(6-((4′-(cyclopentyloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 10d (40 mg, yield 30.0%) as a colorless slime.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]3[C@H:18]([CH3:41])[C@@H:19]4[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:20]4[C:21]=3[C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])[CH2:13][N:12]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:10])[CH2:3]1.[ClH:55]>O1CCCC1.O>[ClH:55].[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([C@@H:11]2[CH2:15][C@H:14]([S:16][C:17]3[C@H:18]([CH3:41])[C@@H:19]4[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:20]4[C:21]=3[C:22]([OH:24])=[O:23])[CH2:13][NH:12]2)=[O:10])[CH2:5]1
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C[C@H](C)N1

Procedure:
The whole of the 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-(cis-3,5-dimethyl-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate prepared as described in step (a) above was dissolved in 4 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 261 μl of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 0.2 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 8(b), to give 27 mg of the title compound as a powder.