Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][C@@H:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:19][C@@H:20]1[O:25][CH2:24][CH2:23][N:22]([C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21]1
Reactant: C[C@H]1CNCCO1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H]1CN(c2ncnc3[nH]cc(-c4cccc(C#N)c4)c23)CCO1
Temperature: 100 °C

Procedure:
To a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (100 mg, 0.393 mmol) and (2S)-2-methylmorpholine (54 mg, 0.53 mmol) in n-butanol (20 mL) was added N,N-diisopropylethylamine (152 mg, 1.18 mol), and the reaction mixture was heated at 100° C. for 18 hours. The reaction mixture was then concentrated in vacuo; purification via preparative HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: ammonia in water, pH 10; Mobile phase B: acetonitrile; Gradient: 27% to 47% B) provided the product as a white solid. Yield: 17.5 mg, 54.8 μmol, 14%. LCMS m/z 320.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 10.71 (br s, 1H), 8.53 (br s, 1H), 7.73-7.89 (m, 2H), 7.51-7.69 (m, 2H), 7.28 (s, 1H, assumed; partially obscured by solvent peak), 3.56-3.77 (m, 3H), 3.39-3.54 (m, 2H), 2.86-2.98 (m, 1H), 2.53-2.65 (m, 1H), 0.93-1.03 (m, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([C:12]2[S:13][C:14]([C:23]([O:25]CC)=[O:24])=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[O:11])[CH2:4]1.C1COCC1.C(O)C.[Na].[OH-].[K+]>C(O)C>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([C:12]2[S:13][C:14]([C:23]([OH:25])=[O:24])=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[O:11])[CH2:4]1
Reactant: CCOC(=O)c1sc(C(=O)OCC2CCC(OC)C2)nc1-c1ccccc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC1CCC(COC(=O)c2nc(-c3ccccc3)c(C(=O)O)s2)C1

Procedure:
To a stirred solution of (±)-2-(3-methoxycyclopentylmethylcarboxy)-4-phenyl-thiazol-5-carboxylic acid, ethyl ester (0.01 mol), which may be prepared as described in Step (d) above, in a solvent such as ethanol, aqueous ethanol, or THF-ethanol, is added a solution of sodium or potassium hydroxide in ethanol at a concentration of from 1 M to about 2 M, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the mixture is rotary evaporated to remove most of the organic solvents, and the concentrated mixture is washed with ethyl acetate. The aqueous layer is acidified with hydrochloric acid to a pH of about 2 to about 4, and the product which precipitates is filtered off to give (±)-2-(3-methoxycyclopentylmethylcarboxy)-4-phenyl-thiazol-5-carboxylic acid, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH2:23])[C:17]=2[N:16]=[CH:15]1.[N+](C1C2N=CSC=2C=CC=1)([O-])=O.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH:23][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:17]=2[N:16]=[CH:15]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2scnc12
Agent: CN(C)c1ccncc1
Agent: O=[N+]([O-])c1cccc2scnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2scnc12
Yield: 45.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitrobenzenesulfonyl chloride (1.7 g, 7.9 mmol), benzothiazol-4-ylamine (Intermediate 222) (1.0 g, 6.6 mmol), DMAP (cat), pyridine (2 ml, 24.8 mmol) and DCM (10 ml) at 0° C. for 5 h, gave the title compound (1.0 g, 45%) which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[N:7][C:6]=1[CH3:13])C.[OH-].[Na+]>CCO>[Cl:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:4]([OH:14])=[O:3])=[C:6]([CH3:13])[N:7]=1
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)nc(C)c1C(=O)O
Temperature: 90 °C

Procedure:
To a solution of 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester (0.200 g, 0.930 mmol) in EtOH (1 mL) was added 4N NaOH (1 mL), and the mixture was heated at 90° C. for 1 h. After the mixture was cooled to room temperature EtOH was removed and the aqueous residue was acidified with 4N HCl to afford a white precipitate. The precipitate (0.152 g, 88%) was collected by filtration and dried under vacuum to give 6-chloro-2,4-dimethyl-nicotinic acid as a white solid. 1H NMR (CD3OD) δ 2.37 (s, 3H), 2.51 (s, 3H), 7.23 (s, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].Cl.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>C1COCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: Brc1ccncc1
Reactant: COc1ccc(Br)c(OC)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccncc2)c(OC)c1

Procedure:
The Grignard reagent, prepared from magnesium (5 g) and 1-Bromo-2,4-dimethoxybenzene (38 g) in THF (300 ml), is added at room temperature to 4-Bromo-pyridine hydrochloride salt in THF (10 ml). The mixture is heated under reflux for 2 hours and then evaporated to dryness. The residue is taken up in ethyl acetate and extracted with 1N hydrochloric acid. The aqueous phase is neutralised with 4M sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried with magnesium sulfate, evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=1:1 (v/v). MS-APCI+ (M+H)+=216
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[S:6][C:7]([CH:11]=O)=[C:8]([Cl:10])[N:9]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[Cl:4][C:5]1[S:6][C:7]([CH:11]=[N:2][OH:3])=[C:8]([Cl:10])[N:9]=1
Reactant: NO
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1sc(Cl)nc1Cl
Reaction time: 0.03 h
Yield: 99 %

Procedure:
First 153 g (2.2 mol) of hydroxylamine hydrochloride in portions, then a solution of 364 g (2 mol) of 2,4-dichloro-5-thiazolecarboxaldehyde (II) in 1 liter of ethanol are added to a solution of 185 g (2.2 mol) of sodium bicarbonate in 5 liters of water at room temperature, with stirring. A voluminous, colourless precipitate separates out after 1 to 2 minutes. After stirring for 1 hour, the solid is filtered off with suction, washed with water and dried. 390 g (=99% of theory) of 2,4-dichloro-5-thiazolecarboxaldehyde oxime (IV) of melting point about 160° C. are obtained. It can be dehydrated to give the nitrile without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])=[O:19])=[CH:16][C:15]=1[O:30][CH3:31])#[N:12]>ClCCl>[C:11]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:27])=[O:19])=[CH:16][C:15]=1[O:30][CH3:31])#[N:12]
Reactant: COc1cc(C(=O)NC2CCCC[C@H]2O)ccc1CC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCCCC2=O)ccc1CC#N
Temperature: 22 °C

Procedure:
To a solution of oxalyl chloride (0.2 mL, 2.2 mmol) in anhydrous dichloromethane (2 mL) at −78° C. was added DMSO (0.32 mL, 4.5 mmol) under Argon. The solution was maintained for 10 min where upon a solution of 4-(cyanomethyl)-N-[(2R)-2-hydroxycyclohexyl]-3-methoxybenzamide (430 mg, 1.5 mmol) in anhydrous dichloromethane (13 mL) was added dropwide. The reaction was stirred at −78° C. for 30 min, whereupon TEA (1 mL, 7.5 mmol) was added. The reaction was warmed to 22° C. for 2 h. Then, 50 mL dichloromethane was added to the mixture, washed with sat NaHCO3 (3×15 mL) and sat. brine (3×15 mL), dried (MgSO4), and concentrated to afford a yellow solid of 4-(cyanomethyl)-3-methoxy-N-(2-oxocyclohexyl)benzamide. MS (ESI) 287 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:14]([O:24][CH3:25])[C:13]=2[N+:26]([O-:28])=[O:27])=[N:2]1.[OH-].[Na+].Cl>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([O:24][CH3:25])[C:13]=2[N+:26]([O-:28])=[O:27])=[N:2]1
Reactant: COC(=O)COc1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(OCC(=O)O)ccc(/C=C/c2n[nH]c3ccccc23)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of methyl (E)-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}acetate obtained in Step 2 in methanol (20 mL) was added with 2 mol/L aqueous sodium hydroxide solution (10 mL) and stirred at 60° C. for 1 hour. To the reaction mixture under ice-cooling, 2 mol/L hydrochloric acid was added to neutralize the mixture. The precipitated solid was collected by filtration to obtain (E)-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}acetic acid (1.9 g, 100%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26]Cl)[N:23]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:23]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: C1COCCN1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
K2CO3 (12.4 g, 90.0 mmol), KI (8.29 g, 51.0 mmol) and morpholine (3.9 mL, 45.0 mmol) were added to a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 30.0 mmol) in acetonitrile (150 mL). The reaction was stirred at 70° C. for 18 h. The solids were filtered off and the solvent was removed in vacuo. The residue was partitioned between DCM (150 mL) and water (150 mL). The organic phase was dried (MgSO4) and evaporated. Chromatography (SiO2, eluted with petrol-EtOAc 0-50%) gave the title compound (9.0 g, 77%) as a white solid. MS: [M+H]+=390.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:17])[C:10]([OH:18])=[C:9]1[C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][O:21][C:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]2[O:17][CH2:24][CH2:25][O:18][C:10]=12)=[O:20]
Reactant: BrCCBr
Reactant: COC(=O)c1c(O)c(O)c(C(=O)OC)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c2c(c(C(=O)OC)n1Cc1ccccc1)OCCO2
Temperature: 107.5 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
A mixture of dimethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (0.1 mol), 1,2-dibromoethane (0.1 mol), and potassium carbonate (0.5 mol) in dry DMF was stirred for 12 h under argon at 105-110° C. After cooling to 25° C., the reaction mixture was poured onto ice-water. The crude product was collected by suction filtration and purified by recrystallization in methanol yielding 6-benzyl-2,3-dihydro-6H-[1,4]dioxino[2,3-c]pyrrole-5,7-dicarboxylic acid dimethyl ester as colourless crystals in 55-65% yield.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([CH2:19][O:20][N:21]=[C:22]([C:62]1[N:63]=[CH:64][S:65][CH:66]=1)[C:23]([NH:25][CH:26]1[C:60](=[O:61])[N:28]2[C:29]([C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[C:30]([CH2:33][S:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([CH:41]=[N:42][N:43]=4)[N:40]=3)[CH2:31][S:32][C@H:27]12)=[O:24])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(OC(CON=C(C1N=CSC=1)C(NC1C(=O)N2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=O)C(CSC3C=CC4N(C=NN=4)N=3)=CS[C@H]12)=O)=O)(C)(C)C>C(OCC)(=O)C>[C:12]([O:16][C:17]([CH2:19][O:20][N:21]=[C:22]([C:62]1[N:63]=[CH:64][S:65][CH:66]=1)[C:23]([NH:25][CH:26]1[C:60](=[O:61])[N:28]2[C:29]([C:44]([O:46][CH:47]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])=[C:30]([CH2:33][S:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([CH:41]=[N:42][N:43]=4)[N:40]=3)[CH2:31][S:32](=[O:9])[C@H:27]12)=[O:24])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3ccc4nncn4n3)CS[C@H]12)c1cscn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CSc3ccc4nncn4n3)=CS[C@H]12)c1cscn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3ccc4nncn4n3)CS(=O)[C@H]12)c1cscn1
Yield: 91 %

Procedure:
A solution of m-chloroperbenzoic acid (0.4 g) (purity: 80%) in ethyl acetate (5 ml) was added to a solution of a mixture (1.4 g) of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) and benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-2-cephem-4-carboxylate (syn isomer) in ethyl acetate (10 ml) under ice-cooling and the resultant mixture was stirred for 1 hour at the same temperature. The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively. The organic layer was dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (1.3 g).
Reaction SMILES: [C:1]1([C:11]([O:13]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>C(O)C>[C:1]1([C:11]([NH:16][NH2:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2ccccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc2ccccc12

Procedure:
The synthesis method of Example 2-(1) was applied. The compound (43.1 g) obtained in (1) above, hydrazine monohydrate (200 ml) and ethanol (80 ml) were used as reagents. After the reaction, a white solid was quantitatively obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[NH:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Clc1cccc(I)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1cccc(Cl)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 1-chloro-3-iodobenzene 0.11 mL, cesium carbonate 0.23 g, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg at room temperature, and it was stirred at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(3-chloroanilino)-4-phenethylbenzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22](=O)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:21]=[C:22]([CH3:23])[C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cn1
Product: COC(=O)c1c(C)cn2cc(OCc3ccccc3)ccc12
Yield: 69 %

Procedure:
This compound is obtained according to the same procedure as the compound of Preparation III using the Tschitschibabin reaction, starting with 19 g of methyl 2-[5-(benzyloxy)pyridin-2-yl]acetate [according to Bull. Pol. Acad. Sci. Chem.; (1990), 38(1-12), 17-27] and chloroacetone. 15.01 g of an orange-coloured solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[Li+:18].[OH-]>C1COCC1.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[Li+:18]
Reactant: COC(=O)CCCCc1ccc(C=O)c(N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(CCCCC(=O)[O-])ccc1C=O

Procedure:
Methyl 5-(3-amino-4-formylphenyl)pentanoate (447 mg) was treated with LiOH (88 mg) in 8.0 mL THF/water(v/v=3/1). Removal of the solvent after the reaction completed afforded lithium 5-(3-amino-4-formylphenyl)pentanoate (X3547-30). MS (ESI+): 222.10 (MH+). H NMR (400 MHz, MeOD): δ 9.72 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 6.55 (d, J=8.0 Hz, 1H), 2.56 (m, 2H), 2.19 (m, 2H), 1.64 (m, 4H).
Reaction SMILES: FC1C=CC2[N:6](C=C(C3C=CC(C(=O)C)=CC=3)N=2)C=1.C[N:21](C)/[CH:22]=[CH:23]/[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]3[CH:41]=2)=[CH:28][CH:27]=1)=O>>[F:40][C:37]1[CH:38]=[CH:39][C:34]2[N:35]([CH:41]=[C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]4[CH:23]=[CH:22][NH:21][N:6]=4)=[CH:27][CH:28]=3)[N:33]=2)[CH:36]=1
Reactant: CC(=O)c1ccc(-c2cn3cc(F)ccc3n2)cc1
Reactant: CN(C)/C=C/C(=O)c1ccc(-c2cn3cc(F)ccc3n2)cc1
Product: Fc1ccc2nc(-c3ccc(-c4cc[nH]n4)cc3)cn2c1
Yield: 69.5 %

Procedure:
The procedure of Referential Example 6 was repeated, except that 1-[4-(6 fluoroimidazo[1,2-a]pyridin-2-yl)phenyl]-1-ethanone (410 mg), which had been produced in Referential Example 28 was used, to thereby yield (E)-3-(dimethylamino)-1-[4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)phenyl]-2-propen-1-one (120 mg). Subsequently, The procedure of Referential Example 3 was repeated, to thereby yield the title compound (75 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][N:8]([CH2:20][C:21](=[O:22])[NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:7]2[CH2:6][C:5]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13]=1[O:18][CH3:19])[CH3:42]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl bromoacetate
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][N:18]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17]1)=[O:15])C1C=CC=CC=1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:41]>C1COCC1>[C:32]([O:31][C:29]([N:18]1[CH2:19][C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C@H:16]([C:14]([OH:41])=[O:15])[CH2:17]1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 60 h
Yield: 81 %

Procedure:
To a solution of the compound (2.5 g) obtained in step 3 in THF (27 mL) was added 4N aqueous lithium hydroxide solution (3.6 mL) at room temperature, and the mixture was stirred for 60 hr. The reaction mixture was made slightly acidic with aqueous citric acid solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 0→70% ethyl acetate/hexane) to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (1.41 g, 81%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:12](Br)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:14]([N:17]=[C:18]=[S:19])([CH3:16])[CH3:15].[H-].[Na+].CCOC(C)=O.CCCCCC>CN(C=O)C>[CH:14]([NH:17][C:18]1[S:19][C:12]2[C:2]([N:1]=1)=[N:3][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=2)([CH3:16])[CH3:15]
Reactant: CC(C)N=C=S
Reactant: CCOC(=O)c1cnc(N)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2nc(NC(C)C)sc2c1
Temperature: 65 °C
Reaction time: 40 h
Yield: 34.5 %

Procedure:
To a solution of ethyl 6-amino-5-bromonicotinate (0.780 g, 3.18 mmol) and isopropyl isothiocyanate (0.34 mL, 3.19 mmol) in DMF (8 mL) was added sodium hydride (60% oil dispersion) at 0° C. in one portion. The mixture was heated at 65° C. for 20 hr, and then at 75° C. for 40 hr. After it cooled to rt, the reaction was quenched with 1N HCl (5 mL). The mixture was poured into saturated NaHCO3 solution and extracted with AcOEt (3×40 mL). The combined extract was washed with 10% lithium chloride solution (2×30 mL) and dried over anhydrous MgSO4. The title compound (0.291 g, 34% yield) was isolated as a white solid by flash chromatography (60% AcOEt/hexane).