Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2Cl)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C(=O)[CH2:30][CH2:29][CH2:28]1.C([Mg]Cl)CC.Cl>C1COCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe].C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH2:28][CH2:29][CH3:30])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2cc3ccncc3cc2Cl)CC1
Reactant: CN1CCCC1=O
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: CCC[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1cc2cnccc2cc1SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To 200 mg (0.52 mmol) 4-(7-Chloro-isoquinolin-6-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (274) dissolved in 5 ml THF and 1 ml NMP were added 20 mg (0.055 mmol) Ferric (III) acetylacetonate. To the red solution 0.3 ml of propylmagnesium-chloride (2M in THF) were added and 2 min stirred at RT. 1 ml 1N HCl and 20 ml diethyl ether were added and the organic layer was washed with brine. The organic phases were dried over Sodium sulfate and evaporated. The residue was purified by HPLC. 85 mg of 4-(7-Propyl-isoquinolin-6-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester could be obtained as the trifluoroacetate.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[CH:9][Cl:10].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])(=[O:19])=[O:20])=[CH:9][Cl:10]
Reactant: CN(C)C(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Yield: 89.4 %

Procedure:
A solution of 10.2 g of dimethylcarbamyl chloride in 10 ml of methylene chloride is added dropwise to a mixture of 10.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide, 12.2 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of methylene chloride at 20° to 25° C. and the mixture is refluxed for 2 hours. The solvent is then evaporated off and the residue is dissolved in 5% sodium carbonate solution. The solution is filtered and acidified with 10% hydrochloric acid, whereupon the product precipitates as crystals. After filtration and drying, 12.1 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N',N'-dimethylurea are obtained. Melting point: 218°-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.Cl.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:3]=1
Reactant: OC1(c2cncc(Br)c2)CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cncc(C2=CCCC2)c1

Procedure:
A solution of 1-(5-bromopyridin-3-yl)cyclopentanol (8) (1.7 g, 11.3 mmol) in 50 ml of toluene containing 5 ml of concentrated hydrochloric acid is heated at 120° C. for 12 hours with continuous carrying away of the water formed. The mixture is then poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 60/40). The title product is obtained in the form of a beige solid (1.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[S:27])[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@H:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:17][CH3:18])=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:9]=[C:10]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@@H:16]([NH:19][C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])[CH2:17][CH3:18])[S:27][C:7]=2[CH:8]=1
Reactant: CC[C@@H](NC(=O)C(F)(F)F)C(=O)NCCNC(=S)Nc1ccc(OC)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Br-]
Solvent: ClCCl
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCNc1nc2ccc(OC)cc2s1
Reaction time: 8 h

Procedure:
A solution of (R)—N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-(2,2,2-trifluoroacetamido)butanamide (412.5 mgs, 1.0 mmol) in methylene chloride (10 mL) was treated with benzyltrimethylammonium tribromide (389.4 mgs 1.00 mmol) and the resulting mixture stirred overnight. The reaction was then quenched with aqueous sodium bicarbonate and extracted into methylene chloride. The organic layer was dried over sodium sulfate, then filtered and concentrated to yield a residue which was purified by normal phase column chromatography, eluting with 5% methanol in chloroform to yield (S)—N-(2-(6-methoxybenzo[d]thiazol-2-ylamino)ethyl)-2-(2,2,2-trifluoroacetamido)-butanamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (108.6 mg, 0.27 mmol) was dissolved in absolute CH2Cl2 (14 ml) under N2 in a 50 ml Schlenk flask. Succinic anhydride (33 mg, 0.33 mmol) and a spatula-tip of 4-(dimethylamino)pyridine (DMAP) were added to the solution. The mixture was stirred at room temperature overnight. The mixture was then evaporated almost to dryness in vacuo and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 8:2:0.1, l=17 cm, V=5 ml). The fractions with the product were evaporated in vacuo and the residue was taken up in CH2Cl2 again. The mixture was filtered with a glass filter crucible G4 and Celite and the filtrate was evaporated in vacuo. The yield gave a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][C@H:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH3:36][N:37]1[C:42](=[S:43])[CH:41]=[CH:40][CH:39]=[CH:38]1.[I-].[Na+].C(=O)([O-])O.[Na+]>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][C@H:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][S:43][CH2+:42]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH3:36])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O[C@H]3CCNC3=O)c3csc(N)n3)[C@H]2SC1
Reactant: Cn1ccccc1=S
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CN1C=CC=C[CH2+]1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O[C@H]3CCNC3=O)c3csc(N)n3)[C@H]2SC1
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 33.3 %

Procedure:
To 4.8 ml of water are added 341 mg of 7β{(Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-oxopyrrolidin-3-yl)oxyimino]acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid, 125 mg of 1-methyl-2-thiopyridone and 900 mg of sodium iodide. The mixture is adjusted to a pH of 6.63 with an aqueous solution of sodium hydrogencarbonate. The mixture is stirred in an argon atmosphere at 65° C. for 3.5 hours. The reaction mixture is concentrated under reduced pressure. The concentrate is introduced into a column packed with HP-20 and is eluted with 20% and 25% methanol solutions. The fractions containing the contemplated compound are collected and concentrated. The residue is lyophilized, giving 128 mg of 7β-{(Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-oxopyrrolidin-3-yl)oxyimino]acetamido}-3-(1-methyl-2-pyridinio)thiomethyl-3-cephem-4-carboxylate as a pale brown compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:15])=[O:14]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 89 %

Procedure:
To a stirring solution of ethyl 5-chloro-2-nitrobenzoate (2 g, 8.71 mmol) and phenylboronic acid (2.124 g, 17.42 mmol) in DMF (20 ml) was added K3PO4 (2.77 g, 13.07 mmol), palladium acetate (0.098 g, 0.436 mmol) and tetrabutylammonium bromide (4.21 g, 13.07 mmol). Reaction mixture was heated at 95° C. for 16 h. Reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated and distilled out to get crude product which was column purified using 10% EtOAC in hexane to get the titled compound in 89% yield.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si](C)(C)C.[OH-].[K+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCCC#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CCCCc1nc(-c2ccccc2)oc1C
Reaction time: 12 h

Procedure:
Alkyne 1-6 (1.9 g, 6.3 mmol) was dissolved in methanol (100 mL) at 23° C. under N2 atmosphere. An aqueous solution of 10% KOH (10 mL) was then added and the reaction stirred for 12 hours. Solvent removed in vacuo and residue partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water, brine and dried over MgSO4. The crude product 1-7 was used in the following step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1>ClCCl.FC(F)(F)C(O)=O>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3cccnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CCn2c(=O)ccc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of 0.26 g of tert-butyl (1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 4 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water and diethyl ether was added to the resultant residue, and the aqueous layer was separated and washed with diethyl ether, and then, thereto was added a 20% aqueous sodium hydroxide solution and the reaction mixture was adjusted to pH 13 to 14. Thereto were added dichloromethane and sodium chloride, the organic layer was separated, and the aqueous layer was extracted with chloroform while being salted out. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.15 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:33][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][N:27]=[C:26]5[Cl:32])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>Cl>[ClH:32].[ClH:32].[ClH:32].[Cl:32][C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([NH:22][C:21]3[C:16]4[CH:15]=[C:14]([C:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=5)[NH:33][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:24]=2)[NH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]nc(Cl)c5c4)ncnc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-[4-(3-chloro-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (45.4 mg, 0.0945 mmol, 1 eq) in 4.0 M of HCl in 1,4-dioxane (3.25 mL, 140 eq) was allowed to stir at rt for 2 h. The reaction was concentrated in vacuo to dryness, affording the title compound, as a yellow solid. 1H NMR (400 MHz, MeOH-d4): δ=2.83 (s, br, 2H), 3.52 (t, J=6.0 Hz, 2H), 3.95 (s, br, 2H), 6.44 (s, 1H), 6.83 (s, br, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.75 (dd, J=8.8, 0.8 Hz, 1H), 8.19 (s, 1H), 8.28 (d, J=0.8 Hz, 1H). MS (ES+): m/z 365.98/368.00 (20/8) [MH+]. HPLC: tR=0.48 & 1.56 min (ZQ2000, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[C:7](C(O)=O)=[CH:6][N:5]=[C:4]2[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:13]([CH3:14])[C:3]=12.[OH-].[Na+]>P(=O)(O)(O)O>[CH3:14][C:13]1[C:3]2[C:2]([OH:1])=[CH:7][CH:6]=[N:5][C:4]=2[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:12]=1
Reactant: Cc1nn(-c2ccccn2)c2ncc(C(=O)O)c(O)c12
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(-c2ccccn2)c2nccc(O)c12
Temperature: 180 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
A suspension of 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.0 g, 6.7 mmol) in phosphoric acid (10 mL) was heated and stirred at 180° C. for 12 hours. The reaction solution was cooled to room temperature, neutralized by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (chloroform:methanol=95:5) gave the title compound (230 mg, 15% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11](O)[CH3:12])=[C:9]2[C:4]([C:5]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]([CH:11]=[CH2:12])=[C:9]2[C:4]([C:5]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:6][CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1cc(C)c(-c2cccc3c(C(C)O)n(C)nc23)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1c2cccc(-c3c(C)cc(C)cc3C)c2nn1C
Yield: 54.7 %

Procedure:
A solution of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazol-3-yl]-ethanol (0.263 g, 0.893 mmol) and 4-toluenesulfonic acid hydrate (0.217 g, 1.14 mmol) in 10 mL of toluene was stirred at 103° C. for 16 h then allowed to cool. The yellow-orange solution was sequentially washed with 10 mL of a 10% aqueous NaOH solution and 10 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to an orange oil. Column chromatography (20% EtOAc/hexanes) afforded 2-methyl-7-(2,4,6-trimethyl-phenyl)-3-vinyl-2H-indazole (15: Ra=Rb=H, Ar=2,4,6-trimethylphenyl; 0.135 g; 55%; m.p. 84.9-95.4) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][CH2:11][C:12](O)=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O.O1CCCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:12][CH2:11][CH2:10][C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=C(O)CCc1cnc2ccccn12
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN(CCCc3cnc4ccccn34)CC2)cc1

Procedure:
To a solution of 3-(imidazo[1,2-a]pyridin-3-yl)propionic acid (4 g) synthesized according to the method described in Japanese Patent Unexamined Publication No. 189179/1983, 1-(4-chlorophenyl)piperazine hydrochloride (4.9 g) and triethylamine (5.9 ml) in dimethylformamide was added dropwise diethyl cyanophosphate (3.8 ml) under ice-cooling with stirring, and the mixture was stirred for 3 hours. After the completion of the reaction, the reaction mixture was concentrated, extracted with chloroform, washed with water and dyed over magnesium sulfate. The solution was concentrated under reduced pressure, and lithium aluminum hydride was added to a solution of the obtained 4-(4-chlorophenyl)-1-(3-(imidazo[1,2-a]pyridin-3-yl)propionyl)piperazine in tetrahydrofuran under ice-cooling with stirring, and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was treated with a mixed solvent of water-tetrahydrofuran and filtered through celite. The filtrate was concentrated under reduced pressure the obtained residue was subjected to silica gel column chromatography to give 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)imidazo[1,2-a]pyridine. This compound was dissolved in a mixture of ethanol (20 ml) and conc. hydrochloric acid (20 ml) and reduced in the presence of 10% palladium-carbon (1 g) in an autoclave at 70° C. and 50 atm. After the completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, m.p. 95-97° C. (m.p. as oxalate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([OH:12])=O)=[N:6][C:7]=1[C:8]#[N:9].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])[CH3:28]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([CH:27]([CH3:29])[CH3:28])[CH2:31][CH2:32]2)=[O:12])=[CH:4][CH:3]=1
Reactant: N#Cc1nc(C(=O)O)ccc1Br
Reactant: CC(C)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc(Br)c(C#N)n2)CC1
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
A mixture of 5-bromo-6-cyano-pyridine-2-carboxylic acid (875 mg, 3.85 mmol), HOBt (882 mg, 6.53 mmol), and EDC (1.11 g, 5.80 mmol) in DMF (32 mL) was stirred for 5 min and then treated with 1-isopropyl-piperazine (943 mg, 7.35 mmol). After 5 h, the mixture was diluted with DCM, washed with 1 N NaOH and water, dried, and concentrated. Purification of the residue by FCC gave a viscous foam that crystallized upon standing. Further purification by reverse-phase HPLC gave the title compound (476 mg, 37%). MS (ESI): mass calcd. for C14H17BrN4O, 336.06; m/z found, 337.2 [M+H]+. 1H NMR (d6-acetone): 8.43 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 3.70-3.68 (m, 2H), 3.51-3.49 (m, 2H), 2.73 (septet, J=6.6 Hz, 1H), 2.58-2.56 (m, 2H), 2.50-2.48 (m, 2H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:9][O:10][CH2:11][CH2:12][O:13][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: Nc1ccc(I)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COCCOc1ccc(N)cc1
Temperature: 25 °C
Yield: 5.3 %

Procedure:
A mixture of 4-iodoaniline (219 mg, 1.0 mmol), 2-methoxyethanol (152 mg, 2.0 mmol), copper iodide (19.0 mg, 0.1 mmol), cesium carbonate (554 mg, 1.7 mmol) and 1,10-phenanthroline (36.0 mg, 0.2 mmol) was stirred in toluene (0.5 mL) at 110° C. overnight. The reaction was then cooled to RT and filtered through silica gel and washed with diethyl ether. The ether was removed in vacuo to obtain a crude solid. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a solid (8.9 mg, 5.3%). 1H NMR (300 MHz, CDCl3) δ 6.82-6.72 (m, 4H), 4.06 (t, 2H), 3.72 (t, 2H), 3.45 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:17][C:16]1[C:11]2[C:12](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][N:10]=2)[CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: Cc1cc(Cl)cc2c(-c3ccc(Br)cc3)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)c2noc(-c3ccc(Br)cc3)c2c1
Yield: 84.3 %

Procedure:
A mixture of 2.1 g (0.0065 mole) of 3-(4-bromophenyl)-5-chloro-7-methyl-2,1-benzisoxazole, 1.2 g (0.0067 mole) of N-bromosuccinimide and a few crystals of dibenzoyl peroxide in 100 ml of carbon tetrachloride was heated at reflux for 2.5 hr under flood light illumination and an argon atmosphere and then filtered while still hot. The filtrate was concentrated under reduced pressure to a solid residue. The solid was recrystallized twice from 2-propanol to give 2.2 g (85%) of light-yellow needles, m.p. 147°-150° C.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([O:11][P:12](C(C)(C)CN)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:10].N1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24]C=1C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C(OCC)(=O)C>[PH:12](=[O:16])([O:11][CH2:9][C:10]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:13][CH2:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOP(=O)(OCC)C(C)(C)CN
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[PH](OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triflate 9 (94 mg, 0.214 mmol) in CH2Cl2 (2 mL) was added a solution of aniline 6 (100 mg, 0.173 mmol) in CH2Cl2 (2 mL) at −40° C., followed by 2,6-lutidine (0.026 mL). The mixture was warmed up to room temperature and stirred for 1 h. Cesium carbonate (60 mg) was added and the reaction mixture was stirred for additional 1 h. The mixture was diluted with ethyl acetate, washed with HCl (0.2N), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC to afford dibenzyl phosphonate (40 mg). To a solution of this dibenzyl phosphonate in ethanol (3 mL) and ethyl acetate (1 mL) was added 10% Pd/C (40 mg). The mixture was stirred under hydrogen atmosphere (balloon) for 4 h. The reaction mixture was diluted with methanol, filtered and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give desired product diacid 10 (20 mg). 1H NMR (CD3OD) δ 7.8 (d, 2H), 7.3 (d, 2H), 7.1 (2d, 4H), 5.6 (d, 1H), 4.9 (m, 2H), 3.4-4.0 (m, 6H), 3.9 (s, 3H), 2.53.2 (m, 9H), 2.0 (m, 2), 1.4-1.7 (m, 2H), 0.9 (2d, 6H); 31P NMR (CD3OD) δ 22.1; MS (ESI): 686 (M+H).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Cc1ccccc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(O)C(=O)c2ccccc2)cc1C

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and o-xylene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 20 minutes. Using the same procedure as in Example 1, 3',4'-dimethylbenzoin was obtained as crystal (258.7 mg, 54.0% yield).