Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccnc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4cccnc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:15][CH2:16][C:17]2[C:25]3[C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=[N:21][C:20]=3[NH:19][CH:18]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH3:14][C:11]1([N:15]2[CH2:16][C:17]3=[CH:18][NH:19][C:20]4[C:25]3=[C:24]([CH:23]=[CH:22][N:21]=4)[C:26]2=[O:27])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC1(NCc2c[nH]c3nccc(C(=O)O)c23)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2Cc3c[nH]c4nccc(c34)C2=O)CC1

Procedure:
3-((1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (34 mg, 0.088 mmol), HATU (67 mg, 0.175 mmol), and pyridine (0.021 mL, 0.263 mmol) were stirred in DMF (3 mL) at room temperature for 2 h. The solution was concentrated in vacuo to give the title compound which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.O>[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:20]=[N+:21]=[N-:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1nc2ccccc2n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc2ccccc2n1Cc1ccccc1
Yield: 72.5 %

Procedure:
A solution of 1-Benzyl-2-chloromethylbenzimidazole hydrochloride (16 g, 0.055 mole) in N,N-dimethylformamide (80 ml) was stirred and a solution of sodium azide (17 g, 0.26 mole) in water (40 ml) was added. The resulting yellow solution was heated on a steam bath for 30 minutes, diluted with water (250 ml) and the crystalline product was filtered, dried in vacuo at room temperature, and recrystallized from 2-propanol to yield 10.5 g (73%) of product: mp 108°-110°.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].NC[C@H](O)[CH2:37][OH:38].CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH2:37][OH:38])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: NC[C@H](O)CO
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 43 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (S)-(−)-3-amino-1,2-propanediol (0.162 g 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (404.3 mg, 43%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.31 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.76 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.80 (m, 1H), 3.53 (m, 3H), 3.39 (m, 1H), 2.19 (s, 3H); ES-HRMS m/z 524.0630 (M+H C22H21BrF2N3O5 requires 524.0627).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:10]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:24]1([CH2:23][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][CH:10]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Reactant: ClCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)c1c[nH]c2ccccc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a 2-liter three necked round bottom flask equipped with an addition funnel was added, under nitrogen, 300 mL of dry tetrahydrofuran (THF) and 68.75 mL of lithium diisopropylamide (1.92M in cyclohexane/THF, 132 mmol). The mixture was cooled to -78° C., and a solution of indole-3-acetic acid, methyl ester (11.36 g, 60 mmol) in 300 mL of dry tetrahydrofuran was added dropwise. The mixture was then allowed to sit at -78° C. for 15 minutes, and then a solution of benzyl chloride (7.59 g, 60 mmol) in 300 mL of tetrahydrofuran was added dropwise. The reaction mixture must be stirred vigorously so that the precipitated dianion of indole-3-acetic acid, methyl ester reacts completely with the benzyl chloride. After 3 hours, TLC analysis indicated complete consumption of starting material, and 200 mL of aqueous saturated ammonium chloride was added. The aqueous layer was separated and washed with ether (2×100 mL). The combined ether extracts were added to the organic layer which was dried over magnesium sulfate, filtered and concentrated to 15.0 g (quantitative yield) of red-brown oil. This material was reduced to the corresponding tryptophol without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](Cl)=O)=[CH:20][CH:21]=2)[C:16]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:15]1)(=O)C.O>N1C=CC=CC=1>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:1][C:23]=1[C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:14][N:15]=[C:16]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nc5ccccc5[nH]4)cc23)cc1
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 2-nitroaniline (92 mg, 0.67 mmol) in pyridine (4 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (200 mg, 0.67 mmol). The reaction was stirred at room temperature overnight when water (30 mL) was added and the solid filtered and dried in a vacuum oven (45° C.). The solid was then taken up in ethyl acetate (20 mL)/ethanol (20 mL) and a scoup of palladium on carbon added. The resulting heterogenous solution was then subjected to an atmosphere of hydrogen. After stirring overnight, the solution was filtered and concentrated to an oil under vacuo and taken up in 4 N HCl (80 mL) which was refluxed for 12 hours. The reaction was quenched with saturated NaHCO3 and the product collected as a solid. The pure product was isolated after chromatography on silica gel eluting with 7% methanol in methylene chloride. (37 mg, 17% yield). 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 8.86 (s, 1H), 8.29 (d, 1H), 8.16–8.10 (m, 2H), 7.76 (d, 1H), 7.64 (dd, 2H), 7.45 (t, 2H), 7.24 (dd, 2H); ES-MS (m/z) 329 [M+1]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][N:4]1[CH:8]=[N:7][N:6]=[C:5]1[NH:9][NH2:10].[C:11]1([CH3:19])[C:12]([CH:17]=O)=[CH:13][CH:14]=[CH:15][CH:16]=1>C(O)C>[ClH:1].[NH2:3][N:4]1[CH:8]=[N:7][N:6]=[C:5]1[NH:9][N:10]=[CH:19][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NNc1nncn1N
Reactant: Cc1ccccc1C=O
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1C=NNc1nncn1N

Procedure:
To a solution of 14.0 g (0.075 mole) of 4-amino-3-hydrazino-1, 2,4-triazole dihydrochloride in 200 ml of 75 percent ethanol was added 9.0 g (0.075 mole) of o-tolualdehyde. The mixture was stirred and heated at reflux for 1.5 hour. The solution was cooled and the precipitate formed collected by filtration and washed with ether. Yield: 18.4 g, m.p. 230°-232° (D). After recrystallization from aqueous ethanolisopropyl ether the product melts at 233°-234° (D).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].Br[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccco1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)o1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Furan-2-carboxylic acid methyl ester (500 mg, 3.97 mmol) and 1-bromo-adamantane (853 mg, 3.97 mmol) were dissolved in ortho-dichlorobenzene (6 ml) and cooled to 0° C. before adding AlCl3 (1.06 g, 7.94 mmol) as a solid. The reaction mixture was allowed to warm up to room temperature, stirred for 4 h, then heated to 40° C. for 2 h and left standing at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with H2O (10 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×20 ml). The combined organic layers were dried (MgSO4), filtered and the DCM removed in vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gel column and flushed with heptane (100 ml). The title compound was then eluted using a stepped gradient of 0-10% EtOAc in heptane.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([O:19]CC)=[O:18])=[CH:15][N:16]=3)[CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=3)[CH:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1cnc2ccc(-c3sc(C)nc3C)cn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c(-c2ccc3ncc(C(=O)O)n3c2)s1
Temperature: 60 °C

Procedure:
A mixture of ethyl 6-(2,4-dimethylthiazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (145) (190 mg, 0.630 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 4 mL) was heated at 60° C. for 30 minutes. The reaction was cooled to room temperature and the pH was adjusted between 4-5 with 10% citric acid. The solvent was partially reduced and the resulting solid was collected by vacuum filtration to give 6-(2,4-dimethylthiazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (146). 1H NMR (400 MHz, d6-DMSO) δ 9.34 (s, 1H), 8.29 (s, 1H), 7.87 (dd, J=0.8, 9.2 Hz, 1H), 7.62 (dd, J=2.0, 9.2 Hz, 1H), 2.66 (s, 3H), 2.41 (s, 3H). MS m/z 274.06 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1)[CH3:2].N[C:19](N)=[O:20].CCOC(C)=O>CC1C=CC(C)=C(C)C=1C>[CH:12]1([N:11]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=3[NH:10][C:19]2=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC(N)=O
Reactant: CCOc1ccc(N)c(NC2CCCCC2)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccc(C)c(C)c1C
Product: CCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Yield: 39.3 %

Procedure:
A mixture of 3.05 g of the oil obtained in step B) and 1.6 g of urea in 8 ml of 1,2,3,4-tetramethylbenzene is heated at 170°-180° C. for 1 hour 30 minutes. After cooling, it is taken up with AcOEt, washed with water and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is taken up with hexane and the brown precipitate formed is filtered off. The precipitate is chromatographed on silica using a DCM/AcOEt mixture (50/50; v/v) as the eluent to give 1.33 g of the expected product, which was precipitated with isopropyl ether. M.p.=203° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O:18][C:19]([NH:21][C@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>C(O)CCCC>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:23]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: COc1ccc2nccc(Br)c2n1
Solvent: CCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nccc(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c2n1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A mixture of 8-bromo-2-methoxy-[1,5]naphthyridine (1.50 g, 6.27 mmol, prepared as in WO 2006/032466) and (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (1.17 g, 6.27 mmol) in pentanol (5 mL) and DIPEA (1.24 mL, 1.2 eq) was heated at 80° C. over night. The majority of the solvent was removed in vacuo at elevated temperature (50-60° C.). The residue was triturated with ether to remove residual amine. The mother liquor was concentrated and the residue was chromatographed over SiO2 (DCM-MeOH—NH4OH 1000:50:4) to afford the desired intermediate as a beige foam (1.86 g, 86%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([O:7][CH2:8][S:9][CH3:10])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting valeric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 83°-85° C./12 mm Hg, nD20 1.4560.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:13]([O:7][CH:4]1[CH:5]=[CH:6][C:2](=[O:1])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])[CH3:14]
Reactant: CCCCCC1C(=O)C=CC1O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCC1C(=O)C=CC1OC(C)=O
Yield: 92.9 %

Procedure:
Into a flask equipped with a stirrer and a thermometer, dl-3-hydroxy-2-n-pentyl-4-cyclopentenone (16.8 g), p-toluenesulfonic acid (0.1 g) and acetic anhydride (33.6 g) were charged, and the resultant mixture was stirred at 100° C. for 2 hours. After completion of the reaction, acetic anhydride was removed under reduced pressure, and the residue was extracted with toluene. The toluene layer was washed with 1% sodium bicarbonate solution and water. Toluene was removed from the toluene layer to give dl-3-acetoxy-2-n-pentyl-4-cyclopentenone (19.5 g). Yield, 93%. B.P., 105°-110° C./0.2-0.5 mmHg.
Reaction SMILES: C[O:2][C:3]([C@@:5]1([CH3:9])[CH2:8][CH2:7][NH:6]1)=[O:4].[OH-].[Na+].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(O)(=O)C>O>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:6]2[CH2:7][CH2:8][C@:5]2([CH3:9])[C:3]([OH:2])=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@@]1(C)CCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C[C@]1(C(=O)O)CCN1C(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-methyl-azetidine-2-carboxylic acid methyl ester (1 eq.) in water were added aqueous NaOH (1M) (3 eq.) then 4-bromo-benzoyl-chloride (1 eq.) dropwise. The reaction was stirred for 4 h at 20° C. The reaction was neutralised with acetic acid. The solvent was partially removed under reduced pressure and the crude was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH/AcOEt/AcOH/iPr2O: 95/5/98/2/300) to afford (R)-1-(4-bromo-benzoyl)-2-methyl-azetidine-2-carboxylic acid.
Reaction SMILES: [N:1]([C:4]1[C:13]([Cl:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[C:6]([CH3:37])[C:5]=1[F:38])=[N+]=[N-].[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[C:6]([CH3:37])[C:5]=1[F:38]
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)c(C)c2c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N)c(F)c(C)c2c1=O
Yield: 104.9 %

Procedure:
Palladium hydroxide-carbon (180 mg) was added to a solution of ethyl 7-azido-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.75 g) in methanol (9 ml), and the mixture was stirred at room temperature for 2.5 hours in a hydrogen atmosphere. The catalyst was removed by filtration through a membrane filter, and the solvent in the filtrate was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel to conduct elution with chloroform, thereby obtaining the title compound (1.75 g) as a brown oil.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:7]=[C:6]([O:8][CH3:9])[S:5][C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])[CH:36]=[CH:37][CH:38]=[C:39]([CH:41]=O)[CH3:40])[CH3:31].C1OCCC1>C1(C)C=CC=CC=1>[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])/[CH:36]=[CH:37]/[CH:38]=[C:39]([CH3:41])[CH:40]=[CH:10][C:4]1[S:5][C:6]([O:8][CH3:9])=[CH:7][C:3]=1[CH3:2])[CH3:31]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1sc(OC)cc1C

Procedure:
A suspension of 5.9 g. (13.5 mmol) of (3-methyl-5-methoxy-2-thenyl)triphenyl phosphonium chloride and 2.81 g. (13.5 mmol) of ethyl-7-formyl-3-mehtyl-2,4,6-octatrienoate in 70 ml. of butylene oxide and 200 ml. of toluene was heated to 100° C. for 14 hrs. The resulting clear solution was cooled, poured into 500 ml. of a methanol/water mixture (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude, oily material was purified by chromatography (silica gel, hexane/ether, ratio 7:3) to yield after recrystallization from hexane all trans-3,7-dimethyl-9-(3-methyl-5-methoxy-2-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, m.p. 66°-72° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH3:25])=[C:12]([NH:21][C:22]([NH2:24])=[S:23])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](I)[CH3:27]>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH3:25])=[C:12]([NH:21][C:22](=[NH:24])[S:23][CH2:26][CH3:27])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: Cc1c(NC(N)=S)ccc(-n2cccn2)c1CNC(=O)OC(C)(C)C
Solvent: CC#N
Product: CCSC(=N)Nc1ccc(-n2cccn2)c(CNC(=O)OC(C)(C)C)c1C
Yield: 95 %

Procedure:
A mixture of the compound (47 mg) obtained in Example 7e, ethyl iodide (0.026 ml) and acetonitrile (1 ml) was heated under reflux for 4 hours and then concentrated at reduced pressure. Saturated sodium hydrogencarbonate solution was added to the resulting residue and extraction with chloroform was conducted. The organic layer was dried with anhydrous magnesium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol=15:1) to give the titled compound (yield, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[O:4][N:3]=1.[Br-:10].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH2:8][Br:10])[O:4][N:3]=1
Reactant: CC(=O)c1cc(Br)no1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cc(Br)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
A mixture of 3-bromo-5-acetylisoxazole (which was obtained in Example 117) (16.7 g, 87.9 mmol), phenyltrimethylammonium tribromide (33.4 g, 88.8 mmol) and tetrahydrofuran (150 mL) was stirred at ambient temperature for 18 hours, poured into water and extracted with ether. The organic extracts were washed with brine and dried over MgSO4. Evaporation and purification by distillation gave a light yellow oil (8.9 g, 40% yield); 1H NMR (300 MHz, CDCl3) δ 4.40. (s, 3H), 7.10 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([OH:22])=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH:29]1(Br)[CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(Cl)(Cl)Cl>[CH:29]1([O:22][C:17]2[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrC1CCCC1
Reactant: COc1cc2nccc(Oc3cccnc3O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cccnc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
6,7-Dimethoxy-4-(2-hydroxy-pyridin-3-yloxy)-quinoline (21 mg) was dissolved in chloroform (7 ml) to prepare a solution. Potassium carbonate (300 mg) and cyclopentyl bromide (0.2 ml) were added to the solution. The mixture was stirred at room temperature overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (14 mg, yield 55%).
Reaction SMILES: [H-].[Na+].I[CH3:4].[CH2:5]([C:12]1[CH:13]=[C:14]([N:18]2[CH2:22][C@H:21]([OH:23])[C@H:20]([OH:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([C:12]1[CH:13]=[C:14]([N:18]2[CH2:22][C@H:21]([O:23][CH3:4])[C@H:20]([OH:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CI
Reactant: O[C@@H]1CN(c2cccc(Cc3ccccc3)c2)C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Product: CO[C@H]1CN(c2cccc(Cc3ccccc3)c2)C[C@H]1O

Procedure:
This was synthesized in the same manner as in Production Example 11 except that 1 equivalent of each of sodium hydride and iodomethane were used to (3R,4S)-1-(3-Benzylphenyl)-3,4-dihydroxypyrrolidine (Production Example 10).