Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]=[CH:6]2)=[O:2].[OH-].[K+].Cl>CO>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)ccc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=Cc1ccc2[nH]ccc2c1
Yield: 97.3 %

Procedure:
5-formyl-N-tosylindole (0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) containing 5% aqueous KOH solution (5 mL). The mixture was refluxed for 3 h, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (MgSO4), and concentrated. The residue was purified by short column chromatography to provide 240 mg (97%) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:15]([N:19]=[C:20]=[S:21])([O:17][CH3:18])=[O:16]>C(#N)C>[C:15]([NH:19][C:20](=[S:21])[NH:6][C:5]1[CH:7]=[C:8]([S:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])([O:17][CH3:18])=[O:16]
Reactant: COC(=O)N=C=S
Reactant: CCCSc1ccc([N+](=O)[O-])c(N)c1
Solvent: CC#N
Product: CCCSc1ccc([N+](=O)[O-])c(NC(=S)NC(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a stirred mixture of 2-nitro-5-propanylthioaniline (21.2 g.; 0.10 mole) in acetonitrile (50 ml.) is added portionwise carbomethoxy isothiocyanate (11.7 g.; 0.10 mole). The reaction mixture is maintained at room temperature and is filtered to remove a small amount of dark colored insoluble material. The clear filtrate was permitted to stand at room temperature for two hours and the precipitate which forms is collected by filtration, washed with cold acetonitrile and dried to yield 1-(3-carbomethoxythioureido)-2-nitro-5-propylthiobenzene (17.6 g.), m.p. 122°-125° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:46])([F:45])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]6[CH2:41][CH2:40][N:39](C([O-])=O)[CH2:38][CH2:37]6)=[O:35])[CH:32]=5)[NH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[N:36]1([C:34]([C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[CH:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:46])([F:8])[F:45])=[N:11][N:12]=4)[N:15]=3)[CH2:20][CH2:21]2)=[O:35])[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]1
Reactant: O=C([O-])N1CCN(C(=O)c2ccc3[nH]cc(C4CCN(c5ccc6nnc(C(F)(F)F)n6n5)CC4)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1)N1CCNCC1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
TFA (1 mL) was added in one portion at ambient temperature to a stirred solution of tert-butyl [4-[3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carbonyl]piperazine-1-carboxylate (190 mg, 0.32 mmol) in DCM (2 mL). The resulting solution was stirred for 1 hour then applied to an SCX column and eluted with MeOH followed by 2M ammonia in MeOH. Pure fractions were combined and concentrated by evaporation then triturated with ether to give a solid which was collected by filtration and air dried to give 6-[4-[5-(piperazin-1-ylcarbonyl)-1H-indol-3-yl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (156 mg, 99%) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:20][C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[CH:9]=2)[CH:16]=[N:15][CH:14]=[CH:13]4)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:20][C:11]4=[C:12]5[C:17](=[CH:18][CH:19]=[C:10]4[CH:9]=3)[CH:16]=[N:15][CH:14]=[CH:13]5)=[CH:4][CH:3]=2)[CH2:49][CH2:48]1
Reactant: CN1CCNCC1
Reactant: Brc1ccc(-c2cc3ccc4cnccc4c3[nH]2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3cc4ccc5cnccc5c4[nH]3)cc2)CC1
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To 2-(4-bromo-phenyl)-1H-pyrrolo[2,3-f]isoquinoline XIXB (1.54 mmol), 2-(dicyclohexylphosphino)biphenyl (0.154 mmol), palladium acetate (0.154 mmol) and 1-methylpiperazine (15.46 mmol), degassed DMF (5 mL) and sodium tert-butoxide (4.62 mmol) were added. The mixture was submitted to microwaves at 150° C. for 15 min, the solvent was removed and the crude was purified by chromatography on silica gel (eluant: DCM/MeOH/30% aq NH3 92:8:1) affording the title compound (79% yield). ESI (+) MS: m/z 343 (MH+). 1H NMR: 2.24 (s, 3H), 2.45-2.50 (m, 4H), 3.20-3.26 (m, 4H), 6.96 (d, J=1.46, 1H), 7.07 (d, J=8.90, 2H), 7.58 (d, J=8.54, 1H), 7.78 (d, J=8.54, 1H), 7.85 (d, J=8.90, 2H), 8.43 (d, J=5.85, 1H), 8.50 (d, J=5.73, 1H), 9.18 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21](=[O:29])[CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH:10]1[C:11]2[C:20]3[CH2:19][CH2:18][N:17]([C:21](=[O:29])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:8][N:9]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Cc2ccccc2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 70 °C
Yield: 28.6 %

Procedure:
To 1-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone (0.203 g, 0.49 mmol) was added trifluoroacetic acid (2 mL). The reaction was heated at 70° C. for 18 hours. To the crude reaction mixture was added toluene (5 mL) and the resulting mixture was evaporated under reduced pressure to give a crude product. The residue was diluted in dichloromethane (4 mL/mmol) and washed with saturated aqueous sodium carbonate. The combined aqueous layers were washed with dichloromethane. The combined organics extract was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil. The oily residue was triturated with a mixture of dichloromethane and methanol to yield the desired product, 1-(8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone as an off-white solid (0.041 g, 18%). M.p.=164-166° C.; 1H NMR (DMSO-d6), 400 MHz) δ 13.57 (s, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 7.27 (m, 5H), 4.87 (s, 1H), 4.77 (s, 1H), 3.82-3.86 (m, 4H), 3.01 (m, 2H); LCMS [M+H]: 293.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([N:5]3[CH:10]([CH2:11][C:12]2=[O:14])[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH2:7][CH2:6]3)[CH2:3][CH2:2]1.[C-]#[C-].[Li+].[Li+].[CH2:23](N)[CH2:24]N.[ClH:27]>O1CCCC1.CCOCC>[ClH:27].[C:23]([C:12]1([OH:14])[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=32)[CH:4]2[CH2:3][CH2:2][CH2:1][CH:13]12)#[CH:24]
Reactant: NCCN
Reactant: O=C1CC2c3ccccc3CCN2C2CCCC12
Agent: Cl
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC1(O)CC2c3ccccc3CCN2C2CCCC21

Procedure:
According to the general procedure of J. W. Huffman and P. G. Arapakos, J. Org. Chem. 30, 1604 (1965) 10.0 g (0.042 mole) of 1,2,3,3a,5,6,10b,11,12,12a-decahydrobenzo[a]cyclopenta[f]quinolizin-12-one in 50 ml of tetrahydrofuran is reacted with an excess of lithium acetylide-ethylenediamine. The resulting material is dissolved in ether and treated with excess ethereal hydrochloric acid, and the precipitate is recrystallized from butanone-methanol to give 12-ethynyl-1,2,3,3a,5,6,10b, 11,12,12a-decahydrobenzo[a]cyclopenta[f]quinolizin-12-ol hydrochloride, M.P. 230°-240° C.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10](O)[CH3:11])=[S:7])(C)(C)C.Cl>O>[CH2:13]([C@H:9]1[CH:10]([CH3:11])[S:7][C:6]([NH2:5])=[N:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)[C@H](Cc1ccccc1)NC(=S)NC(C)(C)C
Agent: Cl
Solvent: O
Product: CC1SC(N)=N[C@H]1Cc1ccccc1

Procedure:
The process is performed as in Example 3, starting with 0.7 g of diastereoisomer B of N-(tert-butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea which is heated to a temperature in the region of 100° C. for 5 hours in 8.3 cm3 of aqueous 6N hydrochloric acid. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 50° C., 50 cm3 of water are added to the residue obtained and the solution is then extracted with 3 times 25 cm3 of dichloromethane. The aqueous phase is made alkaline by addition of 0.5 cm3 of 30% caustic soda and extracted with 3 times 50 cm3 of dichloromethane. The extracts are combined, dried over sodium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. An oil is obtained, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63μ; diameter 2 cm; height 28 cm), eluting with a dichloromethane/methanol mixture (95/5 by volume). The fractions containing the expected product are collected. These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.10 g of (4S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine is obtained in the form of a pale pink solid melting at 90° C. to become pasty (mixture of diastereoisomers: 82% of cis [(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine] 18% of trans [(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine]). (Rf=0.15 in a 95/5 by volume mixture of dichloromethane/methanol, on a Merck 60F254R silica plate).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:15])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:16]([O-:18])=[O:17])=[C:2]([N:1]3[CH:21]=[CH:25][CH:24]=[CH:23]3)[CH:11]=2)[NH:6][C:7](=[O:15])[C:8]1=[O:14])[CH3:13]
Reactant: COC1CCC(OC)O1
Reactant: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Solvent: CC(=O)O
Product: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc21
Yield: 66.6 %

Procedure:
0.9 g (3.5 mmol) of 7-amino-1-ethyl-6-nitro-2,3(1H,4H)-quinoxalinedione and 0.58 g (4.4 mmol) of 2,5-dimethoxytetrahydrofuran in 20 ml of acetic acid were refluxed for 2 h. The mixture was then concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (mobile phase: toluene/acetone/acetic acid=10:10:1) to yield 0.7 g (68%) of the product. Melting point >300° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[C:4]2[O:13][C@:12]([C:15]([OH:17])=O)([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35].C(N(CC)C(C)C)(C)C>C1COCC1.CN(C=O)C>[OH:8][C:7]1[C:6]([CH3:9])=[C:5]2[C:4](=[C:3]([CH3:18])[C:2]=1[CH3:1])[O:13][C@@:12]([CH3:14])([C:15]([NH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35])=[O:17])[CH2:11][CH2:10]2
Reactant: N[C@H]1CCOC1=O
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)N[C@H]1CCOC1=O)O2
Temperature: 23 °C
Reaction time: 15 h

Procedure:
A solution of 1.82 g (7.27 mmoles) of (R)-Trolox and 1.18 g (7.27 mmoles) of 1,1′-carbonyldiimidazole (CDI) in 15 ml of anhydrous THF is stirred for 1 hour at 23° C., before adding a solution of 1 g (7.27 mmoles) of (S)-2-amino4-butyrolactone hydrochloride and 1.27 ml (7.27 mmoles) of N,N-diisopropylethylamine (DIEA) in 15 ml of anhydrous DMF. The reaction mixture is stirred for 15 hours at 23° C. and finally concentrated to dryness under vacuum. The residue is dissolved in 100 ml of AcOEt and the organic solution is washed successively with 50 ml of 1N aqueous HCl, 50 ml of H2O, 50 ml of a saturated aqueous solution of NaHCO3, 50 ml of H2O and finally 50 ml of salt water. After drying over MgSO4, the organic solution is filtered and concentrated to dryness under vacuum. The residue is taken up in 50 ml of Et2O, followed by agitating and filtering. After rinsing with 2×25 ml of Et2O, the white powder, obtained is dried under vacuum. Melting point: 195-196° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH2:17]2.C1(C)C=CC(S([N:33]=[N+:34]=[N-:35])(=O)=O)=CC=1.C[Si](Cl)(C)C>CCCCCC.O1CCCC1>[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH:17]2[N:33]=[N+:34]=[N-:35]
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21

Procedure:
In a nitrogen stream under stirring, 50 ml of dry tetrahydrofuran is cooled to -78° C. and, then, 20 ml of a solution of 15% n-butyllithium in n-hexane is added thereto. After dropwise addition of 3.66 ml of diisopropylamine, the mixture is stirred at -78° C. for 15 minutes. A solution of 3.1 g of 2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -78° C. for one hour. Then, a solution of 4.34 g of p-toluenesulfonyl azide in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -50° C. to -60° C. for 1.5 hours. To this mixture 5.1 ml of trimethylsilyl chloride is added dropwise and the reaction mixture is heated under reflux for 5 hours. After cooling, the insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is shaken with water and ethyl acetate and the ethyl acetate layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solvent is then distilled off and the residue is purified by silica gel column chromatography to give 2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4.2.0]octan-8-one as a 1:4 mixture of cis- and trans-isomers.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N:19]1([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:29]/[NH:28][C:26](=[O:27])[CH2:25][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)CN1CCOCC1
Product: CCCCCN1C(=O)/C(=N\NC(=O)CN2CCOCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2-morpholin-4-ylacetohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.92 (t, 3H), 1.26 (s, 1H), 1.36 to 1.39 (m, 5H), 1.64-1.72 (m, 4H), 2.61 (d, 4H), 3.29 (s, 2H), 3.84-3.87 (m, 8H), 6.41 (d, 1H), 6.60 (dd, 1H), 7.75 (d, 2H), 13.86 (br s, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][CH2:9][C:8]=2[CH2:7]1)[CH2:3][CH2:4][CH3:5].CCOCC>C(O)C.[Pt](=O)=O>[ClH:1].[CH2:2]([N:6]1[CH2:15][CH2:14][C@H:13]2[C@H:8]([CH2:9][CH2:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)[CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1CCC2=C(CCc3ccccc32)C1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCCN1CC[C@@H]2c3ccccc3CC[C@@H]2C1

Procedure:
A mixture of 0.153 g (0.55 mmol) of 3-butyl-1,2,3,4,5,6-hexahydro-benz[f]isoquinoline hydrochloride and 0.080 g of platinum (iv) oxide in 20 ml of ethanol was hydrogenated at 50 p.s.i. overnight. The mixture was filtered and evaporated in vacuo to yield a white gum. Trituration with ether gave the title product as a white solid. NMR δ(D2O) 0.95 (3H, t), 1.35 (3H, m), 1.6-2.2 (6H, m), 2.25-3.85 (11H, m), 7.2 (4H, m). m/z (CI+, NH3) 244 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][NH:6][CH:7]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O>>[Br:12][C:7]1[NH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1c[nH]cc1C(=O)OC
Product: CCc1c(C(=O)OC)c[nH]c1Br
Yield: 84.2 %

Procedure:
Using methyl 4-ethyl-1H-pyrrole-3-carboxylate (2.32 g) and N-bromosuccinimide (2.74 g), a procedure as in Reference Example 40 was performed to give the title compound as white crystals (yield 2.96 g, 84%).
Reaction SMILES: [CH2:1]1[C@@H:6]([OH:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O(C)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>>[CH2:3]1[C:2]([C:11]([OH:13])=[O:12])=[CH:1][C@@H:6]([OH:7])[C@@H:5]([OH:8])[C@@H:4]1[OH:9]
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)C1=C[C@@H](O)[C@@H](O)[C@H](O)C1

Procedure:
An alternative to increasing Kc in order to suppress quinic acid formation was addition of a non-hydrolyzable glucose analog to the fermentation broth. Methyl α-D-glucopyranoside (MαDG) was added to the fermentation medium at the time of inoculation and the fermentation was then run without further adjustment. Addition of 1 mM MαDG to the fermentation of SP1.1/pKD12.112 resulted in the synthesis of 40.3 g/L of shikimic acid (Table 3). Quinic acid was not detected. Although several concentrations were examined, 1 mM MαDG was the minimum concentration that afforded complete suppression of quinic acid formation. Addition of MαDG to SP2.1/pKD12.112 cultures also resulted in quinic acid suppression. After 48 h of culturing in the presence of 0.5 mM MαDG, SP2.1/pKD12.112 (Table 3) synthesized 39.6 g/L of shikimic acid and 4.1 g/L of quinic acid, resulting in a molar ratio 11. Higher concentrations of MαDG showed no further improvement in quinic acid suppression.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[CH2:6][C:7]#[N:8].C[O:15][N:16]=O>>[OH:15][N:16]=[C:6]([C:7]#[N:8])[C:5]1[CH:9]=[CH:10][C:11]([S:12][CH3:13])=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CON=O
Reactant: CSc1ccc(CC#N)cc1SC
Product: CSc1ccc(C(C#N)=NO)cc1SC
Yield: 58.1 %

Procedure:
According to the method described under 1.1., 34.8 g (0.166 mol) of 3,4-bis(methylthio)benzyl cyanide are reacted with 0.166 mol methylnitrite. After the isolation 23.0 g (58%) α-hydroxyimino-3,4-bis(methylthio)benzyl cyanide are obtained as a brown substance with a melting point of 131-133° C. Elemental analysis: C10H10N2OS2 (238.33)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([OH:7])=O.[NH2:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33]>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([NH:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2
Reactant: CC(C)(N)CC(=O)O
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: CC(C)(CC(=O)O)NC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (100 mg, 0.256 mmol) and 3-amino-3-methylbutanoic acid (36 mg, 0.307 mmol). MS (ESI) m/z: Calculated: 489.2; Observed: 490.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][Cl:21].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g) in N,N-dimethylformamide (20 mL) was added cesium carbonate (4.89 g) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. 1-Bromo-3-chloropropane (1.89 g) was added and the mixture was stirred under ice-cooling for 1 hr and at room temperature for 32 hrs. The reaction mixture was poured into water (40 mL), and the mixture was extracted with ethyl acetate (60 mL×2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (1.87 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28]C)=[O:27])[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([OH:28])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
186 mg (0.403 mmol) of methyl 2-{6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate obtained in Example 1 was mixed with 19.3 mg (0.484 mmol) of sodium hydroxide, 1 ml of water and 2 ml of ethanol and the mixture was stirred at room temperature for 24 hours. Then, the mixture was concentrated under reduced pressure and the concentrate was partitioned between water and ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate followed by filtration. The resulting filtrate was concentrated under reduced pressure to obtain 142 mg of 2-{6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:11])[C@@H:4]([NH2:10])[CH2:5][CH:6]([CH3:9])[CH:7]=[CH2:8].N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CO>>[NH2:10][C@@H:4]([CH2:5][CH:6]([CH3:9])[CH:7]=[CH2:8])[C:3]([OH:11])=[O:2]
Reactant: C=CC(C)C[C@H](N)C(=O)OC
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Product: C=CC(C)C[C@H](N)C(=O)O

Procedure:
Entry No. 47: The 2(S)-amino-4-methyl-5-hexenoic acid methyl ester employed for the preparation of this peptide was obtained by converting Boc-Ser-OH to its corresponding β-lactone by the method of J. C. Vederas et ai., J. Am. Chem. Soc., 107 7105 (1985) and reacting the β-lactone with the organolithium derivative derived from 2-propylene bromide according to the method of D. Seebach and H. Neumann, Chem. Ber., 107, 847 (1974) to give 2(S)-amino-4-methyl-5-hexenoic acid. Subsequent esterification of the latter compound with diazomethane gave the desired corresponding methyl ester.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH2:6][O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:21]([O:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH2:6][O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1C(COC(=O)c3ccccc3)COCN1CC2
Temperature: 0 °C
Yield: 55 %

Procedure:
0.01 mole (2.79 g) of 1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino[4,3-a]isoquinoline in 30 ml of absolute pyridine is boiled with 0.012 mole (1.69 g) of benzoyl chloride for 3 hours. The mixture is then poured onto 100 g of ice. The separated crystals are filtered off, washed with water and recrystallized from a mixture of diisopropyl ether and ethanol. Yield: 55%. The melting point and spectroscopical data of the compound are identical with those of the product obtained in Example 25.