Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.S(=O)(=O)(O)O.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:16]([O-])(=O)=O.[Na+]>O.C(O)(=O)C>[I:16][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:15])=[CH:10][CH:11]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: OCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OCc1ccc(I)cc1
Reaction time: 1 h

Procedure:
A solution of glacial acetic acid (1350 ml.) and iodine (250 g.) was heated to 100° and then concentrated sulfuric acid (140 ml. of 95-97%) added, followed by benzyl alcohol (216 g.). Sodium iodate (92 g.) in water (500 ml.) was then introduced dropwise with stirring over a period of 1 hour. The temperature was maintained at 100°-110° for an additional 30 minutes before the reaction mixture was poured onto 1 Kg. of crushed ice. The mixture was extracted with chloroform, the combined chloroform solution washed with water, dried, and concentrated. The remaining oil was distilled at reduced pressure to give p-iodobenzyl alcohol. A mass spectrum (70 ev) parent ion was measured at m/e 233.9545; calculated for C7H7IO, 233.9544. The ir and nmr spectrum were in agreement with the proposed structure. The use of a mass spectrum for identification of compounds is shown, for example, in R. Venkataraghaven, R. D. Broad, R. Klimowsky, J. W. Amy, and F. W. McLafferty, Adv. Mass Spec., 4, 65 (1967) and R. Venkataraghaven, R. J. Klimowsky, F. W. McLafferty, Acc. Chem. Res., 3, 158 (1970).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:25][C:26]([NH:29][C:30](=[O:44])[CH2:31][CH2:32][C:33]([NH:35][NH:36]C(OC(C)(C)C)=O)=[O:34])([CH3:28])[CH3:27])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:25][C:26]([NH:29][C:30](=[O:44])[CH2:31][CH2:32][C:33]([NH:35][NH2:36])=[O:34])([CH3:28])[CH3:27])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH3:9]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)NNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)NN
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (3 mL) was added slowly to a solution of tert-butyl 2-[4-({2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoyl]hydrazinecarboxylate (0.688 g, 1.34 mmol) in dichloromethane (7 mL). The solution was stirred for 2.5 hours, then was concentrated under reduced pressure. The trifluoroacetic acid salt of N-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-4-hydrazino-4-oxobutanamide was applied to anion exchange resins, which were eluted with pyridine in methanol to provide N-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-4-hydrazino-4-oxobutanamide as a free base, which was purified by HPFC on silica gel (gradient elution, 2-50% CMA in chloroform). The appropriate fractions were concentrated under reduced pressure to yield a foam that was heated under vacuum to afford 0.31 g of N-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-4-hydrazino-4-oxobutanamide as a glassy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][Si:12]([CH3:18])([CH3:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])#[N:26]>C(Cl)Cl>[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][Si:12]([CH3:17])([CH3:18])[C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])=[O:31])#[N:26]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a mixture of 2-nitro-4-(dimethyl-t-butylsiloxy)-aniline (10.01 g, 37.30 mmol) and CH2Cl2 (400 mL) at 0° C. was added pyridine (3.4 mL, 42.0 mmol) followed by the 3-cyanobenzoyl chloride (8.65 g, 52.2 mmol). The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with CH2Cl2 (800 mL) and washed with sat. aq. NH4Cl (2×200 mL). The organic layer was MgSO4 dried, filtered, and concentrated. The residue was chromatographed (20% EtOAc/hexanes) to give the title compound as a solid (13.94 g, 94%); IR(CHCl3): 2932, 1689, 1508, 1289, 863 cm−1; NMR(300 MHz, CDCl3): δ0.27 (s, 6H), 1.02 (s, 9H), 7.27 (s, 1H), 7.70 (m, 2H), 7.90 (d, J=7.8, 1H), 8.16 (d, J=1.2, 1H), 8.30 (s, 1H), 8.79 (d, J=9.3, 1H), 11.15 (br s, 1H); MS(FD): 397.0.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[Cl:5][S:6]([N:9]1[C:2]([CH3:3])([CH3:1])[CH2:4][C:10]1=[O:11])(=[O:8])=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC1(C)CC(=O)N1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a 3-neck 12 L flask equipped with an overhead stirrer, a 250 mL addition funnel topped with a nitrogen inlet and a rubber septum to allow a temperature probe and isobutylene needle was charged 450 mL of isobutylene. The flask was cooled in a dry ice-acetone bath. Ethyl ether (450 mL) was added and the resulting solution at -60° C. was treated with 210 mL (2.41 mol) of chlorosulfonyl isocyanate over 5 minutes at a rate so as to maintain the internal temperature below -50° C. The mixture was stirred at -50° C. to -62° C. for 30 minutes then allowed to warm slowly to room temperature and treated with 2250 mL of ether. The resulting solution was treated with 750 mL of 10% aqueous sodium carbonate slowly in 3 portions. The mixture was transferred into a 4 L separatory funnel and the aqueous layer removed. The organic layer was washed with 500 mL of water, then removed and treated with 750 mL of hexane. As crystallization began, additional hexane (250 mL) was added and the mixture concentrated under partial vacuum to a final volume of 3100 mL. The solid that formed was removed by filtration with the aid of 200 mL of hexane for rinsing. After air drying, the wet cake was dried under vacuum at 40° C. overnight to give 253 g (1.28 mol,53%) of product as a pale yellow crystalline solid. Recycling of the mother liquors gave an additional 100 g (19%) of product as a white crystalline solid. 1H NMR (250 MHz,CDCl3): 1.89 (s,6H), 3.05 (s,2H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:20]([NH:22][NH2:23])=[O:21])[CH2:17][CH2:18][CH3:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][CH:16]([CH2:17][CH2:18][CH3:19])[C:20]([NH:22][NH:23][C:3](=[S:4])[NH:2][CH3:1])=[O:21])(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)NN
Reactant: CN=C=S
Solvent: CCO
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)NNC(=S)NC
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Methyl isothiocyanate (683 mg) was added, at room temperature, to an ethanol (85 ml) solution of the 4-chloro-N-[1-(hydrazinocarbonyl)butyl]benzenesulfonamide (2.596 g) obtained in Example 1-(2). The mixture was stirred for 30 minutes, and then stirred for 2 hours under reflux conditions. The solvent was distilled off from the reaction mixture to obtain a solid. The solid was washed with chloroform (100 ml), and then dried to obtain 2-(2-{[(4-chlorophenyl)sulfonyl]amino}pentanoyl)-N-methylhydrazine carbothioamide (2.868 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH3:20]>>[NH2:20][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: N
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Agent: Cl
Product: NS(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Reaction time: 18 h

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g) was added to 0.880 ammonia (60 ml) and the mixture was stirred for 18 h. Concentrated hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(aminosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[OH-].[NH4+:15]>>[NH2:15][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To ice-cold solution of ammonium hydroxide (25%, 250 ml) is added 3-(chlorosulfonyl)benzoic acid (25 g, commercially available, Aldrich) portionwise and the mixture is stirred at room temperature for 15 h. The solvent is removed under vacuum to about 50 ml and the mixture is acidified with cone. HCl. The precipitate is collected by filtration and dried under vacuum to afford 22 g (96%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 13.44 (br s, 1H), 8.38 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.49 (s, 2H), HPLC (max plot) 97%; Rt 0.68 min. LC/MS: (ES−): 199.8.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)cccc2n1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2nc(Cl)nc3cccc(-c4ccccc4)c23)cc1
Reaction time: 12 h
Yield: 37.1 %

Procedure:
To a solution of 2,4-dichloro-5-phenylquinazoline (1 g, 4 mmol) in THF (15 mL) was added diisopropylethyl amine (1.86 mL, 10.9 mmol) followed by methyl 4-(aminomethyl)benzoate (1.19 g, 7.21 mmol). Upon completion of addition, the reaction mixture was stirred for 12 h. At the conclusion of this period, the reaction mixture was diluted with ethyl acetate and then washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to yield a residue. The residue was purified by flash column chromatography using 6% ethyl acetate in petroleum ether to afford methyl 4-((2-chloro-5-phenylquinazolin-4-ylamino)methyl)benzoate (600 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.4 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.38-7.33 (m, 5H), 7.22 (d, J=7.2 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 5.56 (bs, 1H), 4.53 (d, J=4.8 Hz, 2H), 3.39 (s, 3H). LCMS Method O: retention time 2.12 min, [M+1]=404.0. HPLC Method B: purity 97.8%, retention time 18.17 min.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([P:16](Cl)(Cl)=[O:17])([CH3:15])[CH3:14]>>[CH:13]([P:16]1(=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]1[C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:15])[CH3:14]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: CC(C)(C)NCc1ccccc1
Product: CC(C)P1(=O)c2ccccc2CN1C(C)(C)C
Yield: 39 %

Procedure:
The procedure of Example 30 was employed utilizing N-t-butyl-N-benzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -70° C. The crude product produced as a result of the chromatographic separation was distilled at 130° C. and 0.1 mm to yield a colorless oil. The colorless oil was slurried in petroleum ether to yield 1-isopropyl-2-t-butyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (5.8 g, 39% yield) having a melting point of 67°-70° C. and the following analysis:
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[CH:20][N:21]([Si](C)(C)C)[CH:22]=2)=[CH:10][CH:9]=1)=O)(C)(C)C.S(Cl)([Cl:30])=O>>[Cl:30][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]#[N:5])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)CCCc2cn([Si](C)(C)C)cn2)cc1
Reactant: O=S(Cl)Cl
Product: N#Cc1ccc(C(Cl)CCCc2c[nH]cn2)cc1

Procedure:
A solution of 4.5 g of 4-[4-(p-tert-butylaminocarbonylphenyl)-4-hydroxy-n-butyl]-1-trimethylsilylimidazole in 50 ml of thionyl chloride is refluxed for 1 h, cooled and evaporated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate and evaporated to yield the title compound (c).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:27]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:29]=[CH:30][CH:31]=3)[CH2:23][C:22](=[O:40])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [4-chloro-2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M183) (239 mg, 0.406 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (120 mg, 63%).
Reaction SMILES: [C:1]([NH:7][N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([NH:11]NCC1C=CC=CC=1)=[O:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)N>>[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[N:11]([C:9](=[O:10])[N:8]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[C:9](=[O:10])[N:8]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:7]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)C(=O)NN(Cc1ccccc1)C(=O)NNCc1ccccc1
Product: COC(=O)[C@H](Cc1c[nH]cn1)N(C(=O)N(N)Cc1ccccc1)C(=O)N(Cc1ccccc1)NC(=O)C(C)(C)C

Procedure:
N-(3-Pivaloyl-2-benzylcarbazoyl)-N'-benzylhydrazine and L-histidine methyl ester are treated in the same manner as described in Example 13 to give 3 (3-pivaloyl-2-benzylcarbazoyl)-2-benzylcarbazoyl-L-histidine methyl ester.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11].C([O-])(=O)C.[K+]>>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:11]/[C:10]([OH:13])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: [K+]
Product: Cc1ccccc1/C=C/C(=O)O
Temperature: 0 °C
Reaction time: 12 h
Yield: 35.1 %

Procedure:
A mixture of 35.1 g (0.29 mol) of o-tolualdehyde, 47.6 g (0.46 mol) of acetic anhydride, and 18 g (0.174 mol) of fused and pulverized potassium acetate was heated at 155°-160° for 15 minutes and then at 165°-170° for 12 hours. The mixture was diluted with 1 liter of ice water and steam distilled to remove excess aldehyde. On cooling, a yellow solid formed. The solid was collected, washed with water, dissolved in chloroform, treated with charcoal, and filtered. The filtrate was concentrated and the residue was recrystallized from ethanol/ether to give 16.5 g (35%) of trans-2-methylcinnamic acid; mp 173°-175°.
Reaction SMILES: [OH-].[Na+:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]([CH3:15])[CH3:14])=[CH:11][C:6]=2[O:5][CH2:4]1>C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([S:16][CH2:17][C:18]([O-:20])=[O:19])[CH:13]([CH3:15])[CH3:14])=[CH:11][C:6]=2[O:5][CH2:4]1.[Na+:2]
Reactant: CC(C)C(SCC(=O)O)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(SCC(=O)[O-])c1ccc2c(c1)OCO2

Procedure:
3.99 ml of a 2N aqueous solution of sodium hydroxide was added to 2.14 g of [{1-(1,3-benzodioxol-5-yl)-2-methyl-1-propyl}thio]acetic acid to obtain a solution, followed by the addition of ethanol. The mixture was distilled to remove the solvent. Ether was added to the obtained residue to generate a precipitate. This precipitate was separated by filtration and dried to obtain 2.2 g of the title compound as a white powder.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17](OC)=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[NH:22][CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1.CCOC(C)=O>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH2:17][OH:18])=[C:15]([CH3:21])[N:14]=[C:13]4[NH:22][CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2[nH]ccc2c(-c2ccc3c(c2)CCCO3)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice cooled mixture of methyl 4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (519 mg, 90%, 1.449 mmol) in tetrahydrofuran (THF) (10 mL) was treated with LAH (4.35 mL, 4.35 mmol) (2:00 pm) and the mixture was stirred overnight at ambient temperature. The reaction mixture was cooled to 0° C. Added water (160 uL) then stirred several minutes. Then, 15% NaOH (160 uL) was added and stirred several minutes. Finally, added water (480 uL) and stirred 5 minutes. The mixture was diluted with EtOAc, filtered over Celite™ and the filtrate was concentrated to afford the crude (4-(chroman-6-yl)-6-methyl-1 H-pyrrolo[2,3-b]pyridin-5-yl)methanol which was used without further purification: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.51 (br. s., 1 H), 7.26-7.15 (m, 3 H), 6.92 (d, J=8.4 Hz, 1 H), 6.29 (d, J=2.3 Hz, 1 H), 4.75 (s, 2 H), 4.31-4.26 (m, 2 H), 2.91-2.83 (m, 5 H), 2.13-2.07 (m, 2 H); LC/MS (m/z) ES+=295.26 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[CH3:42][O:43][C:44]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)=[O:45]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:49]3[CH:50]=[CH:51][C:46]([C:44]([O:43][CH3:42])=[O:45])=[CH:47][CH:48]=3)=[CH:11][C:6]=2[N:7]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1nc2cc(Cl)ccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3oc(C)nc3c2)cc1

Procedure:
A room temperature solution of 5-chloro-2-methyl-1,3-benzoxazole (110 mg, 0.71 mmol), CsF (325 mg, 2.14 mmol), Pd(OAc)2 (6.0 mg, 0.028 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (14 mg, 0.036 mmol) and 4-(methoxycarbonyl)phenylboronic acid (180 mg, 1.0 mmol) in dioxane (4 mL) was stirred for 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide the desired product. 1H NMR (300 MHz, DMSO-d6) δ8.06 (d, 2H), 8.03 (d, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 7.71 (dd, 1H), 7.29 (d, 2H), 3.90 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1.[H-].[Na+].[CH2:22](Br)[CH2:23][CH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH3:24])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1
Reactant: CCCBr
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(-c2ccc(OC)c(Cl)c2)c2cccc(Cl)c21

Procedure:
Prepared according to Method D Step B from 7-chloro-3-(3-chloro-4-methoxyphenyl)-1H-indazole (1.0 g, 3.4 mmol), sodium hydride (0.15 g, 60% in oil) in DMF followed by propyl bromide (0.4 mL). The title compound was obtained as an oil (0.94 g, 2.8 mmol, 82%).
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:25][C@@H:26]2[O:31][C@@H:30]([CH2:32]O)[C@H:29](O)[C@@H:28](O)[C@@H:27]2[NH:36]C)[C@@]1(O)C=O.C1[C@H]([NH2:47])[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>>[NH2:36][C@H:27]([C:26]([OH:31])=[O:25])[CH2:28][CH2:29][CH2:30][CH2:32][NH2:47]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
pAET7 was introduced into V12Sα obtained in Example 16, and the pMIV-FRTKmFRT-EABDAS#10 plasmid was also introduced to obtain the V12Sα strains where the lysE, dapA, dapB, asd, lysA, and ddh genes were introduced into the chromosome by the method described in Example 16. Randomly selected 200 strains were cultured in an SEII production medium containing 50 mg/L streptomycin and 20 mg/L kanamycin to select a strain which produced the most L-lysine, and was designated as Vmac1. A streptomycin-sensitive strain was selected form the Vmac1 strains to obtain a strain where pAET7 was eliminated. The pFLP31 plasmid shown in Example 9 was introduced into the strain, and a kanamycin-resistant gene region was eliminated from the mini-Mu cassette on the chromosome by the method described in Example 9. The kanamycin-sensitive strains obtained by the procedure were designated as Vmac1S strain. A streptomycin-sensitive strain was selected from the Vmac1S strain to obtain a strain where the pFLP31 plasmid was eliminated. The pAET7 plasmid was introduced again into this strain, and the plasmid pMIV-FRTKmFRT-EABDAS#10 was also introduced again. Then, the strain which produced the most L-lysine was selected and designated as the Vmac2 strain. In the same way as described above, the Vmac2S strain, Vmac3 strain, and Vmac3S strain were obtained. The amount of Lys produced by V12 was defined as 100, and the relative value of the amount of Lys produced by the Vmac3S strain was calculated and shown in Table 10.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH3:7][C:8]1([C:11](=[O:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:10][CH2:9]1.C(O)(=O)C.C([O-])(=O)C.[Na+]>CCOCC.O>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH:12]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:11]([C:8]1([CH3:7])[CH2:9][CH2:10]1)=[O:18]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC1(C(=O)Cn2cncn2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1(C(=O)C(C(O)C(Cl)(Cl)Cl)n2cncn2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
9.2 g (0.0625 mol) of chloral were added dropwise to 8.3 g (0.05 mol) of 1-methyl-1-(1,2,4-triazol-1-yl-acetyl)-cyclopropane, 20 ml of glacial acetic acid and 13.6 g (0.1 mol) of sodium acetate, the internal temperature increasing to approx. 45° C. The reaction mixture was stirred overnight at 80° C. and was thereafter cooled to room temperature and stirred with a mixture of 100 ml of water and 100 ml of ether. The resulting solid was filtered off under suction and recrystallized from methanol. 3.1 g (20% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1yl)-4-(1-methylcycloprop-1-yl)-butan-4-one of melting point 216° to 218° C. were obtained.