Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH3:17][CH:18]1CCCO1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:17]=[CH2:18])[N:5]=[CH:4][N:3]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CC1CCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: C=Cc1ncnc(Cl)c1F
Yield: 71 %

Procedure:
4,6-Dichloro-5-fluoropyrimidine (6 g, 36.0 mmol) was reacted with potassium vinyl trifluoroborate (1.60 g, 37.8 mmol, 1.05 eq), and caesium carbonate (17.58 g, 1.5 eq) in water/methyl tetrahydrofuran. The reaction was treated with Pd(PPh3)2Cl2 (504 mg, 0.02 eq) and PPh3 (189 mg, 0.02 eq) under argon. The reaction was heated to reflux and held under reflux for 20 hours. The reaction was quenched by the addition of further water and tert-butyl methyl ether. The organic phase was atmospherically distilled to remove the solvents. The residue was purified by column chromatography, 12-100% dichloromethane in hexane. The combined fractions were concentrated by fractional distillation to give 4.1 g (71% yield) of the product as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9][N:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1c[nH]c2ccccc12
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCCn1c(Cn2cc(S(C)(=O)=O)c3ccccc32)nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole (120 mg, 0.37 mmol) and 3-(methylsulfonyl)-1H-indole (72 mg, 0.37 mmol) in DMF (3 mL) was treated with K2CO3 (104 mg, 0.74 mmol) at RT. The reaction solution was stirred at RT for overnight. The solid was filtered off and the filtrate was purified by prep-HPLC to give 5-chloro-2-{[3-(methylsulfonyl)-1H-indol-1-yl]methyl}-1-[3-(methylsulfonyl)propyl)-1H-benzimidazole (100 mg, yield: 78%) as off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[OH-].[Na+].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23](Cl)(=[O:25])=[O:24])[CH:16]=[CH:15][CH:14]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].ClCCl>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[N:13]=[CH:14][CH:15]=[CH:16]3)(=[O:24])=[O:25])[CH:3]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1cccc2cccnc12)n1cc(Br)c2cccnc21
Yield: 74 %

Procedure:
Into a round bottom flask was added 3-bromo-7-azaindole (3, 1.18 g, 5.99 mmol) and tetra-N-butylammonium bromide (193 mg, 0.600 mmol), and 5.0 M sodium hydroxide (15.4 mL). 8-Quinoline-sulfonyl chloride (1.64 g, 7.19 mmol) in dichloromethane (5.9 mL) was added dropwise at room temperature. After a few hours, all starting materials were gone. After 30 mL of dichlormethane was added, two layers were separated. The aqueous layer was washed with dichloromethane. The combined organic layers were washed with 1 M sodium bicarbonate, water, and brine and dried over anhydrous sodium sulfate. The crude material was concentrated under reduced pressure and was purified by column chromatography (55-80% ethyl acetate in hexane) to yield the desired product as a light yellow colored solid (44, 1.72 g, 4.43 mmol). MS(ESI) [M+H+]+=389.4.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:15](#[N:19])[CH:16]([CH3:18])[CH3:17].[Sn](Cl)(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:19][C:15]([CH:16]([CH3:18])[CH3:17])=[C:8]([C:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)=[O:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)C#N
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C(=O)c1ccc(F)cc1)=C(N)C(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 18998.8 %

Procedure:
39.2 g of methyl 4-fluorobenzoylacetate (0.20 mmol) and 16.8 g of isobutyronitrile (0.24 mol, concentration >99%) were dissolved in 200 ml of toluene and treated with 57.9 g of tin tetrachloride (0.22 mmol, concentration >99%) at room temperature after the course of 10 minutes. After 30 min at room temperature, the mixture was heated to 80° C. After 8 h, the suspension was again cooled to room temperature and treated with 200 ml of water. The mixture was diluted with 200 ml of ethyl acetate and the phases were separated. The organic phase was washed twice with 40 ml of 1N sodium hydroxide solution and concentrated in vacuo (40° C./25 mbar) after drying over magnesium sulphate. 50.9 g of crude product were obtained in the form of a yellow oil. After chromatography of 12.0 g of crude product on silica gel (eluent: hexane/isopropanol 90:10), 10.08 g of methyl 3-amino-2-[1-(4-fluoro-phenyl)methanoyl]-4-methylpent-2-enoate were obtained in the form of a yellowish oil.
Reaction SMILES: [CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH:31]=O)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH2:31][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:18])[CH3:19])=[O:8])[CH3:2]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.28 g, 0.528 mmol) and morpholine (0.07 g, 0.79 mmol) in dichloroethane (3 mL), acetic acid (0.19 g, 3.16 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by prep. HPLC to afford the title compound (0.12 g, 38.70%).
Reaction SMILES: [Na].O.[CH3:3][C:4]([CH3:17])([CH:11](Cl)[CH:12]=[C:13]([Cl:15])[Cl:14])[CH2:5][C:6]([O:8]CC)=[O:7]>CO>[CH3:17][C:4]1([CH3:3])[CH:11]([CH:12]=[C:13]([Cl:14])[Cl:15])[CH:5]1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reaction time: 2 h
Yield: 88 %

Procedure:
1.4 Parts of metallic sodium was dissolved in 50 parts of anhydrous methanol, and 5.5 parts of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate prepared in the same manner as in Example 1 was added to the solution. The mixture was agitated for 2 hours under reflux of methanol. The liquid reaction mixture was naturally cooled, and 20 parts of water was added thereto and the mixture was agitated at 40° to 50° C. for 2 hours. Then, methanol was distilled under reduced pressure, and the residue was neutralized with hydrochloric acid and extracted with diethyl ether. The ether extract was dried and the ether was distilled to obtain 3.7 parts of the crystal of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylic acid. The yield was 88 % based on ethyl 3,3-dimethyl-4,6,6-trichlorohexenoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([N+:34]([O-:36])=[O:35])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 48.9 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.11 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and the reaction mixture was heated to 80° C. overnight. The crude material was purified by silica gel chromatography (eluting with 0-35% ethyl acetate in hexanes) to yield the product (71 mg, 50%). ESI-MS m/z calc. 484.12. found 485.0 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:19]([OH:21])=O)[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:62]=[CH:61][N:60]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[N:59]=1>CN(C=O)C.O>[CH3:14][C@H:13]([O:15][C:16]1[CH:17]=[C:18]([C:19]([NH:57][C:58]2[CH:62]=[CH:61][N:60]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[N:59]=2)=[O:21])[CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[CH2:12][O:11][CH3:10]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
DIPEA (28.5 mL, 164 mmol) was added to a suspension of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (20.7 g, 65.6 mmol), HATU (31.2 g, 82.0 mmol) and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (15.0 g, 82.0 mmol) in DMF (30 mL) and the reaction mixture stirred for 16 hours at RT. Water (250 mL) was added and the reaction mixture extracted with diethyl ether (3×150 mL). The organic layer was washed with saturated brine solution and dried (MgSO4). The filtrate was concentrated in vacuo and the residue crystallised on standing. The crystals were washed with isohexane to give to give the desired material as yellow crystals (23.4 g; 73%). m/z 482 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+]>Cl.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1

Procedure:
To the solution of 1,445 g of p-chloroaniline in 3,375 ml of 38% hydrochloric acid and 5,650 ml of water the solution of 793 g of sodium nitrite in 3.3 L of water is added during 1 hour at -5° to -8° while stirring under nitrogen. After 15 minutes 7,617 g of stannous chloride in 9 L of 38% hydrochloric acid are added during 30 minutes below 25°. The resulting suspension is stirred in an ice bath for one hour, filtered, the residue suspended in 30 L of water, and 5,000 g of solid sodium hydroxide are added during 1 hour at 0°-25°, while stirring under nitrogen. The mixture is extracted twice with 8 L of diethyl ether, the combined extracts washed twice with 4 L of water and once with saturated aqueous sodium chloride, dried, filtered, evaporated and the residue dried at 5 mmHg and room temperature, to yield the p-chlorophenyl-hydrazine melting at 82°-87°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7](CCS)=[N:6][S:5](=[O:12])(=[O:11])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22]O)[N:21]=1)[CH3:15]>Cl>[CH3:13][N:14]([CH2:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][S:18][CH2:17][CH2:16][NH:14][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:12])[N:6]=2)[N:21]=1)[CH3:15]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: CNC1=NS(=O)(=O)N=C1CCS
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D] in concentrated hydrochloric acid, and then made basic and worked up, produces the title compound which is identical to the product prepared in Example 33.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[CH:7][C:6]=1[N+:17]([O-])=O)[CH:2]=[CH2:3].C(OC1C=C([N+]([O-])=O)C=CC=1C(OCC=C)=O)C=C.N>CO>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[CH:7][C:6]=1[NH2:17])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc(OCC=C)c([N+](=O)[O-])c1
Agent: C=CCOC(=O)c1ccc([N+](=O)[O-])cc1OCC=C
Agent: N
Solvent: CO
Product: C=CCOC(=O)c1ccc(OCC=C)c(N)c1

Procedure:
The above nitro compound was reduced by the method described in example 1, for the reduction of allyl 2-allyloxy-4-nitrobenzoate, except that the solvent was methanol, and using an aqueous solution of ammonia in place of sodium bicarbonate in the work-up, to give allyl 4-allyloxy-3-aminobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH2:17][NH2:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH2:17][NH:18][C:45](=[O:46])[C:44]4[CH:48]=[CH:49][CH:50]=[C:42]([O:41][CH3:40])[CH:43]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1CN
Reactant: COc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)NCc2cc3c(-c4cccc(F)c4)n[nH]c3cc2OC)c1
Yield: 24.2 %

Procedure:
A total of 25.6 mg of C-{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-methylamine obtained in Production Example II-26 was dissolved in 1.9 ml of dimethylformamide, 15.3 mg of 1-hydroxybenzotriazole, 0.066 ml of diisopropylethylamine and 14.4 mg of 3-methoxybenzoic acid were added thereto, and 27.2 mg of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (i.e., WSC.HCl) was added thereto under ice-cooling and stirring. After stirring at room temperature for 5 hours, water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 0.5 N aqueous sodium hydroxide solution, 1 N hydrochloric acid and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (dichloromethane:methanol=10:1), to give 9.24 mg of the title compound as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8].[CH2:29]([OH:32])[CH:30]=[CH2:31].C(=O)(O)[O-].[Na+].O>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][C:22]([CH2:31][CH2:30][CH:29]=[O:32])=[CH:21][CH:20]=1)[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(I)cc2)c(C)c1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCC=O)cc2)c(C)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To a solution of N-(3-hydroxy-benzyl)-N-(4-iodo-phenyl)-2,4,6-trimethyl-benzenesulfonamide (0.36 g, 0.71 mmol) in 3 mL dimethylformamide was added allyl alcohol (0.121 mL, 1.77 mmol), Pd(OAc)2, sodium bicarbonate (0.149 g, 1.77 mmol), and tetrabutylammonium chloride (0.197 g, 0.71 mmol). The reaction mixture was stirred at 50° C. for 24 hr. Additional allyl alcohol (0.121 mL, 1.77 mmol), Pd(OAc)2, sodium bicarbonate (0.060 g, 0.71 mmol), and tetrabutylammonium chloride (0.098 g, 0.36 mmol) were added and the reaction mixture was stirred at 50° C. for an additional 24 hr. The reaction mixture was allowed to cool, water and ethyl acetate were added, and the mixture was filtered through diatomaceous earth. The filtrate was washed with water and the organic layer was dried (magnesium sulfate) and concentrated in vacuo. Medium pressure silica gel chromatography of the residue (3:1 hexanes:ethyl acetate) afforded 0.20 g (64%) of the title compound. MS 436.2 (M−1)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To tetrahydro-2H-pyran-4-ol (1 g, 9.8 mmole) and TEA (2 g, 19.6 mmole) in DCM (20 mL) was added 4-methylbenzene-1-sulfonyl chloride (1.8 g, 9.8 mmole) at 0° C. The mixture was stirred at room temperature for 8 h, washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by ISCO (silica gel, 15% ethyl acetate in hexane) to give the title compound (2.2 g, 89% yield) as white solid. MS (ESI) m/z: Found: 257.3 (M++1). Calc. 256.3 (M).
Reaction SMILES: N#N.[ClH:3].C([O:8][C:9](=[O:27])[C@H:10]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][O:17][CH:18]=[N:19]C(OC(C)(C)C)=O)[NH2:11])(C)(C)C.Cl>O1CCOCC1>[ClH:3].[ClH:3].[NH:19]=[CH:18][O:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][C@@H:10]([C:9]([OH:27])=[O:8])[NH2:11]
Reactant: CC(C)(C)OC(=O)N=COCNCCC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Product: N=COCNCCC[C@H](N)C(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 206.3 %

Procedure:
A solution of 0.75 g (1.96 mmol) N2 -(tert-butoxycarbonyl)-N5 -(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride in 2 mL dioxane at 0° C. was treated with 15 mL of 4N hydrochloric acid in dioxane solution. The solution was stirred overnight at 22° C., concentrated to a crude paste, and freeze-dried from 8 mL of water. The product was freeze-dried a second time to yield 0.53 g N5 -(iminomethoxymethyl)-L-ornithine dihydrochloride. The product analyzed solvated with an additional 0.2 molar hydrochloric acid. 0.1 molar water, and 0.3 molar dioxane
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1onc(-c2nonc2NCc2ccc(CN3CCS(=O)(=O)CC3)cc2)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 46.4 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzamide trifluoroacetate (20 mg, 28 μmol) in pyridine (0.5 mL) was treated with phosphorus pentachloride (18 mg, 85 μmol) and stirred at 0° C. for 4.5 h. The reaction mixture was concentrated, diluted with ethanol (1 mL), treated with sodium cyanoborohydride (5 mg, 85 μmol), and stirred for 2 h. The reaction mixture was purified by preparative LCMS to give the desired product (9 mg, 47%). LCMS for C22H21BrFN6O5S (M+H)+: m/z=579.0, 581.0.
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][O:1][C:2]([CH3:19])([CH3:18])[CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CI
Reactant: CC(C)(O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 122.8 %

Procedure:
To a stirred solution of (S)-tert-butyl 4-(2-hydroxy-2-methylpropyl)-2,2-dimethyl-oxazolidine-3-carboxylate (0.93 g, 3.4 mmol) in anhydrous THF (8 mL), there was added NaH (60 wt % in mineral oil, 0.41 g, 10.2 mmol) followed by iodomethane (1.46 g, 10.2 mmol). The resulting mixture was stirred at rt until no starting material remained (˜5 h). The reaction was quenched by slow addition of water, the organic layer was separated, and aqueous layer was extracted with ether (2×5 mL). The combined organic layers were washed with 1 N aq HCl (5 mL), sat'd aq NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated to give crude (S)-tert-butyl 4-(2-methoxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.2 g, quant.) which was used without purification. MS m/z 310 (M+Na+).