Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].Br[CH2:28][C:29]1([CH:36]=[CH:35][CH:34]=[CH:33][CH:32]1[C:37]([F:40])([F:39])[F:38])CBr>C1COCC1.CS(C)=O>[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:38])([F:39])[F:40])[N:18]=1)=[O:15]
Reactant: O=C(Nc1cc[nH]n1)c1c(Cl)cccc1Cl
Reactant: FC(F)(F)C1C=CC=CC1(CBr)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2ccccc2C(F)(F)F)n1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2,6-dichloro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 44)(26 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzyl bromide (24.7 mg, 0.1 mmol, Apollo Scientific Limited) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using the Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 4) MH+=415, tRET=3.11 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reaction time: 18 h
Yield: 26 %

Procedure:
To a solution of (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.00 g, 7.46 mmol) in 10 mL dimethylformamide was added 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (1.80 g, 8.95 mmol) and sodium hydride (537 mg, 22.4 mmol). After stirring for 18 hours, this was quenched with water. This was extracted with ethylacetate. The ethylacetate layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (900 mg, 1.94 mmol). MS (ESI) 406.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22]C)[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:25])([CH3:24])[C:4]1=[O:26])[CH3:2].[S-]CC.[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[OH:22])[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:25])([CH3:24])[C:4]1=[O:26])[CH3:2]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC)cc21
Agent: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3O)cc21
Temperature: 80 °C

Procedure:
A solution of Compound 2A (240 mg, 0.68 mmol) in 3 mL of dry DMF was treated with sodium thioethoxide (143 mg, 1.7 mmol). The reaction flask was then equipped with a reflux condenser, nitrogen inlet and heated to 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and 5 mL of water is added and the reaction mixture passed through a SPE. The crude compound was eluted with EtOAc. The collected eluant was dried of excess solvent to yield product which was used without further purification in the next step. MS (electrospray): mass calculated for C20H21NO4, 339.15 m/z found 340.1, [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.CO/N=[CH:22]/[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[CH2:32][N:33]([CH3:35])[CH3:34].Cl.[NH4+].[OH-]>O>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1[C:31]3[CH:30]=[C:26]4[O:27][CH2:28][O:29][C:25]4=[C:24]([CH2:32][N:33]([CH3:34])[CH3:35])[C:23]=3[CH2:22][C:9]2=1
Reactant: CO/N=C/c1ccc2c(c1CN(C)C)OCO2
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cnc3c(c2cc1OC)Cc1c-3cc2c(c1CN(C)C)OCO2
Temperature: 100 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
The amine 8 (0.30 g, 1.18 mmol) and oxime ether 13a (0.126 g, 0.534 mmol) were mixed with concentrated hydrochloric acid (7 mL) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled and washed with ether (3×20 mL). It was then brought to basic pH with NH4OH. The mixture was extracted with chloroform (40 mL×3) and the solution was washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was diluted in chloroform (40 mL) and filtered. Hydrochloric acid (2 M HCl in ether, 5 mL) was added to the filtrate. The precipitate that formed was recrystallized from methanol to provide a yellow solid. The solid was dissolved in water, basified with NH4OH and extracted with chloroform. The organic layer was concentrated to dryness. The residue was purified by preparative flash chromatography (SiO2, methanol-chloroform-TEA=3:97:2) to afford the final product 14a as a light yellow solid (0.0162 g, 7.8%): mp 205-207° C. IR (KBr) 2940, 1449, 1408, 1326, 1246, 1159, 1061 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 7.62 (s, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 6.11 (s, 2H), 4.21 (s, 2H), 4.10 (s, 3 H), 4.05 (s, 3H), 2.77 (s, 6H); low resolution ESIMS m/z (rel intensity) 379 (MH+, 100), 334 (90). Anal. (C22H22N2O4.1.25H2O) C, H, N.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[C:29](O)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2.C(C=P(CCCC)(CCCC)CCCC)#N.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][O:20][C:21]1[C:29]([O:1][CH:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2
Reactant: COc1c(O)ccc2[nH]ncc12
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 65.8 %

Procedure:
Under nitrogen, the 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.23 g, 5.01 mmol) obtained in Example 385, (b), the 4-methoxy-1H-indazol-5-ol (0.906 g, 5.52 mmol) obtained in Example 469 and 90%-cyanomethylenetri-n-butylphosphorane (161 g, 6.02 mmol) were dissolved in toluene (20 ml), and the resulting solution was heated under reflux for 5 hours. The reaction solution was cooled to room temperature and water and a 1N-aqueous sodium hydroxide solution were added thereto. The resulting solution was separated by the addition of toluene and the desired compound was extracted from the aqueous layer with toluene. The combined toluene layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the concentration residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, 1/1) to obtain 2-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-1H-isoindole-1,3(2H)-dione (1.29 g, yield 66%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>O.C(Cl)Cl.O>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][N:14]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: C=C1CNN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Yield: 62 %

Procedure:
Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 9, (0.62 g, 2.8 mmol) at room temperature. (4-Fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[CH:25]=CC=[CH:22][CH:21]=1.[OH-].[K+]>CCO>[Cl:12][C:7]1[CH:6]=[C:5]([NH:4][C:1]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:2]=2)[CH:10]=[C:9]([Cl:11])[CH:8]=1
Reactant: CC(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Clc1cc(Cl)cc(Nc2ccccc2)c1
Temperature: 175 °C
Yield: 71.4 %

Procedure:
A mixture of 12 g (58.8 mmole) of N-acetyl-3,5-dichloroaniline, 8.13 g (58.8 mmole) of potassium carbonate (dried at 155° C. under vacuum), 23 g (147 mmole) of bromobenzene (dried over molecular sieves), and 1.12 g (5.9 mmole) of cuprous iodide was heated in a 175° C. oil bath under a reflux condenser under nitrogen for 18 hours. The mixture was cooled to room temperature and triturated with 1 liter of benzene. The solution was concentrated in vacuo. The residue was treated with 50 mL of EtOH and 7.76 g (118 mmole) of potassium hydroxide and the resulting mixture was heated to reflux for two hours. The mixture was cooled and the solvent removed in vacuo. The residue was taken up in 150 mL of hexanes and 20 mL of EtOAc and the resulting solution was washed with 2×100 mL of 2N aqueous HCl and 70 mL of water. The latter wash was back extracted with 60 mL of ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 200 g of silica gel with 2 liters of 50:1 hexanes:ethyl acetate to give 10 g (71%) of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:19].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][I:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Temperature: 62 °C
Yield: 84.5 %

Procedure:
A solution of 2-(S)-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (3) obtained from above, 30 g, 0.10 mol) in anhydrous tetrahydrofuran (600 mL) was cooled to 0° C. Lithium iodide (144 g, 1 mol) was added to the cold reaction mixture as a solid in portions while maintaining the reaction temperature at below 30° C. The reaction mixture was warmed to 62° C. until HPLC showed less than 2% starting material. The reaction mixture was quenched with 10% aqueous sodium thiosulfate (300 mL). Ethyl acetate (600 mL) was added to reaction mixture. The organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×100 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (26.3 g, 78.6% yield). 1H NMR (CDCl3): δ 1.46 (d, 3H, CH3), 1.48 (d, 6H, 2×CH3), 1.792.14 (m, 4H, 2×CH2), 3.14–3.52 (m, 4H, 2×CH2) and 3.88 (m, 1H, CH); [M+H]+ at m/z 312.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7]1([C@@H:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]=2[CH2:36]Br)=[O:18])[CH2:14][CH3:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C>O1CCCC1>[C:7]1([C@@H:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]=2[CH2:36][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[O:18])[CH2:14][CH3:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](NC(=O)c1c(CBr)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Reactant: O=C1CCCN1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(CN2CCCC2=O)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 2-pyrrolidinone (0.1 ml) in tetrahydrofurane (2 ml) sodium hydride (20 mg, 60% dispersion in mineral oil) was added. The reaction mixture was stirred at ambient temperature until the gas evolution ceased then 3-bromomethyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (30 mg) was added. After 30 min acetic acid (0.05 ml) was added and volatiles were removed in vacuo. The product was purified by flash chromatography on SiO2 (5 g, 1,2-dichloroethane then gradient 50% to 100% ethyl acetate in heptane) to give 17 mg of white solid. Yield 56%. LC-MS (m/z) 480.5 (MH+); tR=1.21.
Reaction SMILES: C(#N)C.[I-:4].[Na+].Br[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:8]1.CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=O>CS(C)=O>[I:4][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:8]1
Reactant: [I-]
Reactant: O=C1OC(Br)c2ccccc21
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C1OC(I)c2ccccc21
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Iodophthalide was prepared immediately prior to use by mixing acetonitrile solutions of sodium iodide (1.5mmole) and bromophthalide (1.5mmole) and stirring for 3 minutes. This solution was filtered (to remove precipitated sodium bromide) into an ice cooled DMSO solution of cephalothin (1mmole), stirred 10 minutes and poured into ice water to precipitate the required ester. Yield of crude, neutral product after work up -- 90%. TLC and NMR indicate >90% ceph-3-em ester. δ (CDCl3 /trace DMSO) = 2.08 (d, 3H, --OCOCH3), 3.61 (broad s, 2H, C2--H), 3.88 (s, 2H, α-CH2), 4.6 - 5.4 (ABq + d, 3H, --CH2O-- + C6), 5.6 - 6.0 (m, 1H, C7) 6.9 - 7.4 (d, + t, 3H, thienyl aromatics), 7.5 - 8.2 (m, ca. 5H, phthalidyl aromatics and --OCHO--), 8.2 - 8.6 (2d, 1H, amide N-H). νmax (CHCl3) 3370, 2960, 1793, 1743, 1682, 1505, 1230, 982cm-1 ; λmax (EtOH) 275nm (ε, 7000)
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Ca+2].[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])O)O)O>>[CH:10]1[CH:12]=[C:14]([OH:15])[C:16]([OH:17])=[C:1]([OH:4])[C:7](=[O:6])[CH:8]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=c1cccc(O)c(O)c1O
Reaction time: 96 h

Procedure:
A loopful of Streptomyces tropolofaciens No. K611-97, taken from a mature slant culture was inoculated into 500-ml Erlenmeyer flask containing 100 ml of a seed medium consisted of 3% soybean meal, 2% corn starch, 0.33% MgSO4.7H2O and 1% CaCO3, the pH being adjusted to 7.0 before sterilization. The flask was then incubated at 28° C. for 4 days on a rotary shaker (200 rpm) and 5 ml of the growth was transferred into 500-ml Erlenmeyer flask containing 100 ml of a fermentation medium having the same composition as the seed medium. The fermentation was carried out at 28° C. for 6 days on a rotary shaker. The antibiotic production was monitored by the paper-disc agar diffusion method against Cryptococcus neoformans IAM 4514 as a test organism. For a large scale production, the fermentation studies were carried out in stainless-steel fermentors. The culture was prepared in twenty 500-ml Erlenmeyer flasks incubated at 32° C. for 4 days on the rotary shaker. The resultant culture was transferred into a 200-liter tank fermentor containing 120 liters of a production medium. The seed and production media consisted of 3% soybean meal, 3% glucose, 0.5% Pharmamedia, 0.1% yeast extract and 0.3% CaCO3. Tank fermentation was carried out at 28° C. with stirring at 250 rpm and aeration at 120 liter/min. The production reached a maximum after 115 hours fermentation.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH:18]([CH3:20])[CH3:19])[S:5](=[O:17])(=[O:16])[C:6]2[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:39]([NH2:42])[C:40]#[CH:41]>C1COCC1>[CH3:19][CH:18]([N:4]1[C:3]([CH2:2][NH:42][CH2:39][C:40]#[CH:41])=[CH:8][C:7]2[CH:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:6]=2[S:5]1(=[O:17])=[O:16])[CH3:20]
Reactant: C#CCN
Reactant: CC(C)N1C(CO)=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCNCC1=Cc2cc(S(N)(=O)=O)sc2S(=O)(=O)N1C(C)C
Reaction time: 18 h
Yield: 39 %

Procedure:
To a solution of the product from Example 15, Step E (1.40 g, 4.14 mmol) and triethylamine (1.26 g, 12.4 mmol) in anhydrous THF (80 mL) at 0° C. was added p-toluenesulfonyl chloride (1.18 g, 6.21 mmol) and the mixture was maintained at this temperature for 20 h. Propargylamine (3 mL) was added to the reaction mixture which was stirred for an additional 18 h. The reaction mixture was evaporated to a residue which was mixed with 2N HCl (60 mL) and this mixture was extracted with ethyl acetate (2×50 mL). The aqueous layer was separated and adjusted to pH 7.5 by the addition of a saturated aqueous solution of sodium bicarbonate (100 mL) followed by extraction with ethyl acetate (2×60 mL). The combined extracts were dried (MgSO4), filtered, and evaporated to a residue which was purified by column chromatography (silica, 50% to 75% ethyl acetate/hexane) to give an oil which crystallized from methylene chloride/hexane to provided an off-white solid (0.61 g, 39%): mp 133°-135° C. Analysis: Calculated for C13H17N3O4S3 : C, 41.58; H, 4.60; N, 11.11. Found: C, 41.42; H, 4.60;0N, 11.11.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C(Cl)Cl>[C:19](=[O:20])([O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)[O:10][C@@H:2]1[CH2:1][O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@H:3]12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4:3,6-dianhydro-D-mannitol (3.00 g, 20.5 mmol) and triethylamine (3.15 ml, 22.6 mmol) in DCM (100 ml), 4-nitrophenyl chloroformate (4.55 g, 22.6 g) was added and the mixture was stirred at room temperature for 18 hrs. Then the mixture was washed with a 5% solution of sodium dihydrogen phosphate (2×50 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 20 to 80%), affording the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: COC(=O)NCCCBr
Reactant: Fc1ccc2c(I)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)NCCCn1nc(I)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
to a solution of 6-fluoro-3-iodo-1H-indazole (1.5 g) and methyl (3-bromopropyl)carbamate (1.68 g) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.58 g), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/20→3/2) to give methyl [3-(6-fluoro-3-iodo-1H-indazol-1-yl)propyl]carbamate [REx(102-1)] (836 mg) as a red oil.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]([CH3:28])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:19]=O.O>C1(C)C=CC=CC=1>[CH3:19][C:18]([CH3:28])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:17]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C=C/C(C)(C)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A suspension (17.8 g, 445 mmol) of 60% sodium hydride in liquid paraffin was suspended in toluene (300 ml), and a solution of ethyl diethylphosphonoacetate (99.8 g, 445 mmol) in toluene (50 ml) was added at room temperature. The mixture was stirred for 30 min. A solution of 2,2-dimethyl-3-phenylpropanal (see Tetrahedron Lett., 1273-1275 (1973)) (60.16 g, 370.8 mmol) in toluene (50 ml) was dropwise added, and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water, and the mixture was extracted twice with diethyl ether. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-9/1) to give the objective substance.
Reaction SMILES: [N+]([O-])(OC(C)(C)C)=O.N[C:10]1[O:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1.[ClH:20]>[Cu](Cl)Cl.C(#N)C>[Cl:20][C:10]1[O:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1
Reactant: CCOC(=O)c1coc(N)n1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)O[N+](=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1coc(Cl)n1
Temperature: 80 °C

Procedure:
To a mixture of tert-butyl nitrate (2.86 mL), copper(II) chloride (3.23 g) and acetonitrile (64 mL) was added ethyl 2-amino-1,3-oxazole-4-carboxylate obtained in Step A (2.50 g) at 60° C. The reaction mixture was heated at 80° C. for 3 hr, and cooled to room temperature. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g).