Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH3:15])[NH:10][C:9]1=[O:16])=[O:6])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH3:15])[N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]1=[O:16])=[O:6])[CH3:17]
Reactant: C[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1C
Reaction time: 0.25 h

Procedure:
A solution of (3S-trans)-hexahydro-3-[[(1,1-dimethylethoxy)carbonyl]amino]-7-methyl-2H-azepin-2-one (313 mg., 1.3 mmol.) in tetrahydrofuran (8 ml.) at room temperature under argon was treated with the dropwise addition of 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.7 ml., 1.7 mmol.) immediately followed by the dropwise addition of ethyl bromoacetate (0.30 ml., 2.65 mmol.). The resulting mixture was stirred for 15 minutes, quenched with aqueous ammonium chloride, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated to a yellow oil. Following flash chromatography (E Merck silica gel) eluting with 2:1 hexane/ethyl acetate, 360 mg. of title compound was obtained as a light yellow oil; TLC (1:1 ethyl acetate:hexane) Rf =0.56.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:10]([S:15]([NH:18][C:19](=[O:22])OC)(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]1[CH2:30][C:29]([CH3:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:28][N:27]=1>N1C=CC=CC=1>[F:23][C:8]([F:7])([F:24])[C:9]1[C:10]([S:15]([NH:18][C:19]([N:28]2[C:29]([CH3:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][C:26]([CH3:25])=[N:27]2)=[O:22])(=[O:16])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Reactant: CC1=NNC(C)(c2ccccc2)C1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC1=NN(C(=O)NS(=O)(=O)c2ncccc2C(F)(F)F)C(C)(c2ccccc2)C1
Reaction time: 1 h
Yield: 86 %

Procedure:
A dry dioxane (10 ml) solution containing methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate (0.43 g, 1.5 mmol), 3,5-dimethyl-5-phenyl-2-pyrazoline (0.52 g, 3.0 mmol) and pyridine (0.45 g) was refluxed under heating and stirring for one hour. After cooling the mixture, the solvent was distilled off under reduced pressure, and the residue was stirred together with ethyl ether. Precipitated crystals were collected by filtration and then thoroughly washed with ethyl ether, and the crystals were suspended in 20 ml of water. Then, the pH was adjusted to a level of from 1 to 2 with concentrated hydrochloric acid, and the suspension was stirred at room temperature for 5 minutes. Crystals were collected by filtration, thoroughly washed with water and then with ethyl ether and dried to obtain 0.55 g of desired 1-(3-trifluoromethylpyridine-2-sulfonylcarbamoyl)-3,5-dimethyl-5-phenyl-2-pyrazoline. Melting point: 152°-153° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][C:17]([F:22])=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:10])=[CH:12]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cnc1C
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccc(F)cc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-6-fluoro-1H-quinolin-4-one, 8 mg (0.20 mmol) of 60% sodium hydride and 51 mg (0.20 mmol) of 2-bromo-6-bromomethyl-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 38 mg of a white solid: LC-MSD, m/z for C23H17BrFN3O2 [M+H]+=466.2, 468.1; HPLC retention time: 2.1 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Sn]([N:23]=[N+:24]=[N-:25])(C)(C)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]3[NH:25][N:24]=[N:23][N:13]=3)=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(-c2nnn[nH]2)ccc1NC1CCCCC1
Yield: 88.1 %

Procedure:
A solution of 1.10 g (4.49 mmol) of 4-cyclohexylamino-3-nitrobenzonitrile, Compound 127, and 1.11 g (5.39 mmol) of Me3SnN3 in 50 mL toluene was refluxed overnight. The crystals were collected by filtration, washed with toluene, dried, and treated with 50 mL 4M HCl in dioxane for 4 h. The solids were collected by filtration, washed with dioxane, and dried yielding 1.14 g (88%) red solids. MS: 289.15 (M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH:21]=1.[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[N:18]([CH2:26][CH:25]=[CH2:24])[CH2:19][CH2:20][CH:21]=1
Reactant: C=CCBr
Reactant: COC(=O)CCC1=CCCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1CCC=C(CCC(=O)OC)C1=O
Temperature: -79 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
0.220 ml of NaHMDS solution (1.0 M in THF, 0.22 mmol) was added to 0.5 ml of the THF solution containing 40 mg of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (0.218 mmol) prepared by the Step 1 in a dropwise manner at −79° C. and stirred at −79° C. for 30 mins. After 0.028 ml of allyl bromide (0.327 mmol) was added to the reaction mixture, the mixture was stirred at 0° C. for 3 hrs. The reaction mixture was quenched by 2 ml of sat. NH4Cl solution, and then the organic layer was extracted with 7 ml of ethyl acetate. The combined organic layer was washed with 2 ml of sat. NH4Cl solution and 2 ml of sat. NaCl solution. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc/hexane (1:2) solvent mixture as an eluant to give 36 mg (yield: 74%) of the title compound (i1).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([N+:24]([O-])=O)[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C1COCC1.[Pt]=O>[NH2:24][C:17]1[CH:16]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1C(=O)O
Reaction time: 16 h
Yield: 65.5 %

Procedure:
The obtained 4-(4-benzoylpiperazin-1-yl)-2-nitrobenzoic acid (0.40 g, 93%) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (20 mg, 5%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.24 g, 70%) was obtained after removing of solvents. To a solution of 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.2 g, 0.6 mmol) and benzaldehyde (0.14 ml, 1.3 mmol) added sodium triacetoxyborohydride (0.4 g, 1.8 mmol) and stirred under argon atmosphere overnight. The reaction was quenched with 10 ml water and extracted with ethyl acetate (3×20 ml), followed by drying it over anhydrous sodium sulfate. 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (0.11 g, 40%) was obtained after concentration. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.25-3.88 (m, br, 8H), 4.48 (s, 2H), 6.20 (d, J=2.3 Hz, 1H), 6.22 (dd, J=2.3, 9.1 Hz, 1H), 7.30-7.45 (m, 10H), 7.48 (d, J=9.1 Hz, 1H), 8.25 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16]C(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O>CS(C)=O>[CH:10]1([NH:9][C:8](=[O:16])[NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One molar equivalent (1.97 g) of HNSA was mixed together with one molar equivalent (1.85 g) of dicyclohexylcarbodiimide and one molar equivalent (2.0 g) of biotin in 50 ml of dimethylsulfoxide at room temperature overnight. The reaction resulted in the formation of dicyclohexyl urea as a precipitate. The precipitate was filtered off and 400 ml of dichloromethane was added to the mother liquor. After several hours a solid precipitate was formed. The yield of this crude ester was 59% of theoretical. This precipitate was analyzed spectroscopically as described in Example IA and found to contain 38% biotin-HNSA ester together with 68% of free HNSA. The solid was then purified by column chromatography on LH20 Sephadex in DMF and positively identified as described above for the preparation of mal-sac HNSA ester. The purification yielded biotin-HNSA ester of greater than 99% purity.
Reaction SMILES: [N+:1]([C:4]1[C:5](Br)=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:16]=1)[CH2:9][O:10][CH2:11]3)([O-:3])=[O:2].[Cu][C:19]#[N:20]>CN(C=O)C>[N+:1]([C:4]1[C:5]([C:19]#[N:20])=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:16]=1)[CH2:9][O:10][CH2:11]3)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2c3c(cccc3c1Br)COC2
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1c([N+](=O)[O-])cc2c3c(cccc13)COC2
Temperature: 140 °C
Reaction time: 3 h

Procedure:
5-Nitro-6-bromo-1H,3H-benzo[de]isochromene (23.0 g, 78.2 mmol) was dissolved in anhydrous DMF (500 mL). Then, copper (I) cyanide (10.5 g, 117 mmol) was added to the mixture at room temperature. The mixture was stirred at the internal temperature of 140° C. for 3 hours, and then cooled to 70° C. The resulting insoluble material was separated by filtration. The filtrate was poured into water (1500 mL), and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration, washed with acetonitrile, and air-dried. The title compound was obtained as yellow solid (15.9 g, 85%).
Reaction SMILES: C(OC1C=C2C(C(CO[Si:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([CH3:28])([CH3:27])[CH3:26])CN2S(C)(=O)=O)=CC=1)C1C=CC=CC=1.[CH2:41]([O:48][C:49]1[C:50]2[CH:70]=[CH:69][CH:68]=[CH:67][C:51]=2[C:52]2[CH:53]([CH2:65][OH:66])[CH2:54][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:56]=2[CH:57]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([O:48][C:49]1[C:50]2[CH:70]=[CH:69][CH:68]=[CH:67][C:51]=2[C:52]2[CH:53]([CH2:65][O:66][Si:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:54][N:55]([C:58]([O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:59])[C:56]=2[CH:57]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Reactant: CC(C)(C)[Si](OCC1CN(S(C)(=O)=O)c2cc(OCc3ccccc3)ccc21)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2c1cc(OCc1ccccc1)c1ccccc21
Yield: 96 %

Procedure:
This was synthesized essentially as described for the Cl based analog in A (1) above from 5-(Benzyloxy)-3-(tert-butyloxycarbonyl)-(hydroxymethyl)-1,2-dihydro-3H-benz[e) indole (synthesized as described in D. L Boger et al., J. Org. Chem., 1992, 57, 2873-2876). The product was obtained as a pale yellow oil (96% yield).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:11][S:10][CH:9]([CH2:12][O:13]C(=O)C)[CH2:8][S:7]1)(=O)C.C(=O)([O-])O.[Na+]>CO>[OH:4][CH2:5][CH:6]1[CH2:11][S:10][CH:9]([CH2:12][OH:13])[CH2:8][S:7]1
Reactant: CC(=O)OCC1CSC(COC(C)=O)CS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: OCC1CSC(CO)CS1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.2 %

Procedure:
A 3-L flask equipped with a stirrer was charged with 450 g (1.7 mols) of 2,5-bis(acetoxymethyl)-1,4-dithian and 1500 mL of methanol, to which 314.6 g (3.7 mols) of sodium hydrogen carbonate was added with stirring. The mixture was heated to a temperature at which methanol served as the reflux, at which it was held for 5 hours. It was then cooled to room temperature and filtered to remove the residue. Then, the resultant filtrate was transferred to a 3-L flask equipped with a stirrer, to which 20 g of activated carbon was added. The mixture was again heated to a temperature at which methanol served as the reflux, at which it was held for 30 minutes, and then cooled to room temperature and filtered. The resultant filtrate was concentrated by an evaporator, to obtain a colorless, oily product. It was purified by silica gel chromatography with ethyl acetate/n-hexane as the development medium, to obtain 298 g (yield: 97%) of the 2,5-bis(hydroxymethyl)-1,4-dithian, represented by the formula (1-2). It had 99.9% of purity, as determined by gas chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[NH:10]1.[H-].[Na+].[CH3:31]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[N:10]1[CH3:31]
Reactant: CI
Reactant: CCN(CC)c1cccc2nc3n(c12)CCC(=O)NC3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)N(C)C3c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-(2,4-dichlorophenyl)-7-(diethylamino)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,2-a]benzimidazol-3-one (83.5 mg, 0.200 mmol) in dimethylformamide (1 mL) was added sodium hydride (60%, 20.0 mg, 0.500 mmol) at room temperature. After 15 min, methyl iodide (62.3 μL, 1.00 mmol) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture and by preparative NH TLC eluting with a 33% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (5.0 mg, 0.0115 mmol, 5.7%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8][OH:9])[O:6][CH:7]=1.CC(C)([O-])C.[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[OH:9][CH2:8][C:5]1[O:6][CH:7]=[C:2]([O:1][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:3](=[O:10])[CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)occ1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a solution of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (13.35 g, 94 mmol) in N,N-dimethylformamide (160 ml) stirred under nitrogen at 0° C. was added a solution of potassium tert-butoxide (12.65 g, 113 mmol) in N,N-dimethylformamide (40.0 ml) dropwise over 10 min. The mixture was then stirred at room temperature for 90 minute and 4-methoxybenzyl chloride (15.5 ml, 114 mmol) was added dropwise over 15 min and allowed to stir at 50° C. for 3 days. The reaction was cooled and concentrated under vacuum. Water (400 mL) was added, the resulting precipitate was filtered, washed with water, collected and dried to afford 2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)-4H-pyran-4-one (18.17 g, 69.3 mmol, 73.8% yield) as tan solid. LCMS: (M+H)+: 263.0
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][C@H:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][C@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCC[C@H]1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC[C@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 215 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3R)-3-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([S:10][CH3:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:12][N:13]([CH3:17])[C:14]([N:7]1[C:8]([S:10][CH3:11])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:15]
Reactant: CN(C)C(=O)Cl
Reactant: CSc1nnc(C(C)(C)C)[nH]1
Solvent: c1ccncc1
Product: CSc1nc(C(C)(C)C)nn1C(=O)N(C)C

Procedure:
A solution of 57.6 g (0.338 mol) of 3-tert.butyl-5-methylthio-4H-1,2,4-triazole and 38g (0.355 mol) of dimethylcarbamyl chloride in 300 ml of pyridine was maintained at reflux temperature for 16 hrs. After the pyridine was removed at reduced pressure on the rotary evaporator, water was added followed by chloroform. The organic layer was washed with successive portions of dilute hydrochloric acid, water and brine then dried over Na2SO4. The solvent was removed in vacuo to give 75 g, nD26 1.5165 of an oil. Spectral properties agree with the structure
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[K])(C)(C)C>C1COCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Dissolve 1-fluoro-2-methoxy-4-nitro-benzene (118 g, 689 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (125 g, 724 mmol) in THF (800 mL) and cool to 0° C. To the above solution under a nitrogen atmosphere, add dropwise a 1M solution of tBuOK (1 L, solution in THF). After addition is complete, stir the dark brown solution for 30 min at 0° C., then dilute with water (1 L) over a 10 min period. Stir the mixture for 5 min, then extract with MTBE twice. Combine the organic solutions and wash with brine (2×700 mL), then dry and concentrate. Dry the solid in vacuo at 45° C. for 20 h to obtain 216 g (95%) of the title compounds as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.42 (s, 9H), 3.80 (s, 3H), 4.04 (m, 2H), 4.18 (m, 2H), 4.76 (m, 1H), 6.17 (dd, 1H, J=2.4, 8.5), 6.30 (d, 1H, J=2.6), 6.47 (d, 1H, J=8.5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(Cl)Cl>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([NH:1][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred solution of 1-(3-amino-4-benzyloxy-phenyl)-ethanone (EP 0 659 737) (16.98 g, 70.0 mmol) in pyridine (50 mL) was added dropwise benzenesulfonyl chloride (13.09 g, 73.5 mmol) in 100 mL of pyridine at room temperature. The reaction was stirred for 18 hours under nitrogen atmosphere. The mixture was diluted with CH2Cl2 (700 mL) and washed with 1N hydrochloric acid, water, dried over Na2SO4, and concentrated. The product was purified by flash silica gel chromatography eluting with CH2Cl2 to give the title compound as a tan solid (12.55 g, 47%); 1H NMR (300 MHz, DMSO-d6) δ 3.33 (s, 3H), 5.03 (s, 2H), 7.02 (d, J=8.7 Hz, 1H), 7.35 (m, 3H), 7.44 (t, J=15 Hz, 2H), 7.58 (m, 1H), 7.50 (m, 3H), 7.81 (d, 1H), 9.83 (s, 1H); MS (ES) m/z: 381.9 (MH+, 100%); HRMS Calcd. for C21H19NO4S(MH+): 382.1107. Found: 382.1100.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:35]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(N)C2C(=O)OC(C)(C)C)cc1
Reactant: O=C=NCc1ccccc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)NCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (33 mg, 0.09 mmol) is solved in 3 ml dry-Dioxane. Benzylisocyanate (10.6 μl, 0.086 mmol) is added and the reaction is stirred at room temperature for 1 h. Evaporation of the solvent and flash-chromatography, Dichloromethane/Methanol (7:1) afforded the product: Cal. 515.6 found (M)+ 515.9.
Reaction SMILES: [Mg].CI.Br[C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[CH2:14]1[O:16][CH2:15]1.Cl>C1COCC1>[OH:16][CH2:15][CH2:14][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1
Reactant: Brc1ccc2sccc2c1
Reactant: C1CO1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: OCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a flame dried flask under N2 was added magnesium turnings (6 g, 0.25 mol) and THF (100 ml). The mixture was heated at reflux and a solution of methyl iodide (7.2 ml, d=2.28, 0.116 mol), and 5-bromobenzo[b]thiophene (24.4 g, 0.114 mol) in THF (50 ml) were added dropwise. The mixture was heated at reflux for 5 hours, then cooled to 0°-4° C. and a solution of ethylene oxide (15 g, 0.33 mol) in THF (20 ml) was added dropwise. After the addition, the reaction mixture was allowed to stir at room temperature overnight. The suspension was then cooled and a solution of 3N HCl (75 ml) was added dropwise. The aqueous layer was extracted with ethyl acetate (3×) and the organic layer was backwashed with saturated Na2CO3, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 30% ethyl acetate/hexane to yield 9.3 g (48%) of product, m.p. 56°-57° C.