Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].[ClH:17].O1CCOCC1>>[ClH:17].[CH3:1][N:2]([CH3:16])[C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)C1CNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of t-butyl 3-dimethylcarbamoyl-azetidine-1-carboxylate (0.365 g) and 4N hydrogen chloride/dioxane solution (5 ml) was stirred at room temperature for 5 hr 15 min. The reaction mixture was concentrated under reduced pressure, dioxane was added to the obtained residue and the mixture was concentrated again under reduced pressure. The obtained residue was dried under reduced pressure at 60° C. to give the title compound (0.290 g). The obtained residue was directly used for the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>C(OCC)(=O)C.[Cu]I.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.O>[CH3:19][Si:18]([C:16]#[C:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: Brc1ccncc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccncc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A flask was charged with 4-bromopyridine.HCl (2.46 g, 12.65 mmol) and triethylamine (40 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (1.967 mL, 13.92 mmol) and purged 15 min longer. To this was added copper(I) iodide (0.120 g, 0.633 mmol), and Pd(PPh3)2Cl2 (0.444 g, 0.633 mmol). The reaction was stirred at room temperature for 72 h. The reaction was warmed to 50° C. and held at that temperature for 24 h. The reaction was diluted with ethyl acetate (60 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->25% EtOAc/Hex) gave 667 mg (30%) as a dark oil. 1H-NMR (CDCl3, 500 MHz) δ 8.58 (d, J=6.1, 2H), 7.33 (d, J=6.1, 2H), 0.29 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 149.8, 131.3, 125.9, 102.1, 100.1, −0.2. Mass spec.: 176.14 (MH)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[Cl:21][CH:22](C)[C:23](Cl)=O.Cl>C(#N)C.[Ti]>[Cl:21][CH:22]([CH3:23])[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(Cl)C(=O)Cl
Agent: [Ti]
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)C(C)Cl
Yield: 58 %

Procedure:
Potassium ethyl malonate, 34 g (200 mmole) (Organic Synthesis Coll. Vol. IV, p. 417), 23.75 g (250 mmole) magnesium chloride, and 44.5 ml (320 mmole) triethylamine were suspended in 1.0 L acetonitrile, with stirring, under nitrogen. 2-Chloro-propionyl chloride, 9.7 ml (100 mmole), was added and the mixture was stirred under nitrogen for 18 hours. 100 ml of 5N hydrochloric acid, was added and the reaction was stirred for 2 hours. Layers were separated and organics stripped to give 21.09 g of crude product which was filtered through 300 ml silica, eluting with 20% ethyl acetate/hexane to give 10.37 g (58%) product.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15](=[O:18])[CH2:16][CH3:17].Cl>CO.O1CCOCC1.C(OCC)(=O)C>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)c1c(OCOC)cccc1OCOC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=O)c1c(O)cccc1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2,6-bis-methoxymethoxy-phenyl)-propan-1-one (770 mg) in methanol (12 ml) and 1,4-dioxane (12 ml) was added 4N-HCl (2 ml) at room temperature, then the mixture was heated to 50° C. and stirred for 2 hours. The mixture was diluted with ethyl acetate and washed with water (20 ml) and brine (20 ml). The separated organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate. 1-(2,6-dihydroxyphenyl)-propan-1-one was obtained as a yellow solid (398 mg). EI-MS: m/z 178 (M+); 1H-NMR (CDCl3): δ 1.03-1.08 (2H, m), 1.29-1.35 (2H, m), 2.21-2.31 (1H, m), 6.41 (2H, d, J=8.3 Hz), 7.23 (1H, t, J=8.3 Hz) 9.24 (2H, brs).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C)C=O.C(Cl)(C([Cl:20])=O)=O>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([Cl:20])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(Cl)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc(Cl)cn1
Yield: 94 %

Procedure:
5-chloropyrazine-2-carboxylic acid (1.00 gram, 6.31 mmol) in dichloromethane (30 ml) was treated with catalytic amount of dimethylformamide, followed by (COCl)2 (0.85 ml, 9.46 mmol). The resulting mixture was stirred over night. The reaction was concentrated in vacuo, and dried under vacuum to give desired 5-chloropyrazine-2-carbonyl chloride as solid (1.05 g, 100%).
Reaction SMILES: [CH2:1]([CH:9]1[C:16]2[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=2[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[OH-].[Li+]>>[CH2:1]([CH:9]1[C:16]2[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=2[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2CCc1ccccc1
Yield: 84 %

Procedure:
The title compound was synthesized from methyl 4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and lithium hydroxide monohydrate (81 mg, 1.93 mmol) according to General Procedure 7. Silica gel was added, the solvent stripped off and the silica gel-imbedded material was purified by flash chromatography (0-80% EtOAc/Heptane) to give 4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (18) as a light yellow solid (103.6 mg, 84%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.68-1.87 (m, 2H), 1.98-2.09 (m, 1H), 2.55-2.80 (m, 5H), 2.88-2.97 (m, 1H), 6.68 (s, 1H), 7.11-7.16 (m, 1H), 7.17-7.29 (m, 4H); LCMS-MS (ESI+) 256.0 (M+H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[CH:7]=O)[CH:2]=[CH2:3].[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[CH:2]=[CH2:3]
Reactant: O=C1CSC(=S)N1
Reactant: C=CCc1cc(C=O)cc(CC=C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCc1cc(C=C2SC(=S)NC2=O)cc(CC=C)c1O
Temperature: 0 °C
Yield: 94.6 %

Procedure:
3,5-di-(2-propenyl)-4-hydroxybenzaldehyde (50.5 g), 36.6 g of rhodanine and 164 g of sodium acetate were heated together at reflux temperature in 1.25 liter of acetic acid for 14.5 hours. The resultant solution was cooled, poured into 2 liter of ice water to yield, upon separation, about 75 g of 5-[(3,5-di-2-propenyl-4-hydroxyphenyl)-methylene]-2-thioxo-4-thiazolidinone, m.p. 157°-160° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C=O)C.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(=O)(O)[O-].[Na+]>[C:29]([Si:26]([O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]=1[CH3:12])([CH3:28])[CH3:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(SC#N)c(C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2.0 g (9.0 mmol) of 5-tert-butyl-2-methyl-4-thiocyanato-phenol (prepared in Example GGG), imidazole (0.800 g, 11.8 mmol) and DMF (10 mL) was treated with t-butyldimethylsilylchloride (1.64 g, 10.9 mmol) and stirred overnight. The mixture was diluted with saturated sodium bicarbonate and the mixture extracted with hexanes. The hexane layers were combined, dried (Na2SO4), and the solvent removed in vacuo to yield the title compound. 1H NMR (CDCl3) δ 0.23 (s, 6 H), 1.01 (s, 9 H), 1.45 (s, 9 H), 2.16 (s, 3 H), 6.87 (s, 1 H), 7.49 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]2[N:45]=[C:44](Cl)[N:43]=[C:42]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]3[CH2:57][C:56]([CH3:59])([CH3:58])[N:55]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:54]([CH3:70])([CH3:69])[CH2:53]3)[N:41]=2)[N:3]=1.[CH2:71]([CH2:73][NH2:74])[OH:72]>>[OH:72][CH2:71][CH2:73][NH:74][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]2[N:45]=[C:44]([NH:74][CH2:73][CH2:71][OH:72])[N:43]=[C:42]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]3[CH2:57][C:56]([CH3:59])([CH3:58])[N:55]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:54]([CH3:70])([CH3:69])[CH2:53]3)[N:41]=2)[N:3]=1
Reactant: NCCO
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCCCNc3nc(Cl)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCCCNc3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis{2-chloro-4-[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:14]=2[OH:16])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1[O:16][C:14]2[C:15]3[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)CCCCc3ccccn3)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(CCCCc4ccccn4)oc3c21
Yield: 58.1 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-5-pyridin-2-ylpentanamide (37.7 mg, 0.0953 mmol) and pyridinium p-toluenesulfonate (4.8 mg, 0.0191 mmol) were heated under reflux in xylene (1 mL) for 1.5 hr. The solvent was evaporated under reduced pressure, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→480/20) to give the title compound (20.9 mg, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.Cl.[OH-].[Na+].C(Cl)(Cl)Cl>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:10])[F:11])=[CH:6][C:5]([NH2:12])=[C:4]([F:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(OC(F)F)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1cc(OC(F)F)c(Cl)cc1F
Reaction time: 20 h
Yield: 86.8 %

Procedure:
To 5 g of 4-chloro-5-difluoromethoxy-2-fluoronitrobenzene XII-1 were added 10.4 ml of ethanol and 20.7 ml of hydrochloric acid, and the resultant mixture was stirred at room temperature. A solution of 14 g of stannous chloride dihydrate in 20.7 ml of ethanol was dropwise added in 10 minutes to the mixture, which was stirred for 20 hours. The reaction mixture was basified with 10% aqueous sodium hydroxide and shaken with chloroform. The chloroform layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (100:15 v/v). The eluate was concentrated to give 3.8 g of the titled compound XIII-1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[C:9][CH3:10].CN(C)C=O.[CH2:17]([O:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[NH:33][C:34]([N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[N:35][C:29]=2[CH:28]=[N:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH2:17]([O:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[N:33]([CH2:7][C:8]#[C:9][CH3:10])[C:34]([N:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[N:35][C:29]=2[CH:28]=[N:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3cnn(COCc4ccccc4)c(=O)c3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(COCc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
0.74 g of potassium carbonate and 0.078 g of 2-butynyl bromide were added to a 20-ml N,N-dimethylformamide solution of 0.216 g of t-butyl 4-(6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine-1-carboxylate and the mixture was stirred at room temperature for 16 hours. Then, 50 ml of ethyl acetate was added to the solution. The organic layer was washed three times with 20 ml of water, and then with 10 ml of a saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.139 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O-])(=[O:13])[CH3:12].[Na+].O>C(O)(=O)C>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)cc1
Yield: 65.8 %

Procedure:
A mixture of 4-aminobenzoic acid (Aldrich, 50.0 g, 0.365 mol) and anhydrous sodium acetate (35.0 g, 0.427 mol) in glacial acetic acid (150 mL) was heated to reflux for 15 h. The mixture was poured into cold water (1 L). The precipitate was separated by filtration and washed several times with cold water. The cake was dried in oven at 70° C. and recrystallized from 2:1 water:ethanol to give 43.0 g (68%) of the title compound as off-white flakes, mp 258° C.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:34](OC)[O:35]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>O>[CH2:1]([S:8][CH:9]([CH:34]=[O:35])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.7 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.75 g), Amberlyst (registered trade mark) 15 ion exchange resin (1.0 g), acetone (100 mL) and water (0.4 mL) was stirred at room temperature for 20 hr. Amberlyst (registered trade mark) 15 ion exchange resin was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3-3:2) to give the title compound (4.4 g, yield: 100%) as a colorless amorphous solid. MS: 528(MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([OH:12])[CH2:4][C:5]1([CH3:11])[O:10][CH2:9][CH2:8][CH2:7][O:6]1.C(OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[C:30]12([NH:40][C:41](=[O:49])[C:42]([F:48])([F:47])[S:43](F)(=[O:45])=[O:44])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.Cl>C(OCC)(=O)C.O1CCCC1>[C:30]12([NH:40][C:41](=[O:49])[C:42]([F:47])([F:48])[S:43]([O:12][CH:3]([CH2:4][C:5]3([CH3:11])[O:6][CH2:7][CH2:8][CH2:9][O:10]3)[C:2]([F:1])([F:13])[F:14])(=[O:44])=[O:45])[CH2:39][CH:34]3[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]3)[CH2:37]1)[CH2:31]2
Reactant: CC1(CC(O)C(F)(F)F)OCCCO1
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(F)(F)S(=O)(=O)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC1(CC(OS(=O)(=O)C(F)(F)C(=O)NC23CC4CC(CC(C4)C2)C3)C(F)(F)F)OCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 200 ml round-bottom flask provided having a thermocouple and a dropping funnel was charged with 5 g (23 mmol) of 1,1,1-trifluoro-3-(2-methyl-1,3-dioxan-2-yl)propan-2-ol and 40 g of diisopropyl ether. To the flask, 24.5 ml of 1 mol/L lithium diisopropylamide was added dropwise over 30 minutes in a nitrogen atmosphere at −30° C. or lower (thereby obtaining a solution “C”). The solution was stirred for 30 minutes after the termination of the dropwise addition, followed by increasing the temperature of the solution to room temperature and then stirring it for additional 1 hour. Another 200 ml round-bottom flask provided having a thermocouple and a dropping funnel was charged with 8.0 g of 2-(adamant-1-ylamino)-1,1-difluoro-2-oxoethanesulfonyl fluoride and 30 g of tetrahydrofuran and cooled to −30° C. in a nitrogen atmosphere. To this solution, the previously prepared solution “C” was added dropwise by using the dropping funnel to such an extent as not to exceed an inner temperature of −20° C. The solution was stirred for 30 minutes after the termination of the dropwise addition, followed by increasing the temperature of the solution to room temperature and then stirring it for additional 3 hours. Thereafter, 50 g of ethyl acetate was added thereto, and then 30 ml of 5% aqueous hydrochloric acid solution was added. An organic phase was separated by using a separatory funnel, followed by rinsing with 30 ml of a saturated aqueous sodium hydrogen carbonate solution and then repeating rinsing with 30 ml of water three times. Distillation of a solvent was performed, and then filtration was performed when crystallization was confirmed, thereby obtaining 8.9 g of a crude crystal. This crystal was recrystallized with 50 g of ethyl acetate thereby obtaining 7.1 g of a target 1,1,1-trifluoro-3-(2-methyl-1,3-dioxan-2-yl)propan-2-yl 2-(adamant -1-ylamino)-1,1-difluoro-2-oxoethanesulfonate (hereinafter referred to as “AA-3”). As a result of analyzing this compound by high performance liquid chromatography, it was confirmed that the purity was 98.8%. Additionally, the yield was 60%.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][CH2:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9]>[Sn](F)F>[CH2:1]([O:17][CH2:16][C@@H:14]([C@H:12]([C@@H:10]([C@@H:8]([CH2:7][OH:6])[OH:9])[OH:11])[OH:13])[OH:15])[CH:3]1[O:5][CH2:4]1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: ClCC1CO1
Agent: F[Sn]F
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)COCC1CO1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 750 ml reactor equipped with reflux condenser, thermometer, stirrer and metering device for epichlorohydrin is charged with 72.9 g (0.4 mol) of sorbitol and 1.25 g (0.008 mol) of tin difluoride in 88.5 g (0.957 mol) of epichlorohydrin, and the charge is heated to 110° C. Then, with stirring, 132.1 g (1.429 mol) of epichlorohydrin are added at a rate of 1.5 ml/min, while keeping the temperature at 110°-115° C. Stirring is continued for a further 8 hours at 125°-130° C. Excess epichlorohydrin is removed by distillation under a water jet vacuum and the residue is diluted with 441 g of methyl isobutyl ketone. With efficient stirring, 142.4 g (1.78 mol) of a 50% solution of sodium hydroxide are added dropwise over 1 hour and the reaction mixture is kept for another 2 hours at this temperature. The reaction mixture is neutralised by addition of dry ice and filtered, and the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is dried under vacuum (2 hours/60° C.), giving 155.2 g of sorbitol glycidyl ether for which the following analytical values are obtained: epoxy value: 5.5 eq/kg; total chlorine content 15.56%; hydrolysable chlorine content 1.09%; viscosity at 40° C.: 2460 mPa.s; average molecular weight Mn (GPC): 658.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:8]([Br:28])[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OCc2ccccc2)c2c(ccn2COCc2ccccc2)n1
Solvent: ClCCl
Product: Nc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Yield: 94.3 %

Procedure:
A solution of 2-amino-4-benzyloxy-5-N-benzyloxymethylpyrrolo[3,2-d]pyrimidine (1.0 g) in methylene chloride (30 mL) was stirred in an ice bath while N-bromosuccinimide (0.5 g) was added portion-wise. The solution was concentrated and chromatography afforded 2-amino-4-benzyloxy-5-N-benzyloxymethyl-7-bromopyrrolo[3,2-d]pyrimidine (1.15 g) as a white solid. 13C NMR (CDCl3) δ 158.8, 157.2, 150.9, 137.3, 136.6, 131.8, 129.0, 128.8, 128.6, 128.5, 128.3, 127.9, 111.3, 90.3, 77.8, 70.7, 68.4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[Li]CCCC.[Br:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28](N(OC)C)=[O:29]>C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]([C:28]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=2[NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH:34]=[CH:35][CH:36]=1
Reactant: CON(C)C(=O)c1cccc(Br)c1
Reactant: COc1cc(Br)c(NC(=O)C(C)(C)C)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(C)(C)C)c(C(=O)c2cccc(Br)c2)cc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flamed dried 500 mL three-necked flask was charged N-(2-bromo-4,5-dimethoxyphenyl)-2,2-dimethylpropanamide (30 g, 95 mmol) and dry THF (200 mL) under N2. n-BuLi (114 mL, 2.5 mol/L, 285 mmol) was added dropwise at −78° C. After the mixture was stirred at −78° C. for 1 hour, 3-bromo-N-methoxy-N-methylbenzamide (23.2 g, 94.9 mmol) in dry THF (30 mL) was added dropwise slowly at −78° C. The resulting mixture was stirred at −78° C. for 3 hours, then quenched with saturated NH4Cl (100 mL). The mixture was exacted with EtOAc (100 mL×3). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (30:1 hexanes/ethyl acetate) to afford a N-{2-[(3-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-2,2-dimethylpropanamide as a yellow solid. MS (M+H)=420 and 422.