Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([O:12]CC)=O.[NH2:15][NH2:16]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH:15][NH2:16])=[O:12]
Reactant: CCOC(=O)c1nc2ccccc2s1
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of ethyl benzo[d]thiazole-2-carboxylate (10 g, 48.25 mmol) in ethanol (200 mL) was added hydrazine (15.5 g, 482.5 mmol). The reaction mixture was stirred at RT for 30 min and concentrated under high vacuum to remove hydrazine. The resulting residue was triturated with ethanol (40 mL) to give benzo[d]thiazole-2-carbohydrazide (9.3 g, quant.) LRMS (M+H+) m/z 194.0.
Reaction SMILES: Cl.NC[C:4]1[CH:5]=[C:6]([OH:15])[C:7](=[CH:13][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:16]([N:19](CC)C(C)C)(C)C.C1(=O)N(O[C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])C(=O)CC1>CN(C)C=O.C(OCC)(=O)C>[C:41]([O:40][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([NH:19][CH2:16][O:15][C:6]1[C:7](=[CH:13][CH:14]=[CH:4][CH:5]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:45])=[O:39])([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1ccc(CN)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1OCNC(=O)CCCCCNC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 128.1 %

Procedure:
Ethyl 4-aminomethylsalicylate hydrochloride (0.52 g 1.28 mmoles) was suspended in anhydrous N,N-dimethylformamide (25 mL), and N,N-diisopropylethylamine (0.79 mL, 4.53 mmoles) was added, followed by N-tert-butoxycarbonyl-6-aminohexanoic acid succinimidyl ester (0.74 g, 2.26 mmoles). The mixture was stirred under dry nitrogen for 18 hours, during which time all solids dissolved. The reaction mixture was diluted with ethyl acetate (100 mL) and extracted with 1N aqueous hydrochloric acid (100 mL). The layers were separated, and the ethyl acetate solution was washed with water (100 mL) and saturated aqueous sodium chloride (500 mL). The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to afford an amorphous off-white solid. Finally, the solid was crystallized from ethyl acetate, filtered, and dried in vacuo to afford 0.67 g (73% yield) of ethyl (N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethylsalicylate (m.p. 120°-121° C., open capillary, uncorrected).
Reaction SMILES: S(Cl)([Cl:3])=O.C[C:6](C)=[O:7].C(=O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[C:17]2[CH2:24][CH2:25][CH2:26][C@@H:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][C@@H:28]1[C:40]([OH:42])=O>CO>[ClH:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[C:17]2[CH2:24][CH2:25][CH2:26][C@@H:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[C:40]([O:7][CH3:6])=[O:42]
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)c2c1
Reactant: O=S(Cl)Cl
Reactant: CC(C)=O
Agent: O=C=O
Solvent: CO
Product: COC(=O)[C@H]1CNCC[C@H]1CCCc1ccnc2ccc(OC)cc12
Product: Cl
Reaction time: 16 h

Procedure:
2 cm3 of thionyl chloride were added dropwise to a stirred suspension, cooled to a temperature in the region of −30° C. with a cooling bath of acetone and solid carbon dioxide, of 4.29 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxy-carbonyl)piperidine-3-carboxylic acid in 50 cm3 of methanol. The solution obtained was brought to a temperature in the region of 20° C. and the reaction mixture was stirred for 16 hours at this temperature. After evaporating the solution under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., the residue obtained was triturated in approximately 30 cm3 of diisopropyl ether. The crystals obtained were filtered off, washed with 2 times 10 cm3 of diisopropyl ether, and then dried in the air. 4.20 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate hydrochloride were obtained in the form of a solid with a light yellow color which melts with softening at a temperature in the region of 140° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.S(O)(O)(=O)=O.[CH3:41][S:42][C:43](=[NH:45])[NH2:44].C([O-])(=O)C.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:45][C:43]([S:42][CH3:41])=[N:44]2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: CSC(=N)N
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC1=NC(c2ccc(Cl)c(Cl)c2)C(C(=O)OCCCc2ccccc2)=C(COCCN2CCCCC2)N1
Temperature: 60 °C
Yield: 10.2 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (10.6 g, 30.6 mmol), 3,4-dichlorobenzaldehyde (5.9 g, 34.0 mmol), 2-methyl-2-thiopseudourea sulfate (6.15 g, 22.1 mmol) and sodium acetate (2.78 g, 34.0 mmol) was stirred in N,N-dimethylformamide (50 mL) for 4 days at room temperature, then heated to 60° C. for 24 h. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. This oil was further purified by flash chromatography to give the title compound (1.3 g) as an oil. The oil can be converted into a mono or dihydrochloride salt, by dissolution in ether and addition of one or two equivalents of hydrogen chloride. Electrospray MSm /z 576/578 [M+H]+.
Reaction SMILES: [CH:1](=[O:5])/C=C/C.[CH2:6]([N:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:7][CH:8]=[CH2:9]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C(OC(C)C)=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[C:11]([N:10]([CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH:1]=[O:5])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:22]
Reactant: C=CCCN(C(=O)c1ccc(OC)c(OC)c1)c1ccccc1
Reactant: C/C=C/C=O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)N(CC/C=C/C=O)c2ccccc2)cc1OC
Temperature: 40 °C
Yield: 97 %

Procedure:
Crotonaldehyde (0.5 mL, 3 equiv) was added to a solution of compound 34 (608 mg, 1.95 mmol) in degassed CH2Cl2 (17 mL). Hoveyda-Grubbs' 2nd (31 mg, 2.5% mol) was added and the reaction mixture was heated to 40° C. under Ar atmosphere overnight. The reaction mixture was filtered over Celite and the filtrate was concentrated to dryness. The residue was purified by column chromatography on SiO2 (Petroleum ether/EtOAc=2:3) to afford the title compound 35 as white solid (Yield 644 mg, 97%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=1.CCN(C(C)C)C(C)C.Cl.[NH2:31][C@:32]([CH3:39])([CH2:37][CH3:38])[C:33](OC)=[O:34]>C(OCC)(=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.ClCCl>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:33](=[O:34])[C@:32]([CH2:37][CH3:38])([CH3:39])[NH:31][C:5]2=[O:11])=[CH:16][N:15]=1
Reactant: Nc1cnc(Cl)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@](C)(N)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2cnc(Cl)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphosgene (1.38 g, 4.65 mmol) in Ethyl acetate (20 ml) at 0° C. a solution of 2-chloro-5-aminopyrimidine (1 g, 7.75 mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added (20 minutes) and the reaction mixture was stirred for 15 minutes at the same temperature. Maintaining the reaction mixture at 0° C., vacuum was applied (10 minutes) for removing the excess of phosgene. A solution of DMAP (0.945 g, 7.75 mmol) in ethyl acetate/dichloromethane 1:1 (8 ml) was added and the reaction mixture was stirred for 5 minutes at the same temperature. A solution of methyl (R)-2-amino-2-methyl-butyrate hydrochloride (2.59 g, 15.5 mmol) in ethyl acetate (30 ml) was slowly added (15 minutes) at 0° C. and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with aqueous buffer (pH3) while the pH was allowed to reach ˜5-6 and two phases were separated. The organic layer was washed with aqueous buffer (pH3) (2×20 ml) and then brine (20 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as orange foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3cccnc32)cc1

Procedure:
(16.4 mg, 41%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.8 mg, 0.12 mmol) and 4-methoxybenzoyl chloride (35 μL, 0.24 mmol); HRMS-FAB+ for C21H21N3O2: calculated MH+:348.17120; found:348.16994.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[NH:14][N:13]=[N:12][N:11]=1.[N:15]([O-])=O.[Na+].Cl>C(Cl)(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C:10]3[N:11]([N:12]=[N:13][N:14]=3)[N:15]=[N:1][C:2]=2[CH:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(-c2nnn[nH]2)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)nnn1nnnc21
Yield: 51.1 %

Procedure:
The above-named compound was prepared from 1 g of 5-(2-amino-4-methoxyphenyl)tetrazole, 0.45 g of NaNO2, and concentrated HCl and isolated from the reaction mixture by the procedures of Example 2. The residue obtained by evaporation of the chloroform extracts was a dark reddish-brown solid shown by liquid chromatographic analysis to be largely the named compound plus several minor impurities. The product was purified by percolating its chloroform solution through two 7-10 ml portions of 80-200 mesh alumina and evaporating the treated solution under nitrogen at room temperature. A yield of 0.54 g of orange solid was obtained. This purified material showed only trace impurities on thin layer chromatographic examination and its structure as the named compound was confirmed by magnetic resonance and infrared absorption analyses.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)=[CH:9][C:7]=2[CH:8]=1)(=[O:31])=[O:30]
Reactant: N#Cc1cccc(-c2ccc3oc(CCO)cc3c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The product from Example 112C (170 mg, 0.65 mmol) and triethylamine (100 μL, 0.72 mmol) were dissolved into CH2Cl2 (3 mL) and cooled to 0° C. The solution was treated with methanesulfonyl chloride (55 μL, 0.71 mmol), and after 10 minutes it was permitted to slowly warm to room temperature. More methanesulfonyl chloride (10 μL, 0.13 mmol) and triethylamine (10 μL, 0.072 mmol) were added. The mixture was stirred until the reaction was nearly complete and then washed consecutively with water and brine, dried (Na2SO4), concentrated, and used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[Cu][C:17]#[N:18]>CN(C=O)C.O.Cl.C1(C)C=CC=CC=1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:17]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15])#[N:18]
Reactant: N#C[Cu]
Reactant: COc1cc(Br)c2c(c1OC)C(=O)CC2
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C#N)c2c(c1OC)C(=O)CC2
Reaction time: 5.75 h

Procedure:
A mixture of 6.57 g (24.2 mmol) of 4-bromo-6,7-dimethoxy-1-indanone [Can. J. Chem. 57, 1603 (1979)] and 2.5 g (28 mmol) of copper(I) cyanide in 7 ml of DMF is stirred for 5.75 hours at 170°. The reaction mixture is then cooled to 100° and then 70 ml of toluene and a solution of 9.7 g (36 mmol) of iron(III) chloride hexahydrate in 15.6 ml of water and 3.5 ml of concentrated hydrochloric acid are added in succession thereto. The reaction mixture is then stirred for 30 minutes at 80°, cooled and diluted with toluene and water. The organic phase is separated off, washed with water, a semi-saturated sodium hydrogen carbonate solution and again with water, dried and concentrated by evaporation. The residue is distilled at 150°-160°/0.1 mbar in a bulb tube still and corresponds to starting compound (a), m.p. 150°; IR (CH2Cl2): 2220, 1710 cm-1 ; 1H-NMR (CDCl3): δ=7.33 (s,1H); 4.12 (s,3H); 3.90 (s,3H); 3.19 (m,2H); 2.76 (m,2H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[CH:5][N:6]([CH2:11][CH2:12][N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[N:7]=4)[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc2nn(CCN3CCCC3)cc2c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4nn(CCN5CCCC5)cc4c3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (170 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (106 mg, 0.50 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:10]Br)[CH2:9][CH2:8]1.CN(C)C=O.[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[C:20]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:19]=1>C(OCC)(=O)C>[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH2:10][CH:7]2[CH2:9][CH2:8]2)=[C:20]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:19]=1
Reactant: BrCC1CC1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2ncn(CC3CC3)c2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Potassium carbonate (36.0 g, 260.5 mmol) and cyclopropylmethyl bromide (20.2 g, 143.3 mmol) were added to an N,N-dimethylformamide suspension (400 ml) of 2-chloro-6-morpholin-4-yl-9H-purine (32.4 g; purity, approx. 96%; 130.2 mmol) at room temperature and the resulting mixture was stirred at 80° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was left standing to cool, then poured into ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting solid was washed with diethyl ether and collected by filtration to give the title compound (26.9 g, 70%) as a colorless acicular crystal. The mother liquor was further concentrated by the same procedure to give the secondary crystal of the title compound (7.68 g, 20%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)=[N:4][N:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[C:22]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Cl:1])=[N:3][N:4]=2)[CH2:13][CH:14]1[C:18]([O:20][CH3:21])=[O:19])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 4-(4-chlorophthalazin-1-yl)piperazine-2-carboxylate (563 mg, 1.84 mmol) was dissolved in DMF (6 mL) and N,N-diisopropylethylamine (1 mL). Benzoyl chloride (0.23 mL, 2.02 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL), washed with aqueous K2CO3 (10%), water, and then saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-75% ethyl acetate gave an off-white foam. MS (M+H)+=381.8.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Si:9]([O:26][CH2:27][C@H:28]([OH:35])[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>C(#N)C>[Si:9]([O:26][CH2:27][C@@H:28]1[O:35][C:2](=[O:3])[C:31]2=[N:32][CH:33]=[CH:34][N:30]2[CH2:29]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](OC[C@H](O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)[Si](OC[C@H]1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Slowly add trichloromethyl chloroformate (5.80 mL; 2.0 equiv; 48.35 mmoles) over 15 minutes to a 0° C. solution of (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (9.2 g; 1.0 equiv; 24.17 mmoles) and pyridine (15.64 mL; 8 equiv; 193.40 mmoles) in acetonitrile (450 mL). Stir for 1 hour and then allow the solution to warm to ambient temperature over 1 hour. Add water (30 mL) and concentrate the reaction mixture. Add dichloromethane (50 mL), and slowly pour the resulting solution into 50% saturated sodium bicarbonate (200 mL). Separate the layers and further extract the aqueous layer with dichloromethane (3×150 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purification by column chromatography (10% to 100% ethyl acetate in hexanes) affords the desired (6R)-6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (5.50 g; 56%). MS (m/z): 407(M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][C:12]1[C:13]([O:21][C@@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])=[N:14][NH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][C:12]1[C:13]([O:21][C@@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])=[N:14][N:15]([CH2:38][CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:16]=1[C:17]([F:18])([F:20])[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](Oc2nn(CCOCc3ccccc3)c(C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole (300 mg) in N,N-dimethylformamide (3 mL) were added (2-bromoethoxymethyl)benzene (379 mg) and cesium carbonate (957 mg), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give the title compound (154 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]1[C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][C:24]2[CH2:25][CH:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:23]=2[CH:22]=1.Cl>CN(C)C=O>[CH3:12][O:11][C:9](=[O:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][CH2:20][C:21]2[C:37]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:36][C:24]3[CH2:25][CH:26]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:23]=3[CH:22]=2)=[CH:7][CH:6]=1)([CH3:14])[CH3:13]
Reactant: BrCCCc1cc2c(cc1OCc1ccccc1)CC(CCc1ccccc1)O2
Reactant: COC(=O)C(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1ccc(OCCCc2cc3c(cc2OCc2ccccc2)CC(CCc2ccccc2)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a stirring solution of methyl 2-(4-hydroxyphenyl)-2-methylpropionate (0.81 g; 4.19 mmol) in dry diemthylformamide (8 mL) was added sodium hydride (192 mg, 4 mmol) as a 50% dispersion in oil. The mixture was stirred at room temperature for 30 minutes. A solution of 6-(3-bromopropyl)-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E88, in dry dimethylformamide (2 mL) was added. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into cold dilute HCl (1N, 25 mL) and extracted twice with ethylacetate (50 mL). The combined organic extracts were washed with 1N HCl (25 ml×2) and brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel to give 500 mg (87% yield) methyl-2-[4-[3-[2,3-dihydro-5-benzyloxy-2-(2-phenylethyl)benzofuran-6-yl]propoxy]phenyl]- 2-methylpropanoate, E42.