Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8](=[NH:10])[NH2:9])=[CH:6][CH:5]=1.CN([CH:18]=[C:19]([CH2:24][NH+](C)C)[CH2:20][NH+](C)C)C.F[B-](F)(F)F.C[O-:34].[Na+]>C(O)C>[F:2][C:3]([F:13])([F:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]2[N:9]=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][N:10]=2)=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: CN(C)C=C(C[NH+](C)C)C[NH+](C)C
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of containing 4-(trifluoromethyl)benzimidamide hydrochloride (50 g, 0.22 mol) and 2-dimethylaminomethylene-1,3-bis(dimethylammonio)propane bis(tetrafluoroborate (50 g, 0.27 mol) in ethanol (500 mL) was added sodium methoxide (36 g, 0.67 mol). The mixture was stirred for 1 h at 90° C. then cooled to room temperature. The mixture was extracted with ethyl acetate (200 mL*3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via silica gel chromatography to give 2-(4-(trifluoromethyl)phenyl)pyrimidine-5-carbaldehyde (25 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 9.19 (s, 2H), 8.61 (d, J=8.0 Hz, 2H), 7.72 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]=2[C:13]([NH:15][CH:16]([CH2:21][OH:22])C(OC)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29](N(S(F)(F)F)CC)C.[C:38](=[O:41])([O-])[O-:39].[K+].[K+]>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:12]=2[C:13]2[O:22][CH2:21][CH:16]([C:38]([O:39][CH3:29])=[O:41])[N:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(CO)NC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1COC(c2c(-c3ccccc3)cnnc2-c2ccccc2)=N1
Temperature: -76 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of methyl 2-(3,5-diphenylpyridazine-4-carboxamido)-3-hydroxypropanoate (220 mg, 0.58 mmol) in DCM (15 mL), (diethylamino)sulfur trifluoride (188 mg, 1.16 mmol) was added at −76° C. and stirred at −76° C. for 2 h. Potassium carbonate (400 mg, 2.8 mmol) was added to the reaction mixture at −78° C. and the resulting reaction mixture was warmed to rt. Reaction was quenched by addition of saturated Na2CO3, extracted with DCM (2×25 mL), washed with brine (1×10 mL) and dried over anhy. Na2SO4. Evaporation of the solvent under reduced pressure gave crude product methyl 2-(3,5-diphenylpyridazin-4-yl)-4,5-dihydrooxazole-4-carboxylate (compound 25) (130 mg, 61%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1[C:31](Cl)=[O:32].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:27]4[S:28][CH:29]=[CH:30][C:26]=4[CH3:25])=[O:32])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Yield: 53.6 %

Procedure:
As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.177 g (1.1 mmol) of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of dichloromethane and 0.111 g of triethylamine for 2 hours at room temperature to give crystals. Recrystallization from dichloromethane-hexane gives 0.235 g of crystals, m.p. 201°-204° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[O:8][C:7]=1[CH3:14])=[O:5])[CH3:2].S(N)(=O)(=O)[OH:16].Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:11][C:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[O:8][C:9]=1[C:12]([OH:16])=[O:13]
Reactant: CCOC(=O)c1c(C)oc(C=O)c1C
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)oc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4-Dimethyl-5-formylfuran-3-carboxylic acid ethyl ester (1.78 g, 9.1 mmol) reported in the references was dissolved in a mixture of acetic acid (32 ml) and water (8 ml). Amidosulfuric acid (1.19 g, 12.2 mmol) was added to the solution, and cooled to 0° C. in an ice bath. Sodium chlorite was added and stirred for 2 hours, and after addition of water to reaction mixture, precipitate was collected by filtration, thereby giving 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (1.01 g, 52%) as a white solid.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1O)[CH:17]=[CH2:18].CC1C=CC=C(C)N=1>ClCCl>[O:8]([C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[CH2:16][CH:17]=[CH2:18])[S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CCc1cc([N+](=O)[O-])ccc1O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CCc1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 3 h

Procedure:
Triflic anhydride (1.63 ml) was added dropwise to a mixture of 2-allyl-4-nitrophenol (1.79 g) and 2,6-dimethylpyridine (1.18 g) in dry dichloromethane (15 ml) at -20° C. under an atmosphere of argon. The reaction mixture was allowed to reach ambient temperature over 3 hours. The mixture was partitioned between water and dichloromethane. The organic phase was separated, washed with 1M aqueous sodium hydroxide solution, water, dried (MgSO4) and evaporated to give 2-allyl-4-nitrophenyl triflate (2.71 g) as an oil; microanalysis, found: C, 38.7; H, 2.6; N, 4.2%; C10H8F3NO5S requires: C, 38.6; H, 2.59; N, 4.5%; NMR: 3.7(2H,d), 5.19-5.35(2H,m), 5.97-6.17(1H,m), 7.84(1H,d), 8.36-8.55(2H,m); m/z 311(M).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([OH:25])=[O:24].[CH2:26]([OH:33])C(N)(CO)CO.CC[O:36][CH2:37]C>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([O-:25])=[O:24].[OH:1][CH2:2][N+:7]([CH2:26][OH:33])([CH2:37][OH:36])[CH3:6]
Reactant: CCOCC
Reactant: NC(CO)(CO)CO
Reactant: CC(C)(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)[O-])cnc3c2c1
Product: C[N+](CO)(CO)CO
Reaction time: 1 h

Procedure:
4-Oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (1.31 g) was suspended in N,N-dimethylformamide (13 ml). To this suspension was added tris (hydroxymethyl)aminomethane (0.466 g) at ambient temperature. After one hour, the starting material was dissolved completely. To this solution ether was added and the precipitated crystals were collected by filtration and washed with ether to give tris-(hydroxymethyl)methyl-ammonium 4-oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.63 g).
Reaction SMILES: C([OH:6])/C=C\CC.[H-].[Na+].[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]#[N:12].[C:15]1([CH3:22])[C:16](C)=[CH:17]C=C[CH:20]=1>>[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]([NH:12][CH2:22][C:15](=[CH2:20])[CH2:16][CH3:17])=[O:6]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC/C=C\CO
Reactant: Cc1ccccc1C
Agent: [H-]
Agent: [Na+]
Product: C=C(CC)CNC(=O)C(Cl)(Cl)Cl

Procedure:
Cis-2-pentene-1-ol was treated with NaH and trichloroacetonitrile followed by work up and treatment in refluxing xylene by the method of EXAMPLE 208 to produce the material.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-nitrobenzoic acid (7.40 g), 1-hydroxybenzotriazole (6.59 g), dicyclohexylcarbodiimide (10.90 g), dry N,N-dimethylformamide (74 ml), and morpholine (4.3 ml) was stirred at room temperature for 2 hours. The insolubles were filtered out, and washed with N,N-dimethylformamide. The filtrate and the washing were combined, and concentrated to obtain a yellowish brown solid (16.01 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C-:14]#[N:15].[K+]>CS(C)=O.CCOC(C)=O>[C:14]([CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:15]
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CCC#N)cc1
Reaction time: 20 h

Procedure:
Bromide 23-2 (0.52 g, 2.14 mmol) and KCN (167 mg, 2.57 mmol) were combined in 10 mL DMSO. After 20 h, at RT and 1.5 h at 70° the reaction mixture was diluted with EtOAc, washed with water, sat. NaHCO3, 10 % KHSO4 and brine, dried (MgSO4), and concentrated providing 23-3 as a yellow solid. Rf 0.23 (30% EtOAc/hexanes).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]=1.N>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][N:7]=[CH:6]2)=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: C1=NCCc2ccccc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To concentrated sulfuric acid (70 ml) was added 15 g of potassium nitrate, followed by adding a solution of 18 g (0.14 mol) of 3,4-dihydroisoquinoline in concentrated sulfuric acid (70 ml) at −15 degrees over 20 minutes. After stirring at room temperature for 1 hour, the mixture was heated at 60 degrees for 40 minutes. The reaction mixture was poured onto ice water, and the mixture was basified with aqueous ammonia and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. To the residue were added decalin (100 ml), nitrobenzene (100 ml) and Pd-Black (2 g), followed by heating at 200 degrees in a stream of nitrogen overnight. The reaction mixture was washed with ethyl acetate and extracted with 2 N hydrochloric acid. The aqueous layer was washed with ethyl acetate, followed by adding an aqueous sodium hydroxide. The resulting precipitates were collected by filtration and washed with water, to give 14.4 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: C1COCCN1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-morpholin-4-yl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and morpholine following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][CH2:23][CH2:24][CH:25](NN)[CH2:26][CH2:27][CH3:28].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH2:24]([CH2:25][CH2:26][CH2:27][CH2:28][N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]2)[C:14]1=[O:21])[CH2:23][CH3:22]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: CCCC(CCC)NN
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: CCCCCCCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CC=CC[C@@H]2C1=O

Procedure:
Prepared from compound 3 and 4-heptylhydrazine as described for compound 8. Purified by chromatography and crystallized from petroleum ether (60-80° C.) M.p. 71-73° C.
Reaction SMILES: [OH-].[Li+].[N:3]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[C:19]([F:22])([F:21])[F:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1.O>[N:3]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:19]([F:20])([F:21])[F:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.6 %

Procedure:
Lithium hydroxide (2.83 g, 67.5 mmol, 2 eq.) was added to a solution of methyl 4-piperidin-1-yl-3-(trifluoromethyl)benzoate (9.7 g, 33.7 mmol, 1 eq.) in THF (50 mL) and water (5 mL) and the reaction mixture was stirred at room temperature for 12 hours. The solvent was removed in vacuo and the residue taken up in water. The aqueous layer was washed with DCM, acidified to pH 2 with conc. HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound (3.0 g, 95%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.CCN(CC)CC>ClCCCl>[OH:9][CH:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:2][CH2:3]1)[CH3:8]
Reactant: CC(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
(±)-1-(4-Piperidinyl)ethanol (see reference: WO 9725992A, 12.44 g, 65.7 mmol) in 1,2-dichloroethane (500 mL) was stirred at room temperature and BOC2O (14.36 g, 65.8 mmol) was added followed by Et3N (19 mL, 136 mmol). The stirred mixture was heated at gentle reflux for 15 min and then allowed to cool to room temperature and stirred overnight. The solution was washed twice with 10% citric acid, once with 10% Na2CO3, dried over MgSO4, filtered and concentrated to afford (±)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (14 g, 93% yield) as a light amber oil. 1H NMR (400 MHz, DMSO-d6): δ 4.35 (d, 1H, J=4.8 Hz), 3.92 (m, 2H), 3.32 (m, 1H), 2.59 (m, 2H), 1.68 (m, 1H), 1.47 (m, 1H), 1.34 (s, 9H), 1.25 (m, 1H), 1.08-0.88 (m, 2H), 0.97 (d, 3H, J=6.4 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH2:29]([O:31][CH2:32][CH2:33]I)[CH3:30]>C(#N)C>[CH2:29]([O:31][CH2:32][CH2:33][N:12]1[C:8]([CH3:7])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:30]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Reactant: CCOCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCn1c(C)c(C(=O)OCC)c(-c2ccccc2)c1C(=O)OCC
Yield: 100.8 %

Procedure:
Potassium carbonate (1.82 g, 13.3 mmol) was added to a solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (1.0 g, 3.32 mmol) and 1-ethoxy-2-iodo-ethane (1.98 g, 9.96 mmol) in acetonitrile (20 mL) and the mixture heated at reflux for 72 h. The inorganic salts were filtered off and the filtrate was concentrated in vacuo to afford diethyl 1-(2-ethoxyethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (1.25 g, quantitative).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.Cl.[CH3:21][O:22][NH:23][CH3:24].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>C(#N)C>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:23]([O:22][CH3:21])[CH3:24])=[O:6]
Reactant: CNOC
Reactant: COc1cccc(C(=O)O)c1Br
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COc1cccc(C(=O)N(C)OC)c1Br
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-Bromo-3 methoxy benzoic acid (14.2 g, 61.5 mmol) was dissolved in acetonitrile (250 mL), added with 4-methylmorpholine (13.5 mL, 123 mmol), N-methoxy methanamine hydrochloride (7.19 g, 73.8 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (20.4 g, 73.8 mmol), and stirred for 17 hours at room temperature. 1 N aqueous hydrochloric acid solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 85:15-25:75, V/V) to give the title compound as a colorless oily substance (16.8 g, quantitative).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2nc(Cl)ncc2Br)cc1
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22.0 mmol), 4-methoxyphenol (2.72 g, 22.0 mmol) and potassium carbonate (6.07 g, 44.0 mmol) in DMF (20 ml) was stirred for 24 hours. The mixture was added to water (100 ml) and the solid which separated out was collected by filtration, washed with water (50 ml) and dried under high vacuum to give the product (6.6 g, 96%). NMR: 3.8 (s, 3H), 7.0 (d, 2H), 7.2 (d, 2H), 8.8 (s, 1H).
Reaction SMILES: [C:1](N[C@@H](C(O)=O)CO)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C[N:19]1CCOCC1.[CH2:25]([O:29]C(Cl)=O)[CH:26]([CH3:28])[CH3:27].COCC1C=CC(CN)=CC=1>C1COCC1>[CH3:1][O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:27][CH:26]([CH3:28])[C:25]([NH2:19])=[O:29])=[CH:9][CH:10]=1
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Reactant: CN1CCOCC1
Agent: COCc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COCc1ccc(CC(C)C(N)=O)cc1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 157.9 %

Procedure:
A THF solution (75 mL) of (R)-Cbz-serine (5.30 g, 22.0 mmol) was stirred and cooled at −78° C. under Ar and then 4-methylmorpholine (NMM) (2.9 mL, 26.4 mmol) was added dropwise. After 2 min of stirring at this temperature, isobutylchloroformate (IBCF) (3.5 mL, 26.4 mmol) was added dropwise leading to the precipitation of a white solid, and the reaction was allowed to proceed for additional 2 min. 4-Methoxymethylbenzylamine (4.00 g, 26.4 mmol) was added portionwise at −78° C. and the mixture was stirred at room temperature (2 h). The white solid was filtered and the organic layer was concentrated in vacuo. The residue was triturated with EtOAc resulting in a solid that was filtered and recrystallized with EtOAc to give (R)-2-N-(benzyloxycarbonyl)amino-3-hydroxy-N-(4-methoxymethy (benzyl) propanamide as a white solid (7.20 g, 88%): Rf=0.63 (EtOAc); mp 138-140° C.; [α]25.8D −34.0° (c 1, DMSO); IR (nujol) 3385, 3294, 3106, 2923, 2859, 1690, 1646, 1544, 1458, 1373, 1307, 1243, 1098, 1028, 919, 738, 694 cm−1; 1H NMR (CDCl3) δ 3.36 (s, OCH3), 3.64 (dd, J=5.1, 10.8 Hz CHH′OH), 3.88-4.06 (br d, CHH′OH), 4.19-4.29 (m, CH), 4.34-4.45 (m, CH2OCH3, NCH2), 5.06 (s, CH2O), 6.96 (d, J=7.2 Hz, OC(O)NH), 7.02-7.14 (br s, NH), 7.19 (d, J=7.8 Hz, 2 ArH), 7.27 (d, J=7.8 Hz, 2 ArH), 7.30-7.38 (m, 5 ArH); 13C NMR (CDCl3) δ 43.2 (NCH2), 55.5 (OCH2CH), 58.1 (CH3O), 62.7 (OCH2CH), 67.3 (CH2O), 74.3 (CH2OCH3), 127.6, 128.0, 128.1, 128.3, 128.5, 135.9, 137.0, 137.5 (8 ArC), 156.7 (OC(O)N), 170.7 (C(O)); HRMS (M+H+)(ESI+) 373.1764 [M+H+] (calcd for C20H24N2O5H+ 373.1763); Anal. Calcd. for C20H24N2O5.0.25H2O: C, 63.73; H, 6.55; N, 7.43. Found: C, 63.35; H, 6.43; N, 7.29.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2Br)(=[O:3])[CH3:2].C([N:38]([CH2:41][CH3:42])CC)C.[CH2:43](O)[CH3:44]>>[C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:38][C@@H:41]1[C:42]2[C:9](=[CH:5][CH:6]=[CH:43][CH:44]=2)[CH2:8][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O[C@H]1n1cnc2c(Br)ncnc21
Reactant: CCN(CC)CC
Reactant: CCO
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21

Procedure:
(2R,3S,4R,5R)-2-(6-Bromo-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diyl diacetate (0.402 g, 0.703 mmol) was stirred in ethanol (10 mL) and S-(+)-1-aminoindan (0.14 mL, 1.06 mmol) was added followed by triethylamine (0.2 mL, 1.41 mmol). The reaction mixture was heated at overnight. The brown solution was concentrated and purified by flash chromatography, eluting with 10 to 35% ethyl acetate/hexanes to give the title compound as a white solid (0.142 g) and deacylated product (0.161 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[O-:18][C:19]#[N:20].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:19]([NH2:20])=[O:18])=[CH:11][CH:12]=1
Reactant: N#C[O-]
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N(C(N)=O)c2ccc(OC)cc2)cc1

Procedure:
A solution of 423 mg (1.85 mmol) bis-(4-methoxy-phenyl)-amine in 8 ml acetic acid is treated with 120 mg (1.85 mmol)sodium cyanate. After 4.5 h the reaction mixture is poured onto a solution of 8 g sodium hydroxide in 100 ml water. The resultant precipitate is filtered off and dried.