Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:27]([O:29][CH3:30])=[O:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:27](=[O:28])([O:29][CH3:30])[O:16][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][C:9]=1[C:11]([C:12]#[N:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C#N)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C#N
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of compound 15 (126.6 g, 0.564 mol), DMAP (6.0 g) and DIEA (188 g, 1.46 mol) in anhydrous DCM (1500 mL) was added dropwise methyl chloroformate (110 g, 1.17 mol) in anhydrous DCM (300 mL) at 0° C. within 2 hours. After stirring for 12 hours at 0° C., ice-water (1.5 L) was added and the mixture was stirred at 0° C. for 30 minutes. The organic layer was separated and washed with 1 N HCl, water, and brine. The DCM solution was dried over MgSO4 and concentrated in vacuo to give compound 16 as a yellow solid. 1H NMR (DMSO-d6; 400 MHz) δ 7.47 (m), δ 7.39 (d), δ 7.24 (d), δ 3.84 (s), δ 1.71 (s), δ 1.30 (s).
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[S:45])=[CH:28][C:27]=1[F:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.C[O-].[Na+].CO.S(OC)(O[CH3:22])(=O)=O>CO.O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:22])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1O
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 4-amino-5-chloro-2-hydroxybenzoic acid (1.88 g, 10 mmol) in absolute methanol (20 mL) was treated with 25% sodium methoxide/methanol (2.16 g, 10 mmol), stirred for 30 minutes, and concentrated in vacuo. The solid residue was taken up in anhydrous acetone (30 mL), treated with dimethyl sulfate (1.64 g, 13 mmol),and refluxed for 2 hours. The resultant solution was diluted with water (100 mL), and the precipitate was filtered, washed with water, and dried exhaustively in vacuo to afford 1.75 g (87%) of fine colorless needles. The material was recrystallized from ethyl acetate/hexane; mp 138°-139° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][O:36][CH2:37]Cl.CN([CH:42]=[O:43])C>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:35][O:36][CH3:37])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]1[CH:23]([CH3:24])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:35]([O:36][CH2:37][O:43][CH3:42])=[CH:14][CH:15]=2)[C:10]([C:18]([OH:20])=[O:19])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(OCOC)cc12
Product: COCOc1ccc2c(c1)c(C(=O)O)c(C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid, ethyl ester (Compound 1, 345 mg, 1.0 mmol) in DMF (2 ml) was added diisopropylethylamine (iPr2NEt, 1.7 ml, 10.0 mmol) and chloromethyl methyl ether (MOMCl, 0.38 ml, 5.0 mmol). The mixture was stirred at room temperature for 72 h, and concentrated under vacuum, and purified by flash chromatography on silica gel eluting with 10-20% EtOAc-hexanes to yield 1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indole-3-carboxylic acid, ethyl ester (Compound 2) as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[CH:8]=1)([O-])=O>CCOC(C)=O.CCO.O=[Pt]=O>[N:11]1([CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cnn(CCN2CCc3ccccc32)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnn(CCN2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline (183 mg, 0.71 mmol) in EtOAc (0.7 mL, degassed) and EtOH (2 mL, degassed), PtO2 (14 mg, 0.07 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 18 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as an oil, which was used in the next step without further purification. LC-MS conditions A: tR=0.51 min, [M+H]+=229.26.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:37][C:32]2[CH:33]=[CH:34]C=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NC1(C#N)CC1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:37][C:32]1([C:31]#[N:36])[CH2:34][CH2:33]1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-(3-chloro-4-hydroxyphenyl)propanoic acid (3.86 g, 12.2 mmol, Eq: 1.00) was dissolved in DMF (50 mL). HATU (9.3 g, 24.4 mmol, Eq: 2.00), 1-amino-1-cyclopropanecarbonitrile hydrochloride (1.74 g, 14.7 mmol, Eq: 1.20) and Hunig's Base (3.16 g, 4.27 mL, 24.4 mmol, Eq: 2.00) were added to the obtained suspension. The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was poured into aqueous 0.1M HCl (300 mL), extracted with dichloromethane (3×125 mL), dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 65% AcOEt in n-heptane) to yield a white solid (3.13 g; 67%). m/z=378.1 [M−H]−.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([N:16]=[C:17]=[O:18])[CH:11]=[CH:12][C:13]=1[C:14]#[N:15]>CC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:5][C:3](=[NH:6])[CH3:4])=[O:18])[CH:11]=[CH:12][C:13]=1[C:14]#[N:15]
Reactant: CC(=N)N
Reactant: N#Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(=N)NC(=O)Nc1ccc(C#N)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.06 g. sodium in 250 ml. dry acetone, 9.2 g. acetamidine hydrochloride and 16 g. 3-chloro-4-cyanophenyl isocyanate in 250 ml. dry acetone, there was obtained after filtration of the reaction mixture a solid which on washing with water and recrystallization from methyl alcohol gave 1-(3-chloro-4-cyanophenyl)3 -(acetimidoyl)urea; m.p.182°-183°C.
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O:29]CC)=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3C#N)=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.O[Li].O.[ClH:45]>C1COCC1>[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:45])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(-c5ccccc5)cc4)cc3)c(C#N)cc21
Reactant: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
Ethyl 7-(4-(2-(biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (62.5 mg, 0.1124 mmol) was dissolved in THF (1 ml) and 1M solution of LiOH—H2O (224.8 μL, 0.2248 mmol) was added. The mixture was stirred for 3 days at ambient temperature. The mixture was quenched with 1M HCl solution (400 μL, 0.400 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 48.8 mg of the title compound as a white solid (82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.C(Cl)Cl.[C:19](Cl)(Cl)=[S:20].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]=[C:19]=[S:20])=[N:10][CH:11]=1
Reactant: Nc1ccc(Oc2cccc(F)c2)cn1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1cccc(Oc2ccc(N=C=S)nc2)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 77.2 %

Procedure:
5-(3-Fluorophenoxy)-2-pyridinamine (210 mg, 1 mmol) was dissolved in dry degassed methylene chloride (5 ml) and thiophosgene (0.11 ml, 1.3 mmol) was added through syringe during 5-10 min to the stirred solution. Pyridine (0.18 ml, 2 mmol) was added to the reaction mixture right after the addition of thiophosgene and the reaction mixture was stirred at ambient temperature for 1.5-2 h. Then the reaction mixture was poured into water (15 ml) and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine and dried over magnesium sulfate. Solvent was then removed by rotary evaporation and the oil obtained was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 190 mg of pure product as dark brown-purple solid. Yield 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:62]=[CH:61][C:55]([O:56][CH2:57][CH2:58]CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:58][CH2:57][O:56][C:55]2[CH:61]=[CH:62][C:52]([F:51])=[CH:53][CH:54]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCOc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccc(F)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 74.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (66 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (92 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-fluorophenoxy)-1-propanol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 70%).
Reaction SMILES: N[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH2:10].[CH3:11][Si:12]([CH3:27])([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]1[CH2:20][O:19]1.C([OH:30])C>>[CH3:11][Si:12]([CH3:27])([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]([OH:19])[CH2:20][NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:30]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: NCCOCCOCCN
Reactant: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCCOCCOCCO
Temperature: 70 °C

Procedure:
2-[2-(2-Amino-ethoxy)-ethoxy]-ethylamine (5.40 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 ml RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess raw material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[F:8][C:4]1[CH:5]=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[CH2:10][CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14]1
Reactant: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reaction time: 18 h

Procedure:
To a suspension of 4-(2,6-difluorophenyl)thiomorpholine 1,1-dioxide (Step 1, 300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL, ca. 6 mol, fuming, 90%) is added over 30 minutes at ambient temperature. A yellow precipitate forms within minutes and increases over time. The reaction is kept at room temperature for 18 h and is then poured into 6 L of water. After stirring for 2 h, the yellow suspension is filtered. The precipitate is washed with water (1.5 L×3) and ethanol (0.5 L×2) and dried at 50° C. overnight to give the title compound, 1H NMR (DMSO-d6) δ 8.05 (m, 2H), 3.69 (m, 4H), 3.26 (m, 4H).
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1N1C=CC(=O)NC1=O.[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]2[N:23]=[CH:24][NH:25][C:21]=2[CH:20]=1>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>[Cl:28][C:27]1[C:19]([Cl:18])=[CH:20][C:21]2[N:25]([C@@H:3]3[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@H:2]3[F:1])[CH:24]=[N:23][C:22]=2[CH:26]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: OC[C@H]1O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
2'-Deoxy-2'-fluorouridine, compound 13 (0.99 g, 4 mmol), which can be prepared by the method of Codington et al. (Codington et al., 1968), was dissolved in 800 mL of 50 mM pH 6.0 citrate buffer. 5,6-dichlorobenzimidazole, compound 14 (0.30g, 1.6 mmoles), which can be prepared by the method of Townsend et al. (Townsend et al., 1970), was added and the reaction was placed in a 50° C. water bath. N-deoxyribo-furanosyl transferase (60,000 units; see Cook et al., 1990) was added and the reaction mixture was gently shaken overnight. 5,6-dichlorobenzimidazole, compound 14 (0.30 g, 1.6 mmoles) was added and the reaction continued for 2 days. The enzyme was precipitated by heating to 80° C. followed by cooling to room temperature. Celite® (50-60 g) was added and the reaction mixture filtered. The product was extracted with ethyl acetate (3×). The ethyl acetate was removed in vacuo and the residue purified by chromatography on 75 g of basic alumina eluted with chloroform/methanol (95:5, v/v) followed by (9:1, v/v), then (2:1, v/v), and finally (1:1, v/v). The product containing fractions were combined and the solvents removed in vacuo to give 0.54 g (67%) of compound 15.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23].[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[C:32]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:31]=[C:30]1[CH2:42][C:43]([O-])=[O:44].[Na+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:43](=[O:44])[CH2:42][C:30]2[N:29]([CH3:28])[C:34](=[O:35])[CH:33]=[C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:31]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(Cl)c2)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
120 ml of pyridine, 182 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 210 mg of 3-chloro-4-fluoroaniline are added to a solution of 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 2.5 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature overnight and is then concentrated under reduced pressure. Water is added, followed by extraction with ethyl acetate, further washing with water, and concentration under reduced pressure. The residue obtained is washed with ethyl acetate and then rinsed with ethyl ether. 76 mg of N-(3-chloro-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a violet solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[N:11]([C:13]([CH2:16]O)=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N1C=C(C2C=CC3N(C(CN)=[N:34][N:35]=3)N=2)C=N1)(C)C.C1CCN2C(=[N:42]CCC2)CC1.C1(C)C=CC=CC=1>>[N:42]([CH2:16][C:13]1[N:11]2[N:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=[N:9][C:10]2=[N:15][N:14]=1)=[N+:34]=[N-:35]
Reactant: C1CCC2=NCCCN2CC1
Reactant: OCc1nnc2ncc(-c3ccccc3)nn12
Reactant: CC(C)n1cc(-c2ccc3nnc(CN)n3n2)cn1
Agent: Cl
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1nnc2ncc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 16 mm test tube was charged with (6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanol (0.500 g, 2.20 mmol), Reactant 2 (0.951 ml, 4.40 mmol), DBU (0.663 ml, 4.40 mmol), and toluene (8.16 ml, 77.0 mmol), flushed with argon, sealed, then stirred at room temperature for 3 hours. The dark maroon mixture was concentrated and the resulting dark purple/black oil was purified by column chromatography using a gradient of 3-5% MeOH/DCM over 20 minutes. 3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine was isolated as a brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[NH:9][C:10]=1[CH2:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH:12]1([CH2:11][C:10]2[NH:9][C:8]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[N:7][C:6]=2[C:4]([OH:5])=[O:3])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)c1nc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a suspension of the product of step b (1.73 g, 4.62 mmol) in ethanol (25 ml) was added the solution of sodium hydroxide (1.29 g, 32.3 mmol) in water (5 ml). The reaction mixture was heated under reflux for 48 h, allowed to cool to room temperature and concentrated under reduced pressure. The aqueous solution was diluted with water (30 ml) and acidified to pH=2 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried to afford the product as an off-white solid (1.53 g, 96%). 1H NMR (300 MHz, d6-DMSO) 8.77 (1H, s), 8.24-7.98 (4H, m), 7.64 (2H, m), 2.91 and 2.64 (2H, 2×d), 2.03 (1H, m), 1.69-1.24 (12H, m).
Reaction SMILES: [C:1]([Si:5]1([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][CH2:9][CH:8]([CH2:11]O)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:24][CH2:11][CH:8]1[CH2:9][O:10][Si:5]([C:13]([CH3:16])([CH3:15])[CH3:14])([C:1]([CH3:4])([CH3:3])[CH3:2])[O:6][CH2:7]1
Reactant: CC(C)(C)[Si]1(C(C)(C)C)OCC(CO)CO1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si]1(C(C)(C)C)OCC(CBr)CO1
Temperature: -10 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
Compound 19n (123 mg, 0.5 mmol) was dissolved in dichloromethane (10 mL) and cooled to −10° C. with an ethanol-ice bath. Pyridine (1 mL) was added followed by carbon tetrabromide (220 mg, 0.66 mmol). Triphenylphosphine (174 mg, 0.66 mmol) was added in portions and the solution was stirred at −10° C. for 2 hr then raised to room temperature overnight. Solvent was removed under reduced pressure and residue was applied for silica gel column chromatography (10% ethyl acetate in hexane) to afford compound 20n (130 mg, 84%): 1H NMR δ 4.20 (m, 2H), 3.93 (t, 2H), 3.20 (d, 2H, J=6.19 Hz), 2.39 (m, 1H), 1.04 (s, 9H), 1.01 (s, 9H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4](=O)[CH3:5].[S-:20][C:21]#[N:22].[K+]>O>[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[C:4]([CH3:5])=[N:22][C:21](=[S:20])[N:2]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)C(N)CCCCNC(=O)c1ccccc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC1=NC(=S)N=C1CCCCNC(=O)c1ccccc1
Yield: 25.3 %

Procedure:
A solution of 3-amino-7-benzamidoheptan-2-one hydrochloride (16.39 g, 0.0576 mol) and potassium thiocyanate (7.30 g, 0.0755 mol, excess) in water was heated under reflux for 20 hours. The aquesus phase was decanted off and the organic phase was washed with water, and recrystallised from acetonitrile to give 4-(4-benzamidobutyl)-5-methylimidazole-2-thione (4.18 g, 25%) m.p. 180°-184°.
Reaction SMILES: Cl.[C:2](=[NH:8])(OCC)[CH2:3][CH3:4].Cl.[NH2:10][CH2:11][C:12]#[N:13].[F:14][C:15]([F:23])([F:22])[C:16](=O)[CH2:17][C:18](=O)[CH3:19].C(N(C(C)C)CC)(C)C>ClCCCl.C(OCC)(=O)C>[CH2:3]([C:2]1[NH:8][C:11]2=[N:10][C:18]([CH3:19])=[CH:17][C:16]([C:15]([F:23])([F:22])[F:14])=[C:12]2[N:13]=1)[CH3:4]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: N#CCN
Reactant: CCOC(=N)CC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1nc2c(C(F)(F)F)cc(C)nc2[nH]1
Yield: 46.7 %

Procedure:
Ethyl propionimidate hydrochloride (1.37 g, 10.0 mmol), aminoacetonitrile hydrochloride (0.93 g, 10.0 mmol), 1,1,1-trifluoro-2,4-pentanedione (3.64 mL, 30.0 mmol) and diisopropylethylamine (5.23 mL, 30.0 mmol) were stirred in 1,2-dichloroethane (50 mL) under reflux for 4 hr. Ethyl acetate was added to the mixture, and the mixture was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/70) to give the title compound (1.07 g, 47%).