Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C@H:3]1[O:21][CH3:22].[CH2:23]([C:25]1[NH:29][C:28]([C:30](O)=[O:31])=[N:27][C:26]=1[C:33]([F:36])([F:35])[F:34])[CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:23]([C:25]1[NH:29][C:28]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=3)[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:4][C@H:3]2[O:21][CH3:22])=[O:31])=[N:27][C:26]=1[C:33]([F:35])([F:36])[F:34])[CH3:24]
Reactant: CO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC(C)(C)C)c3)C[C@H]2OC)nc1C(F)(F)F
Yield: 67 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)benzoate obtained in Example (42d) (about 0.26 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (50 mg, 0.24 mmol), WSC hydrochloride (137 mg, 0.71 mmol) and HOBT (32 mg, 0.24 mmol), to obtain 79.7 mg of the title compound as a white solid (67%).
Reaction SMILES: [N:1]1([NH:10][C:11]([C:13]2[C:14]([CH3:26])=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[N:1]1([NH:10][C:11]([C:13]2[C:14]([CH3:26])=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NN1CCc2ccccc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2ccccc21
Yield: 74.2 %

Procedure:
A suspended solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (2,3-dihydro-indol-1-yl)-amide (0.72 mmol) and MnO2 (3.60 mmol) in DCM (10 mL) is stirred at rt for 40 min. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-40% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid indol-1-ylamide (185 mg, 75%) as a solid. MS: 347 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.73 (s, 3H), 6.53 (s, H), 7.03 (d, H), 7.08-7.36 (m, 4H), 7.37-7.75 (m, 2H), 8.04-8.40 (m, 2H), 8.56 (br, H), 8.81 (br, H). IC50=10 nM.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[CH:6]1([CH2:12][C@H:13]2[CH2:15][O:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[NH4+].[Cl-]>CN(C=O)C>[CH:6]1([CH2:12][C@H:13]([OH:14])[CH2:15][S:3][CH2:1][CH3:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCS
Reactant: C1CCC(C[C@H]2CO2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCSC[C@@H](O)CC1CCCCC1
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
Ethanethiol (317 μL, 4.3 mmol) was added to a 60% dispersion in mineral oil NaH (180 mg, 4.5 mmol) slurry in DMF (26 mL) at ambient temperature. After stirring for 15 min, the product from Example 1308C (300 mg, 2.1 mmol) in DMF (2.0 mL) was added to the reaction vessel. After stirring for 30 min, a solution of saturated NH4Cl was added to the mixture followed by extraction with EtOAc (2×). The organics were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes 1:20) to afford a light yellow oil (347 mg, 80%). 1H NMR (CDCl3, 300 MHz) δ0.80-1.00 (m, 2H), 1.12-1.32 (m, 7H), 1.39-1.75 (m, 6H), 1.81 (m, 1H), 2.42 (dd, J=9, 14 Hz, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.74 (dd, J=3, 14 Hz, 1H), 3.76 (m, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>CN(C=O)C.CO.O.C(#N)C>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH2:23]([N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[C:14]([OH:16])=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nnc2ccc3[nH]c(C(=O)O)cc3n12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reaction time: 8 h

Procedure:
The mixture from Step 3 containing 1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.298 g, 1.38 mmol) was mixed in DMF (6 mL) and acetonitrile (6 mL) and was treated with Cs2CO3 (1.8 g, 5.5 mmol) and was stirred for 10 minutes before the addition of benzyl bromide (0.30 mL, 2.5 mmol, Aldrich). The reaction was stirred overnight. Water was added and the product was extracted with three portions of EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM, was used to purify the desired alkylated ester (265 mg). This was stirred with 1.0 M NaOH (10 mL, 10 mmol) and methanol (10 mL) overnight. Some TFA was used to aid in dissolving insolubles and the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.1% TFA). Yield: (44 mg, 7%). LCMS (M+H)+: 307.0.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C.Cl>CN(C)C=O>[C:1]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: -25 °C
Reaction time: 0.58 h

Procedure:
Propionyl chloride (1.8 g) was added dropwise over a period of 15 minutes to a mixture of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (2.0 g) and triethylamine (2.4 g) in dimethylformamide (8 ml) at -30° C. under nitrogen. The reaction mixture was stirred for a further period of 35 minutes at -25° C. and was then poured into 2% hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer was washed with sodium chloride solution and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by chromatography on silica gel using 1% methanol in dichloromethane as eluent to yield the required product as a yellow crystalline solid m.p. 84°-86° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(OCCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of methyl 4-(2-phenylethoxy)benzenepropanoate (0.65 g, 2.3 mmol) in methanol (3 mL) was added 2N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 1 hr. 2N Hydrochloric acid (2.5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.50 g, yield 81%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:18][CH2:17][C:8]2[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH2:1]([N:5]1[CH2:18][CH2:17][C:8]2[N:9]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccc(C)nc1
Reactant: CCCCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2-butyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:5]=1[C:6]([CH:8]([C:16](=[O:18])[CH3:17])C(OC(C)(C)C)=O)=[O:7])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:5]=1[C:6](=[O:7])[CH2:8][C:16](=[O:18])[CH3:17])([O-:3])=[O:2]
Reactant: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 68.9 %

Procedure:
A mixture of crude t-butyl 2-(2-nitro-4-trifluoromethylbenzoyl)-3-oxobutanoate (9.1 g) and 4-toluenesulphonic acid (0.1 g) in dry toluene (100 ml) was stirred and heated at reflux for 3 hours. The cooled mixture was extracted with aqueous sodium hydroxide solution (2M, 2×50 ml) and water (2×50 ml). The combined aqueous extracts were acidified to pH 1 and extracted with ether (3×100 ml). The combined organic layers were washed with water (50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from petroleum spirit (bp 60°-80° C.) to give 1-(2-nitro-4-trifluoromethylphenyl)-butan-1,3-dione (4.6 g) as an off white solid mp 80°-81° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:14])=[CH:5][C:6]2[S:7][CH2:8][C:9](=[O:13])[NH:10][C:11]=2[N:12]=1>C(Cl)Cl.O=[Mn]=O>[CH3:14][C:4]1[C:3]([CH:2]=[O:1])=[N:12][C:11]2[NH:10][C:9](=[O:13])[CH2:8][S:7][C:6]=2[CH:5]=1
Reactant: Cc1cc2c(nc1CO)NC(=O)CS2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc2c(nc1C=O)NC(=O)CS2
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
To a solution of 6-(hydroxymethyl)-7-methyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one (290 mg, 1.38 mmol) in MeCl2 (20 mL) and was added MnO2 (1.2 g, 13.8 mmol). The reaction was vigorously stirred at RT for 12 h and then filtered and the solvent was removed at reduced pressure. Purification provided 176 mg of the desired aldehyde: MS (ES) m/z 209 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[C:16]([CH3:24])=[N:17][C:18]([CH3:23])=[C:19]([Cl:22])[C:20]=1[S-:21].[Na+]>>[Cl:14][C:15]1[C:16]([CH3:24])=[N:17][C:18]([CH3:23])=[C:19]([Cl:22])[C:20]=1[S:21][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1nc(C)c(Cl)c([S-])c1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)c(C)nc(C)c2Cl)s1

Procedure:
Prepared according to the procedure described for example 18 from methyl 5-chloro-4-nitrothiophene-2-carboxylate (300 mg, 1.36 mmol) and sodium 3,5-dichloro-2,6-dimethylpyridine-4-thiolate (282 mg, 1.36 mmol) from above. The titled product was obtained as a solid (380 mg, 77% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.27 (1H, s), 3.83 (3H, s), 2.07 (3H, s), 2.05 (3H, s).
Reaction SMILES: C([O:3][C:4](=[O:38])[C@@:5]([CH3:37])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[CH3:37][C@:5]([O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)[C@](C)(Cc1ccc(OCCc2nc(CCc3ccccc3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(CCc2ccccc2)nc1CCOc1ccc(C[C@](C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
(S)-2-Methyl-3-{4-[2-(5-methyl-2-phenethyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (340 mg, 0.66 mmol) in MeOH (10 mL) was treated with 2N NaOH (10 mL) and warmed to 55° C. After 18 h, the mixture was concentrated under reduced pressure and then acidified with 5N HCl to pH=1. The solution was extracted with EtOAc and then the organic phases dried (MgSO4), filtered and concentrated to a white foam (273 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 7.27-7.15 (m, 9H), 6.95 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.7 Hz, 2H), 6.78 (d, J=7.7 Hz, 2H), 4.10 (t, J=6.2 Hz, 2H), 3.27 (A of ABq, J=13.9 Hz, 1H), 3.13 (B of ABq, J=13.9 Hz, 1H), 3.04 (s, 4H), 2.89 (t, J=6.2 Hz, 2H), 2.26 (s, 3H), 1.41 (s, 3H); MS (EI+) 486.1 (M+H), (EI−) 484.1 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])[CH3:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:9]([CH3:10])=[N:20][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[C:6]=1[CH3:7])=[O:12])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2ccccn2)c1C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
Dissolve 2-acetyl-3-oxobutyric acid ethyl ester (20.74 g, 0.120 mol) and 2-pyridylhydrazine (14.5 mL, 0.133 mol) in acetic acid (160 mL) and stir the mixture for 18 hr. Concentrate, dilute with DCM, wash with saturated sodium bicarbonate, dry (sodium sulfate), filter and concentrate to give 3,5-dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester as an oil (28.6 g, 97%). MS (m/z): 246 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)=[CH:4][CH:3]=1.ClC[C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[NH2:25][C:23]1[C:24]2=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=3)[CH:15]=4)[CH:17]=[C:18]([CH:26]3[CH2:27][CH2:28][N:29]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:30][CH2:31]3)[N:19]2[N:20]=[CH:21][N:22]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 49 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(4-fluorobenzyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethycarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 20 mg (49%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.05 (s, 1 H) 7.89 (s, 1 H) 7.78 (d, 1 H) 7.74 (s, 1 H) 7.33-7.39 (m, 2 H) 7.24 (dd, 1 H) 7.10 (ddd, 2 H) 6.59 (s, 1 H) 5.61 (s, 2 H) 3.79 (d, 2 H) 3.38-3.47 (m, 1 H) 2.97 (td, 2 H) 2.84 (s, 6 H) 2.17 (d, 1 H) 2.14 (s, 1 H) 1.76-1.71 (m, 2 H). LC-MS [M+H]+=513.1, RT=2.57 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2nc(N)c3nc(O)n(Cc4ccccc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 4-methoxybenzyl chloride (0.098 ml, 0.72 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (80 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[N:16]=O)[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]3)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:16][C:15]1[N:14]2[C:10]([S:11][C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=32)=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Nc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Reaction time: 8 h
Yield: 26.7 %

Procedure:
While suspending 9 g of 2-(p-chlorophenyl)-3-nitrosoimidazo[2,1-b]benzothiazole in 200 ml of acetic acid, 6 g of zinc powder was gradually added to the suspension at temperatures below 15° C. Insoluble materials were filtered away and 3 drops of concentrated sulfuric acid were added to the filtrate to form precipitates. After filtering away the precipitates, 20 ml of concentrated sulfuric acid was added to the mother liquor and the mixture was allowed to stand overnight. The crystals which formed were recovered by filtration and added to a mixture of ethyl acetate and water. After adding thereto potassium carbonate followed by stirring, the ethyl acetate layer which formed was recovered, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to form crystals, which were recovered and recrystallized from toluene to provide 2.3 g of 3-amino-2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: C([C@H]1COC(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)=N1)(C)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:46]=[CH:45][C:43](=[O:44])[NH:42][C:40]3=[O:41])[C@H:36]([OH:47])[C@@H:35]2[OH:48])=[CH:27][CH:26]=1.[C:63]1([N:69]=[C:70]=[O:71])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>[Cu](Cl)Cl.C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:46]=[CH:45][C:43](=[O:44])[NH:42][C:40]3=[O:41])[C@H:36]([OH:47])[C@@H:35]2[O:48][C:70](=[O:71])[NH:69][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:29][CH:30]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
The THF solution (2 ml) including 2,6-bis[(4S)-isopropyl-2-oxazoline-2-yl]pyridine (0.05 mmol, 15.2 mg) and copper chloride (II) (0.05 mmol, 6.9 mg) was stirred for a day at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (2 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.5 mmol, 274 mg) and the THF solution (2 ml) of phenyl isocyanate (0.5 mmol, 59.6 mg) are added thereto. After the mixture was continuously stirred for two hours at 0° C., the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 94:6, and the transformation ratio of the reaction was not less than 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1>C(O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: COc1ccccc1OCC1CO1
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCC(N2CCCNC2=O)CC1

Procedure:
A solution of 9 g of 1-(o-methoxy-phenoxy)-2,3-epoxypropane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from ethyl acetate/petroleum ether to yield the 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 130°-133° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[NH2:5].[O:23]=[C:24]1[N:28]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][N:25]1[C:35](Cl)=[O:36].O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:5][C:35]([N:25]2[CH2:26][CH2:27][N:28]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:24]2=[O:23])=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3Cl)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)c(F)c3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A mixture of 3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.250 g, 0.784 mmol) and TEA (0.150 mL, 1.076 mmol) in DCM (5 mL) was treated drop-wise with a solution of Example B2 (0.219 g, 0.941 mmol) in DCM (5 mL), warmed to RT and stirred overnight. The mixture was treated with water, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with MeCN, sonicated and the resulting solid collected via filtration to afford N-(3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (242 mg, 60%). 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 8.18 (t, J=8.9 Hz, 1 H), 7.97 (s, 1 H), 7.25-7.20 (m, 2 H), 6.65 (dd, J=5.7, 2.4 Hz, 1 H), 3.90 (m, 3 H), 3.84 (s, 3 H), 3.81 (m, 2 H), 3.47 (m, 2 H), 3.38 (m, 2 H), 1.77-1.65 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: (M+H+): 515.1.
Reaction SMILES: [CH:1]1([N:4]2[S:8](=[O:10])(=[O:9])[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]1([N:4]2[CH2:5][CH2:6][NH:7][S:8]2(=[O:10])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2)S1(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)NCCN1C1CC1
Reaction time: 2 h
Yield: 165.8 %

Procedure:
400 mg of tert-butyl 5-cyclopropyl-1,1-dioxo-[1,2,5]thiadiazolidine-2-carboxylate were dissolved in 10 ml of CH2Cl2/trifluoroacetic acid 1:1 and left to stand for 2 hours. The volatile constituents were removed in vacuo and coevaporated twice with 50 ml of CH2Cl2 each time. 410 mg of pale yellow oil were obtained and were directly employed further.