Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[O:14]=[CH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([OH:14])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCC(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of 2,5-dibromopyridine (5 g, 21 mmol), in dry toluene (200 mL, 0.1 M) is cooled to −75° C. under a blanket of nitrogen. 2.5 M n-BuLi in hexanes (16 mL, 25 mmol, 1.2 eq) is added drop-wise maintaining a temp less than −73° C. and the reaction mixture is stirred at −73° C. to −78° C. for 2 hours. The mixture is then added to a solution of tert-butyl (3-oxopropyl)carbamate (3.66 g, 21 mmol) in toluene (50 mL) at −78° C. The reaction mixture is stirred at −78° C. for 1 hour, before being allowed to warm slowly to room temperature and stirred overnight. The reaction mixture is quenched with saturated ammonium chloride solution (100 ml) and the toluene phase is separated and concentrated. The crude material is purified by chromatography (0-45% ethyl acetate in heptane) to give the title compound (3.1 g). MS (ESI+) m/z 331.0 [M+H].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 95 %

Procedure:
A stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3.07 g, 15 mmol), tert-butyl piperazine-1-carboxylate (3.35 g, 18.00 mmol) and DIPEA (3.85 mL, 22.50 mmol) in DMF (25 mL) was heated at 100° C. for 1 hour. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was triturated with ether and the solid was collected by filtration, washed with ether and dried under vacuum to afford tert-butyl 4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (5.05 g, 95%) as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[C:47]#[N:48]>>[C:47]([C:46]1[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)#[N:48]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: N#Cc1ccccc1OCCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4C#N)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.105 g of 2-(4-bromobutoxy)benzonitrile are reacted. The title compound is obtained as a colourless oil. Rf=0.18 (2:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14]C(C)(C)[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][CH2:9][CH:10]([CH2:15][OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(COCc2ccccc2)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: OCC(CO)COCc1ccccc1
Yield: 79.6 %

Procedure:
A mixture of 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxane (3.40 g, 14.4 mmol) and a few crystals of p-toluenesulfonic acid monohydrate in 100 mL of methanol was stirred at room temperature for 20 h. The methanol was removed in vacuo and the residual oil purified by column chromatography on silica gel (ethyl acetate) to give 2.25 g (80%) of 2-benzyloxymethyl-1,3-propanediol as a colorless, clear liquid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[N:18]1([CH2:24][CH2:25]O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH2:24][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(OCCN3CCOCC3)cc2)n1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (WO2005/110994, 0.462 g, 2 mmol), 2-morpholin-4-yl-ethanol (0.327 g, 2.5 mmol) and triphenylphosphine (1.05 g, 4 mmol) in THF (5 mL) under a nitrogen atmosphere was treated with diisopropyl azodicarboxylate (0.808 mg, 4 mmol). The reaction mixture was stirred at RT for 16 H, then diluted with diethyl ether. The organic layer was washed with water. The resulting aqueous layer was basified with potassium carbonate and extracted with EtOAc. The resulting organic layer was washed with aq. citric acid solution, and the resulting aqueous layer was basified with potassium carbonate, and extracted with EtOAc (three times). The resulting organic layer was dried (Na2SO4), evaporated to dryness then sonicated with diethyl ether (10 mL) and filtered to give the title compound (0.297 g, 43%) as a white solid. LCMS (Method 5): Rt 0.41, 2.16 min, m/z 345 [MH+]. 1H NMR (400 MHz, CDCl3): δ 7.46-7.39 (2 H, m), 6.98-6.93 (2 H, m), 5.50 (1 H, s), 4.15-4.08 (2 H, m), 3.75 (4 H, t, J 4.5), 3.63 (2 H, bs), 2.83-2.78 (2 H, m), 2.59 (4 H, t, J 4.3), 1.34-1.26 (9 H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](F)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1ccc(F)c2ccccc12
Product: CCOC(=O)c1ccc(N2CCCC2)c2ccccc12
Reaction time: 0.08 h
Yield: 70 %

Procedure:
154BG85-11 (156 mg, 0.7 mmol) was transferred to a Pyrex tube and pyrrolidine (1 mL) was added. The tube was capped and the reaction tube was exposed to microwave irradiation (100° C., 3 min). The microwave exposure was repeated for 5 min at 130° C. The pyrrolidine was evaporated and the reaction mixture was transferred to a separation funnel with ethyl acetate and washed with 2 M NaOH. The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate. The organic phases were collected, dried over Na2SO4, filtered and concentrated to yield 135 mg (70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH:31][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:15])(=[O:30])=[O:29])[CH:23]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: NS(=O)(=O)c1cccnc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1cccnc1

Procedure:
As the starting substances, methyl 4-chloro-2-phenoxycarbonylaminobenzoate and pyridine-3-sulfonamide were used and the same method was applied as in Example 36 to obtain N-(3-pyridine sulfonyl)-N'-(2-methoxycarbonyl-5-chlorophenyl)urea and further to obtain from 1.3 g (3.66 mmol) of N-(3-pyridine sulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 1.1 g of the above-identified compound (yield 88.3%). Properties: colorless crystal, Melting point: >226° C. (decomposition), PMR (δppm, DMSO-d6):7.10 (1H,s), 7.24 (1H,d), 7.73 (1H,t), 7.85 (1H,d), 8.50 (1H,d), 7.93 (1H,d), 9.23 (1H,s), 11.68 (1H,s).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([S:11][CH:12]([CH3:14])[CH3:13])=[C:8]([C:15]([OH:17])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>C(#N)C>[Cl:1][C:2]1[C:10]2[C:9]([S:11][CH:12]([CH3:14])[CH3:13])=[C:8]([C:15]([NH2:20])=[O:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Sc1c(C(=O)O)sc2cccc(Cl)c12
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)Sc1c(C(N)=O)sc2cccc(Cl)c12
Yield: 35 %

Procedure:
A mixture of 4-chloro-3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxylic acid (0.43 g, 1.5 mmol) and 1,1'-carbonyldiimidazole (0.25 g, 1.5 mmol) in 5.0 mL of acetonitrile is stirred at reflux for 2 hours. The cooled reaction solution is added slowly to 20 mL of cold ammonium hydroxide solution. The precipitated solid is filtered, washed with water, and recrystallized from aqueous acetonitrile to give 0.15 g (35%) of product; mp=182°-184° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:12]=1>CN(C=O)C>[CH2:35]([C:13]1[N:12]=[C:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[NH:16][C:15](=[O:17])[C:14]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=1)[CH2:36][CH2:37][CH3:38]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc(N)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: CN(C)C=O
Product: CCCCc1nc(NC(=O)Nc2ccccc2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
0.27 g of phenylisocyanate were added to a solution containing 0.3 g of 2-amino-6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl) -methyl]pyrimidin-4-one in ml of dry DMF at 0° C. After stirring at room temperature for 30 minutes the mixture was evaporated to dryness and the residue was crystallized from DMF; 0.22 g of a white solid was obtained (yield 56%, m.p. 217°-219° C.).
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[H-].[Na+].[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1F)[CH2:9][CH2:10][CH3:11]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:5][CH2:1][C@@H:2]([OH:4])[CH3:3])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Reactant: C[C@H](O)CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)O)sc2ccncc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.2 %

Procedure:
(S)-propane-1,2-diol (52 mg, 0.68 mmol) in THF (1 mL) was treated with NaH (60% dispersion; 27 mg, 0.68 mmol) at room temperature for 20 minutes. The mixture was cooled to 0° C. and a solution of Example 20B (90 mg, 0.23 mmol) in THF (1 mL) was added. The mixture was allowed to warm to room temperature, and stirred for 4 hours. The mixture was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 19 mg (19%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.48 Hz, 3H) 1.28 (d, J=6.41 Hz, 3H) 1.47-1.59 (m, 2H) 1.88-1.98 (m, 2H) 3.87 (t, J=8.85 Hz, 1H) 4.21-4.31 (m, 1H) 4.35 (dd, J=9.15, 2.75 Hz, 1H) 4.51-4.59 (m, 2H) 7.12 (d, J=8.85 Hz, 1H) 7.72 (dd, J=8.54, 2.14 Hz, 2H) 8.51 (d, J=1.83 Hz, 2H) 8.75 (s, 1H); MS (DCI/NH3) m/z 454 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>ClCCl>[CH3:35][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: Cc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (550 mg, 2.30 mM) and triethylamine (0.4 mL) in dry dichloromethane (DCM, 10 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, o-tolyl isocyanate (428 mg/ml, 3.45 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8a as colorless oil. Yield: 700 mg, 81.78%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
In a round-bottomed flask, 4.0 g of 1H-indazole-3-carboxylic acid, 2.6 g of N,O-dimethylhydroxylamine hydrochloride, 9.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 8.4 ml of pyridine are placed in 120 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 20 h. The mixture is concentrated and the residue is taken up in water. The yellow precipitate obtained is washed with water and then dried under reduced pressure. 3.5 g of compound are obtained.
Reaction SMILES: Br[C:2]1[N:3]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[N:5]=2.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][C:2]1[N:3]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[N:5]=2
Reactant: C[O-]
Reactant: Nc1nc(OCC2CCCO2)nc2c1nc(Br)n2C1CCCCO1
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OCC3CCCO3)nc2n1C1CCCCO1

Procedure:
8-Bromo-2-[(tetrahydro-2-furanylmethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.3748 g) was dissolved in methanol (10.2 mL) and treated with 25% (w/v) sodium methoxide in methanol (2.2 mL). This was heated to reflux under nitrogen for 3.5 hours. The reaction mixture was evaporated under reduced pressure to dryness and saturated ammonium chloride solution was added (100 mL). This was then extracted with ethyl acetate (100 mL, 3 times). The organic layers were combined and washed with brine (100 mL) and then dried by passing through a hydrophobic frit after separating the aqueous layer. The organic was evaporated under reduced pressure to give the title compound as white foam (1.1614 g) and used in the next stage without requiring purification.
Reaction SMILES: COC1N=C2N=CN(C3SC(C(OC)=O)=C(O)C=3)C2=CC=1OC.[CH3:24][O:25][C:26]1[N:31]=[C:30]2[N:32]([C:35]3[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[C:37]([OH:44])[CH:36]=3)[CH:33]=[N:34][C:29]2=[CH:28][C:27]=1[O:45][CH3:46].C([O-])([O-])=O.[K+].[K+].Br[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]([F:64])([F:63])[F:62]>CN(C)C=O>[CH3:24][O:25][C:26]1[N:31]=[C:30]2[N:32]([C:35]3[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[C:37]([O:44][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:62])([F:63])[F:64])[CH:36]=3)[CH:33]=[N:34][C:29]2=[CH:28][C:27]=1[O:45][CH3:46]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)nc32)cc1O
Agent: COC(=O)c1sc(-n2cnc3nc(OC)c(OC)cc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)nc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of an isomeric mixture of 1.76 g of methyl 5-(5,6-dimethoxy-1H-imidazo[4,5-b]pyridin-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(5,6-dimethoxy-3H-imidazo[4,5-b]pyridin-3-yl)-3-hydroxythiophene-2-carboxylate (example C7) in 20 ml anhydrous N,N-dimethylformamide were added 0.86 g K2CO3 and 1.51 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene under a nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature, poured into 200 ml of ice water and stirred for 1 h. The solid was filtered, dissolved in acetonitrile and the isomeric mixture was separated and purified by preparative HPLC to yield compound B4a and compound B4b. The structural assignment of compound B4a was unequivocally established by two-dimensional 1H NMR experiments (NOESY, COSY).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[Cl:23][C:24]1[N:25]=[N:26][C:27]([N:30]([CH3:32])[NH2:31])=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:31][N:30]([C:27]3[N:26]=[N:25][C:24]([Cl:23])=[CH:29][CH:28]=3)[CH3:32])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CN(N)c1ccc(Cl)nn1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 3-chloro-6-(1-methylhydrazinyl)-pyridazine (CAN 76953-33-8) as starting materials; LC-MS (UV peak area/ESI) 96.8%, 472.0538 (M+H)+.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:14]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[C:20](=[O:31])[N:19]([CH2:32][CH2:33][CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C:18](=[O:42])[N:17]([CH3:43])[C:16]=2[N:15]=1>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:22]2[C:21]3[C:20](=[O:31])[N:19]([CH2:32][CH2:33][CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[C:18](=[O:42])[N:17]([CH3:43])[C:16]=3[N:15]=[C:14]2[O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:29][CH:28]=1
Reactant: OCCOC1CCCCC1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOC1CCCCC1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 2-(cyclohexyloxy)ethanol (63.4 mg, 0.439 mmol, intermediate 38) in THF (5 mL) was added sodium hydride (23.4 mg, 0.586 mmol, 60% dispersion in mineral oil) at 0° C., and the mixture was stirred at room temperature for 30 min. Then a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.293 mmol, intermediate 14) in THF (1 mL) was added and the resulting mixture was stirred at reflux for 1 h. The reaction was cooled and quenched with ice-water. The mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give 7-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (123 mg, 73% yield) as a yellow solid. LCMS retention time 2.064 min; LCMS MH+-THP 491.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1C=CN[N:12]=1.[CH3:17][C:18]1[N:19]=CN[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[NH:12][CH:17]=[C:18]([CH3:22])[N:19]=1
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Reactant: Cc1c[nH]cn1
Product: Cc1c[nH]c(CC(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that 4-methylimidazole (3.7 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (5% MeOH/CH2Cl2) to yield a light yellow solid.
Reaction SMILES: [CH2:1]1[CH2:8][NH:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Br)[CH:17]=1>CN(C=O)C.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[C:16]([CH2:18][N:7]2[CH2:8][CH2:1][CH2:2][CH2:3][S:4]2(=[O:6])=[O:5])[CH:15]=[N:14][CH:13]=1
Reactant: O=S1(=O)CCCCN1
Reactant: BrCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)CCCCN1Cc1cncc(Br)c1
Reaction time: 0.25 h

Procedure:
To a vial is added 1,4-butanesultam (81 mg, 0.60 mmol) in 2 ml of DMF, followed by the addition of 60% NaH (24 mg, 0.6 mmol) at 0° C. The reaction mixture is stirred for 15 minutes, followed by the addition of To a vial is added 3-bromo-5-bromomethyl-pyridine, Intermediate E (100 mg, 0.40 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 86 mg of 2-(5-bromo-pyridin-3-ylmethyl)-[1,2]thiazinane 1,1-dioxide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=O)[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:28].C(P(=O)(OCC)OCC)#N.Cl.[CH3:40][NH:41][CH3:42].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]([C:21]([N:41]([CH3:42])[CH3:40])=[O:23])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19]2)=[O:11])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: CCCCC(C(=O)O)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N(C)C)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10.4 %

Procedure:
To a solution of 2-[4-({[(6-amino-5-chloro-2-methoxypyridin-3-yl)carbonyl]amino}methyl)piperidine-1-yl]hexanoic acid (500 mg, 1.2 mmol) in dimethylformamide (30 ml) was added diethyl cyanophosphonate (300 mg, 1.8 mmol), N,N-dimethylamine hydrochloride (148 mg, 1.8 mmol) and N,N-diisopropylethylamine (0.63 ml, 3.6 mmol). The mixture was stirred for 72 h at room temperature. The mixture was concentrated in vacuo. The resultant amorphous solid was chromatographed on a column of silica gel eluting with dichloromethane/methanol (20:1) to give 55 mg (10%) of the title compound as a colorless amorphous solid.