Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[S:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1>C(Cl)(Cl)Cl.CO>[C@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[S:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccn([C@@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]1
Yield: 85 %

Procedure:
A solution of 1-(2-deoxy-4-thio-3,5-di-O-toluoyl-β-D-ribofuranosyl)uracil (formula 15) (175 mg, 0.36 mmol) in anhydrous MeOH (30 mL) was stirred at room temperature with a freshly prepared solution of sodium methoxide (39 mg, 0.72 mmol) in MeOH (6.5 mL). A TLC aliquot at 2.5 hours showed complete reaction (CHCl3 -MeOH, 95:5). The solution was rendered neutral with Dowex 50W-X8 (H+) ion-exchange resin, the suspension filtered, and the resin was washed with MeOH. The filtrate was combined and evaporated to dryness, and methyl p-toluate was removed at 50° C./0.01 torr. Crystallization of the residue from absolute EtOH gave pure 2'-deoxy-4'-thiouridine (76 mg, 85%); mp 186°-88° C.; TLC 9:1 CHCl3 -MeOH, Rf 0.30; MS z/e 245 (M+1)+, UV λmax pH 1 266 (9.88), pH 7 266 (9.76), pH 13 266 (8.08); 1H NMR (DMSO-d6, 300 MHz) δ2.10-2.22 (m, 2H, H-2'), 3.20-3.34 (m, 1H, H-4'), 3.52-3.62 (m, 2H, H-5'), 4.36 (s, 1H, H-3'), 5.18 (br s, 1H, OH), 5.30 (br s, 1H, OH), 5.68 (d, 1H, H-5, J=8 Hz), 6.26 (t, 1H, H-1', J=7.0 Hz), 8.0 (d, 1H, H-6, J=8 Hz), 11.34 (br s, 1H, H-3). 13C NMR (DMSO-d6, 300 MHz) δ41.246 (C-2'), 58.981 (C-4'), 60.108 (C-1'), 63.465 (C-5'), 73.438 (C-3'), 102.133 (C-5, J=175.92 Hz), 141.354 (C-6, J=180.75 Hz), 150.615 (C-2), 162.743 (C-4). Anal. Calcd. for C9H12N2O4S: C, 44.25; H, 4.95;N, 11.46; S, 13.12. Found: C, 44.20; H, 4.97; N, 11.42; S, 13.03. 1-(2-deoxy-4-thio-3,5-di-O-toluoyl-α-D-ribofuranosyl)uracil was deprotected in a similar manner as described for 2'-deoxy-4'-thiouridine to provide pure 1-(2-deoxy-4-thio-α-D-ribofuranosyl)uracil (75 mg, 85%), mp 190°-192° C.; TLC 9:1 CHCl3 -MeOH, Rf 0.30; MS z/e 245 (M+1)+, UV λmax pH 1 266 (9.24), pH 7 266 (9.52), pH 13 265 (8.72); 1H NMR (Me2SO-d6, 300 MHz) δ2.0-2.28 (m, 1, H-2'), 2.44-2.54 (m, 1H, H-2'), 3.30-3.38 (m, 1H, H-5'), 3.40-3.48 (m, 1H, H-5'), 3.50-3.56 (m, 1H, H-4'), 4.32 (br dd, 1, H-3', J=2 and 8 Hz), 5.64 (d, 1H, H-6, J=8 Hz), 6.14 (dd, 1, H-1', J=3 and 7.5 Hz), 8.26 (d, 1H, H-5, J=8 Hz); 13C NMR (Me2SO-d6, 300 MHz) δ42.16 (C-2), 60.01 (C-4'), 60.95 (C-1'), 63.57 (C-5'), 74.14 (C-3') 101.16 (C-5, JC,H =175.24 Hz), 142.92 (C-6, JC,H =181.88 Hz), 150.69 (C-2), 162.97 (C-4). Anal. Calcd. for C9H12N2O4S: C, 44.25; H, 4.95; N, 11.46; S, 13.12. Found: C, 44.17; H, 4.97; N, 11.39; S, 13.21.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:35][NH2:36]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:35][NH:36]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccccc5Cl)c[nH]4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc(-c4ccccc4Cl)c[nH]3)C2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
A mixture of 4-(2-amino-6-{2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-4-pyrimidinyl)-2-fluorobenzonitrile (50 mg, 0.105 mmol) and hydrazine (0.167 mL, 5.25 mmol) in ethanol (2 mL) was heated at 120° C. under microwave conditions with stirring for 1 hour. The reaction mixture was filtered and concentrated, and the resulting residue dried in vacuo to afford the title compound (40 mg) as a yellow solid. LC-MS (ES) m/z=488 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.10-3.16 (m, 1H), 3.22-3.28 (m, 1H), 3.71-3.76 (m, 1H), 4.04-4.07 (m, 1H), 4.30-4.34 (m, 1H), 4.65-4.68 (m, 1H), 4.73 (m, 1H), 5.38 (s, 2H), 6.20 (s, 2H), 6.71 (s, 1H), 7.21-7.25 (m, 1H), 7.33-7.37 (m, 1H), 7.46-7.48 (m, 1H), 7.60-7.63 (m, 1H), 7.69-7.73 (m, 2H), 7.99 (s, 1H), 8.11-8.13 (m, 1H), 11.52 (s, 1H), 12.53 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:7][CH:6]([CH2:8][OH:9])[CH:5]([OH:10])[CH:4]1[OH:11].C(N(CC)CC)C.[C:19]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([CH:8]([OH:9])[C@H:6]1[O:7][C@@H:3]([O:2][CH3:1])[C@H:4]([OH:11])[C@@H:5]1[OH:10])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC1OC(CO)C(O)C1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a mixture of methyl-β-D-ribofuranoside (460 mg, 2.8 mmol, Sigma, St. Louis, Mo.) and anhydrous methylene chloride (20 ml) were added triethylamine (0.468 ml, 3.36 mmol), t-butyldiphenylchlorosilane (0.9 ml, 3.46 mmol), and DMAP (13.7 mg, 0.112 mmol) successively at room temperature. The reaction mixture was stirred at room temperature for 18 h under nitrogen. It was washed with water (20 ml), saturated ammonium chloride (20 ml), and brine (20 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (CHCl3 --MeOH, 50:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside (618 mg, 54.8%) as a thick syrup. 1H NMR (DMSO-d6) δ0.96 (s, 9H, t-Bu), 3.22 (s, 3H, --OCH3), 3.61 (dd, J=11.0 and 5.3 Hz, 1H), 3.74 (d, J=4.4 Hz, 1H), 3.81 (dd, J=11.0 and 2.7 Hz, 1H), 3.90 (m, 1H), 4.00 (m, 1H), 4.68 (s, 1H, H-1'), 4.84 (br s, 1H, exchangeable with D2O, OH), 5.05 (br s, 1H, exchangeable with D2O, OH), 7.45 and 7.67 (m, 10H, Ph2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](I)[CH3:24]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:23][CH3:24])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Product: CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 73 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and ethyl iodide (0.12 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.24 g, 73%) as a colorless oil.
Reaction SMILES: C([Cl:4])(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:28][CH2:27][CH2:26][C:13]3([CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][CH2:14]3)[CH2:12]2)=[CH:7][CH:6]=1>C(O)C>[ClH:4].[ClH:4].[ClH:4].[N:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:28][CH2:27][CH2:26][C:13]3([CH2:14][CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCCN(c3ccncc3)C2)C1
Reactant: CC(=O)Cl
Solvent: CCO
Product: Cl
Product: c1cc(N2CCCC3(CCCNC3)C2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The synthesis was carried out analogously to the synthesis of amine AMN-07. For this, in step (i) tert-butyl 2,8-diazaspiro[5.5]undecane-2-carboxylate was reacted with 4-chloropyridinium chloride (yield: 66%). The Boc protective group was then split off. In step (ii), ethanol (8 ml) and acetyl chloride (0.45 ml, 6.335 mmol) were added to tert-butyl 8-(pyridin-4-yl)-2,8-diazaspiro[5.5]undecane-2-carboxylate (0.42 g, 1.267 mmol) and the mixture was stirred at room temperature for 12 h. When the reaction was complete, the solvent was removed in vacuo. Yield: 0.39 g (90%)
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:24])C.[Na+].C(N(CC)CC)C>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:24])[CH2:15][CH2:16]1
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.1 %

Procedure:
To 21.1 mg (0.072 mmol) of 1-methyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2-one in 1.5 mL of DCE was added 21.2 mg (0.072 mmol, 1 eq.) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide, 19 mg (0.09 mmol, 1.25 eq.) of sodium triacetoxyborohydride and 12 μL (0.086 mmol, 1.2 eq.) of triethylamine. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (DCM/MeOH: 0 to 100) and redissolved in 1 mL of methanol and 100 μL of HCl (1N). The solution was then concentrated in vacuo and diluted with 2 mL of water to give after lyophilization 17.5 mg (40%) of 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[1-methyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide hydrochloride.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.ClC1C(Cl)=CC2=NC(=O)N=C2C=1.C(O[C@@H:29]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]1[O:31][C:32](=[O:34])[CH3:33])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Br:1][C:2]1[N:3]([C@@H:29]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]2[O:31][C:32](=[O:34])[CH3:33])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C1N=c2cc(Cl)c(Cl)cc2=N1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (7) (47.867 g, 180 mmol) in 540 mL of dry MeCN, was added 45 mL (180 mmol) of BSA. The reaction mixture was stirred at room temperature for 15 min to give a clear solution. A small amount of solid impurity remained unsilylated, believed to be 5,6-dichlorobenzimidazol-2-one from the starting material(7). 1,2,3,5-Tetra-O-acetyl-β-D-ribofuranose (60.14 g, 189 mmole) was added to this solution and then TMSOTf (38.267 mL 198 mmol) was added dropwise over 20 min. After the addition had been completed, stirring was continued at room temperature for 30 min. The reaction mixture was diluted with 2 L of EtOAc. The EtOAc solution was washed with 1:1 saturated aquenous NaHCO3 /saturated aquenous NaCl (1.5 L×2), dried (Na2SO4, 100 g), decolorized (activated charcoal, 6 g), and filtered through Celite. The filtrate was evaporated and the residue was recrystallized from MeOH to give 82.21 g (4 crops, 87%) of 52a as white needles. MP: 140°-144° C. This product was pure by 1H NMR.
Reaction SMILES: [P:1](=[S:17])(Cl)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[NH2:19][NH2:20].NN>>[P:1](=[S:17])([NH:19][NH2:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: S=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: NNP(=S)(Oc1ccccc1)Oc1ccccc1
Yield: 84 %

Procedure:
O,O-Diphenyl phosphorochloridothioate, (PhO)2P(S)Cl, (38 g, 0.13 mole) was added slowly to hydrazine hydrate, (25 g of 60% solution ≅0.47 mole hydrazine) at 65°-75° C. The mixture was allowed to cool slowly and the solid product was then recovered by filtration, washed with water and dried. Recrystallization from benzene/petroleum ether (1:1) gave 30.5 g product (84% yield) melting at 59°-61° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16])([CH3:8])([CH3:7])[CH3:6].[CH:17](OCC)(OCC)[O:18]CC.Cl>ClC1C=CC=CC=1>[C:5]([C:9]1[C:10]([OH:16])=[CH:11][C:12]([CH3:15])=[C:13]([CH:14]=1)[CH:17]=[O:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc(O)c(C(C)(C)C)cc1C=O
Temperature: -10 °C
Reaction time: 6 h

Procedure:
Aluminum chloride (26.6 g, 200 mmol) was added to chlorobenzene (40 mL), and the mixture was cooled to −10° C. A solution of 2-tert-butyl-5-methylphenol (16.4 g, 100 mmol) in triethyl orthoformate (32.5 g, 220 mmol) was added dropwise. When addition was complete, the reaction mixture was warmed to 0° C. to 5° C. and kept at that temperature for 6 hours. Five percent HCl (100 mL) was added, and the mixture was extracted with 1:1 EtOAC:toluene. The organic phase was extracted with 23% KOH (3×50 mL) and water (25 mL), and the water extract was combined with the KOH extracts. The pH of the combined aqueous extracts was adjusted to 4 with 37% HCl. The resulting precipitate was filtered, washed with water (3×50 mL), and dried to give the title compound, mp 171-171° C.
Reaction SMILES: Cl.[NH2:2]O.[C:4](=[O:7])([O-])[OH:5].[Na+].[F:9][C:10]1([F:50])[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH2:48][CH3:49])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.O>CS(C)=O>[F:50][C:10]1([F:9])[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:2][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH2:48][CH3:49])=[CH:21][CH:22]=2)[CH2:14][CH2:15]1
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC(F)(F)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(F)(F)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
A suspension of hydroxylamine hydrochloride (661 mg) and sodium hydrogen carbonate (941 mg) in dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, and then 4′-[(1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (635 mg) was added to the mixture, and the mixture was stirred at 90° C. for 12 hr. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 mL), and then 1,1′-carbonyldiimidazole (272 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (0.25 mL) were added thereto. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was successively washed with water and saturated brine (20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow amorphous solid (12.1 mg, 2%).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH:29][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2cc(N)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(NS(C)(=O)=O)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.9 %

Procedure:
To a solution of 2-(4-tert-butylbenzoylamino)-5-amino-N-(4-methoxyphenyl)benzamide (150 mg, 0.36 mmol) in methylene chloride (5 mL) cooled to 0° C. was added pyridine (32 μl, 0.40 mmol) followed by methanesulfonyl chloride (31 μl, 0.40 mmol). After 5 min, the reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate/70% methylene chloride) to give 130 mg (73%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:8][C:7]=1[S:26]([NH-:29])(=[O:28])=[O:27].N1C=CC=CC=1.[C:36](Cl)(Cl)=[O:37]>ClCCCl>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:8][C:7]=1[S:26]([N:29]=[C:36]=[O:37])(=[O:27])=[O:28]
Reactant: O=C(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S([NH-])(=O)=O)c(Cl)cc2F)c1=O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)N=C=O)c(Cl)cc2F)c1=O
Temperature: 60 °C

Procedure:
At 60° C., 7.4 g (62.3 mmol) of thionyl chloride were added dropwise with stirring to a suspension of 10.0 g (24.9 mmol) of 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]-benzenesulfonylamide in 1,2-dichloroethane. The mixture was then boiled under reflux for 4 h. The mixture was then cooled to 60° C., a catalytic amount of pyridine was added and phosgene was introduced under reflux for 12 h until a clear solution was obtained. After cooling to 30° C., the product was freed from the solvent. This gave 11.6 g (98% of theory) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:20]([C:15]1[C:14]([CH2:13][O:12][C:9]2[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=2)=[C:18]([CH3:19])[O:17][N:16]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OCC)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1noc(C)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (960 mg, 3.0 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (252 mg, 6.0 mmol) in water (10 mL) and the resulting mixture stirred at room temperature for 30 min. The mixture was acidified to pH 1 with HCl (1 N) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (850 mg, 87%) which was obtained as a red gum. MS: m/e=290.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH:10](=[N:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][CH3:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Cl-:1].[CH:10](=[N:17][N+:18]1[CH:22]=[CH:21][N:20]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:19]=1[CH2:23][CH3:24])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCc1nccn1N=Cc1ccccc1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CC#N
Product: CCc1n(Cc2ccc(Cl)cc2)cc[n+]1N=Cc1ccccc1
Product: [Cl-]

Procedure:
1.61 g (10 mmol) of p-chlorobenzyl chloride are added to a solution of 1.99 g (10 mmol) of 1-(benzylidene)amino-2-ethylimidazole in 10 ml of acetonitrile. After heating under reflux for 24 hours the precipitated product is filtered off and recrystallized from ethanol/ether. There is obtained 1-(benzylideneamino)-3-(p-chlorobenzyl)-2-ethylimidazolium chloride of melting point >200°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].C(N(CC)C(C)C)(C)C.[CH3:20][O:21][CH2:22]Cl.[C:24]([O:27][CH2:28]C)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.Cl>[CH3:20][O:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:24][O:27][CH3:28])[C:3]=1[CH:4]=[O:5]
Reactant: CCOC(C)=O
Reactant: O=Cc1c(O)cccc1O
Reactant: COCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(OCOC)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
2,6-Dihydroxybenzaldehyde (75 mg, 0.54 mmol) was placed in a 20 mL reaction vessel, and dissolved in 1.6 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), 4-dimethylaminopyridine (4 mg, 0.03 mmol), and chloromethyl methyl ether (103 μL, 0.68 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with 25 mL of ethyl acetate and 5 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a pale yellow oil (96.9 mg, 79%).
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:30])[CH2:24]4)=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>ClCCl>[C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][C@H:25]([CH3:30])[N:26]([C:46](=[O:48])[CH3:47])[C@H:27]([CH3:29])[CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cccc(O[Si](C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1[C@H](C)CN(Cc2cc3nc(-c4cccc(O[Si](C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)C[C@@H]1C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-6-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (80 mg, 0.14 mmol) in dichloromethane (5 mL) was added triethylamine (40 μL, 2.0 equivalents) followed by acetyl chloride (15 μL, 1.5 eq.). After stirring overnight, the reaction mixture was diluted with dichloromethane, washed with aqueous sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo to yield 1-((2R,6S)-4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl}-2,6-dimethyl-piperazin-1-yl)-ethanone (80 mg) as a white solid. Removal of the tert-butyldimethylsilyl protecting group was performed as described above to yield the title compound.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])[CH3:4].O1CCOCC1>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: CC(=O)c1ccco1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Bromine (71.14 ml, 1.39 mol) is added dropwise over 1 hour to a solution of 117.59 g (1.07 mol) of 2-acetylfuran (1) in a mixture of 900 ml of either and 400 ml of 1,4-dioxane, at 0° C. under a nitrogen atmosphere. The reaction is warmed to ambient temperature and stirred for 18 hours, then quenched with 1.1 liter of saturated aqueous ammonium chloride and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dark oil. Flash-chromatography on neutral silica gel using chloroform as eluent followed by distillation using a Kugelruhr apparatus gives 190.81 g (94%) of compound 2 as a light yellow oil, boiling point 85° C. (0.30 mmHg).