Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]([CH3:38])([CH2:36][OH:37])[CH2:34][OH:35]>C1COCC1>[OH:35][CH2:34][C:33]([NH:32][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)([CH3:38])[CH2:36][OH:37]
Reactant: CC(N)(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 72 h

Procedure:
The product of Example 48 (300 mg, 0.67 mmol) and 2-amino-2-methyl-1,3-propanediol (158 mg, 1.5 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-25% EtOAc/CH2Cl2. Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 158-160°, LC MS m/z=471 (MH+) Retention time=1.75 min.
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].O.[OH:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[N:19][OH:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[OH:10][C@H:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:12](=[N:19]/[OH:20])/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ON=C(c1ccccc1)C(O)c1ccccc1
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: c1ccccc1
Solvent: O
Product: O/N=C(\c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
2.00 g (17.5 mmol) of (1R,2R)-(-)-1,2-cyclohexanediamine of α!D20 =-36.7° (c 4.14, H2O) and 4.00 g (17.6 mmol) of dl-1-hydroxy-2-hydroxyimino-1,2-diphenylethane were added to 10 ml of benzene and then heated and stirred, and the solution was cooled to room temperature. Afterward, the precipitated crystals were collected by filtration and then recrystallized from 30 ml of benzene twice to obtain 2.30 g of (1R,2R)-(-)-1,2-cyclohexanediamine·(R)-(-)-(E)-1-hydroxy-2-hydroxyimino-1,2-diphenylethane. Physical properties of the product are as follows.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[C:12]([O:16][C:17]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25](=[O:45])[CH2:26][N:27]([CH2:41][C:42]([OH:44])=O)[C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].ON1C2N=CC=CC=2N=N1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH2:61].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH:61][C:42]([CH2:41][N:27]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][CH:33]=1)[CH2:26][C:25]([N:22]1[CH2:23][CH2:24][C@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:21]1)=[O:45])=[O:44]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2ccc(Oc3ccccc3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)NCc2cccc(Cl)c2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (144 mg, 0.75 mmol) was added to a solution of [[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]acetic acid 20 (176 mg, 0.37 mmol), 1-hydroxy-7-azabenzotriazole (103 mg, 0.76 mmol), 3-chlorobenzylamine (0.092 mL, 0.76 mmol) and N-methylmorpholine (0.11 mL, 1.02 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature and then diluted with ethyl acetate and washed with 10% hydrochloric acid (×2), brine, saturated aqueous sodium bicarbonate (×2) and then brine, dried (Na2SO4) and evaporated onto silica gel. Flash column chromatography, using ethyl acetate as the eluent, gave the title compound as a hard foam (159 mg, 71%). 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.55 (3H, s), 1.8-2.4 (2H, m), 3.35-3.90 (5H, m), 3.95-4.40 (4H, m), 4.55-4.70 (2H, m), 6.48 (2H, m), 6.75-7.05 (6H, m), 7.12 (3H, m), 7.25 (2H, m) and 9.81 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:32][C@H:33]1[CH2:35][C@H:34]1[NH2:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:36][C@@H:34]1[CH2:35][C@@H:33]1[F:32])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccc(Cl)nc1Cl
Reactant: N[C@@H]1C[C@@H]1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN[C@@H]1C[C@@H]1F)C(=O)c1ccc(Cl)nc1Cl
Temperature: -15 °C

Procedure:
Next, this crude ethyl 2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate (2.11 g, 6.62 mmol) and the para-toluenesulfonic acid salt of 2-(S)-fluoro-1-(R)-cyclopropylamine (2.45 g, 9.91 mmol) were suspended in dichloromethane (30 ml), and triethylamine (2.77 ml, 19.87 mmol) was added dropwise gradually thereto while stirring at −15° C. After completion of dripping, the reaction solution was stirred at room temperature for 15 hours. After adding ethyl acetate (100 ml) to the reaction solution, the organic layer was washed with a 10% aqueous citric acid solution (80 ml), saturated sodium bicarbonate water (80 ml), and saturated saline solution (80 ml), in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and 2.10 g (90%, 2 processes) of the title compound was thereby obtained as a yellowish-brown, oily substance (E/Z mixture). This resulting substance was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1.P([O-])(O)(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][CH2:6][C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(CO)o1
Reactant: CC(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C=O)o1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
10.05 ml of acetyl chloride were added at 5° C. to a solution of 16.2 g of 5-hydroxymethyl-2-furancarboxaldehyde and 200 ml of methylene chloride and 11.4 ml of pyridine and 50 ml of methylene chloride were then added. The reaction mixture was stirred for 3 hours at 20° C. and the reaction mixture was treated with an aqueous sodium dihydrogenphosphate solution and extracted with methylene chloride. The extract was dried and concentrated to obtain 19.35 g of the desired product after chromatography on silica by eluting with a hexane/ethyl acetate (7/3) mixture.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Br:21].CN([CH:25]=[O:26])C.[Cl-].[NH4+]>C1COCC1>[Br:21][C:15]1[C:14]([CH3:13])=[CH:19][C:18]([F:20])=[C:17]([CH:16]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(F)c(C=O)cc1Br
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (2.5 mL, 19.1 mmol) was dissolved in THF (24 mL) and the solution was cooled to −70° C., then the solution was added with n-butyllithium (1.57 mol/L hexane solution, 12 mL, 19.1 mmol), followed by stirring for 10 minutes. After warmed to room temperature, the mixture was cooled to −70° C. again and a solution of 2-methyl-4-fluorobromobenzene (3.0 g, 15.9 mmol) in THF (4 mL) was added dropwise thereto. After stirring for 15 minutes, the mixture was added with DMF (1.9 mL, 23.8 mmol) and warmed to 0° C., followed by stirring for 20 minutes. The reaction mixture was added with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-bromo-2-fluoro-4-methylbenzaldehyde as a crude product. In a similar manner to Reference Example 2, 2-amino-6-bromo-7-methylquinazoline (2.0 g, 50%) was obtained using the above-obtained 5-bromo-2-fluoro-4-methylbenzaldehyde. In a similar manner to Reference Example 3 and Reference Example 4, Compound A11 was obtained using the above-obtained 2-amino-6-bromo-7-methylquinazoline.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[N:8]=1)=O.O.[NH2:23][NH2:24]>C(O)C>[CH3:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:5]3[C:4]([CH2:17][CH2:18][CH3:19])=[C:3]([S:2][CH3:1])[NH:24][N:23]=3)=[N:8][C:9]=2[CH:15]=1
Reactant: CCCC(C(=O)c1nc2cc(C)ccc2[nH]1)=C(SC)SC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCc1c(-c2nc3cc(C)ccc3[nH]2)n[nH]c1SC

Procedure:
A mixture of 2-(bis-methylsulfanyl-methylene)-1-(5-methyl-1H-benzoimidazol-2-yl)-pentan-1-one [˜0.49 mmole, Reference Example 2(l)] and hydrazine hydrate (200 μL) in ethanol (6 mL) was heated at reflux temperature for 2 days, then evaporated. The mixture was then treated with hydrochloric acid (4 mL, 4N) and heating was continued at reflux temperature for a further 24 hours. The reaction mixture was cooled, then neutralised by addition of sodium hydroxide solution (4N) and then extracted with dichloromethane. The extract was evaporated to give 5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole. MS: 287 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: CNCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC1CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 0.1 g of (4-bromo-phenyl)-[4-(6-methylamino-hexyloxy)-phenyl]-methanone, 0.13 ml of diisopropylethylamine and 0.06 ml of bromomethyl-cyclopropane in 20 ml of dimethyl-acetamide is stirred at 50° C. for 24 hrs., concentrated and the residue is treated with sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. The residue is purified over silica gel with CH2Cl2 /MeOH/NH4OH (94/5.410.6 to 85/12.5/2.5). There is obtained 0.68 g of (4-bromo-phenyl)-[4-[6-(cyclopropylmethyl-methyl-amino)-hexyloxy]-phenyl]-methanone which is converted into the fumarate, MS: m/e 443 (M+H+, 1Br).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[CH:9][CH:8]=1>C(O)(=O)C>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH:23][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:9][CH:8]=1
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Reactant: ClCC1CO1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Epichlorohydrin (84.5 mL, 1.08 mol) was added to a solution of 1,4 -diaminoanthraquinone (Aldrich Chemical Company, Milwaukee, Wis.) (10 g, 42 mmol) in glacial acetic acid (200 mL) at room temperature. The solution was stirred for 30 minutes at 90° C. and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH2Cl2 :MeOH/25:1) and recrystallized from CH2Cl2 -Ether-Hexanes to give a pure blue solid of the title compound (12.46 g, 70%), mp 167°-169° C.: 1H NMR (CDCl3) δ3.21 (broad, 2H, OH) , 3.5-3.6 (m, 6H, CHCH2), 3.75 (d, J=3 Hz, 4H, CH2), 4.19 (broad, 2H, NH), 7.03 (d, J=3.2 Hz, 2H, ArH (2, 3)), 7.69 (m, 2H, ArH (6, 7)), 8.27 (m, 2H, ArH (5, 8)). Anal. Calcd for C20H20O4N2Cl2 ×0.25 H2O: C, 56.15; H, 4.83; N, 6.55. Found: C, 56.18; H, 4.76; N, 6.29.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[CH:4]=[C:5]([C:8]([NH:10][N:11]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[O:9])[NH:6][CH:7]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F.N1CCCNC1=O.[O:38]=[C:39]1[C@@H:42]([NH:43][C:44](=[O:53])[O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:41][NH:40]1.Cl[S:55]([N:58]=[C:59]=[O:60])(=[O:57])=[O:56].Cl>C(OCC)(=O)C.ClCCl>[OH:1][C:2]1[C:3](=[O:18])[CH:4]=[C:5]([C:8]([NH:10][N:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:55]([NH:58][C:59]([N:40]3[CH2:41][C@H:42]([NH:43][C:44](=[O:53])[O:45][CH2:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:39]3=[O:38])=[O:60])(=[O:57])=[O:56])[C:12]2=[O:17])=[O:9])[NH:6][CH:7]=1
Reactant: O=C(NN1CCCNC1=O)c1cc(=O)c(O)c[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: Cl
Agent: O=C1NCCCN1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.73 g (10.82 mmol) 1,4-dihydro-5-hydroxy-4-oxo-N-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)-2-pyridinecarboxamide and 8.63 g (43.29 mmol) N-methyl-N-trimethylsilyltrifluoroacetamide were dissolved in ethyl acetate and stirred for 1 hour (solution A). To a suspension of 2.38 g (10.82 mmol) (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 80 ml ethyl acetate was added 1.53 g (10.82 mmol) chlorosulfonyl isocyanate. After stirring for 1 hour, the solution was cooled to 0° C. and 9 ml dichloromethane and subsequently solution A were added. After stirring overnight at room temperature ice water was added and the pH was adjusted to 1.3 with 3N hydrochloric acid. The precipitate was filtered off, washed with water, dried in vacuo and slurried with ether. Yield 4.95 g, melting range 150°-230° C. (dec.).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:15](Cl)=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:17][CH3:18])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[K+].[H][H]>CO.[C].[Pd]>[CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:17][CH3:18])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COc1cc(NC(=O)C2CC2)c(Cl)cc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NC(=O)C2CC2)ccc1C(=O)O

Procedure:
A 2.0 g portion of 4-cyclopropylcarbonylamino-5-chloro-2-methoxybenzoic acid and 856 mg of potassium hydroxide were dissolved in 30 ml of methanol, and 600 mg of 10% palladium-carbon powder was added, followed by stirring at room temperature for 9 hours in an atmosphere of hydrogen. The reaction solution was filtered, and the filtrate was concentrated under a reduced pressure, diluted with 1N hydrochloric acid aqueous solution and then extracted with chloroform. The organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under a reduced pressure and the resulting residue was washed with diethyl ether to give 1.60 g of 4-cyclopropylcarbonylamino-2-methoxybenzoic acid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8](/[C:10](=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])/[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH:13][S@@:14]([C:16]([CH3:17])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](N[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Reaction time: 2 h

Procedure:
To a chilled (−78° C.) solution of (R)-2-methyl-propane-2-sulfinic acid[1-(5-methanesulfonyl-furan-2-yl)-prop-(E)-ylidene]-amide (0.360 g, 1.18 mmol) in THF (15 mL) was added a 1 M solution of L-Selectride (2.4 mL, 2.4 mmol) in THF in several portions. After stirring for 2 hours, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(5-methanesulfonyl-furan-2-yl)-propyl]-amide.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(C)C.CC(OC)(C)C>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4)CC3)c(=O)oc2c1
Yield: 50 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 1-phenylpiperazine; yield 50%; m.p. 112°-114° C. (from isopropanol/TBME).
Reaction SMILES: O=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[CH:10][C:5]=2[O:4][CH2:3]1.[C:16]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].[C:39]1(C)C=CC=C[CH:40]=1>>[CH2:39]([O:18][C:16](=[O:17])[CH2:19][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[CH:10][C:5]=2[O:4][CH:3]=1)[CH3:40]
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: CC(=O)OCc1ccc2c(c1)OCC2=O
Product: CCOC(=O)Cc1coc2cc(COC(C)=O)ccc12
Temperature: 25 °C

Procedure:
To a solution of acetic acid 3-oxo-2,3-dihydro-benzofuran-6-ylmethyl ester (1.50 g, 7.27 mmol) in toluene (260 mL) was added (caboxymethylene)triphenyl phosphorane (12.67 g, 36.37 mmol) and the mixture was refluxed for 24 h. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was purified by column chromatography (ethylacetate:hexane; 5:95) to give the (6-acetoxymethyl-benzofuran-3-yl)-acetic acid ethyl ester as a off white solid (1.15 g, 57%). 1H NMR (CDCl3, 400 MHz) 1.27 (t, J=7.1 Hz, 3H), 2.11 (s, 3H), 3.69 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 5.21 (s, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 13C NMR (CDCl3, 100 MHz) 14.2, 21.0, 29.9, 61.1, 66.4, 111.6, 113.1, 119.8, 123.1, 127.7, 132.6, 143.5, 155.2, 170.5, 170.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=S)=[C:5]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:4]=1)#[N:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[C:5]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1NC(=S)Nc1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reaction time: 0.42 h
Yield: 104.1 %

Procedure:
To a solution of N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)thio urea (3.4 g, 7.4 mmol) in methylene chloride (40 mL) at 0° C. was added triethylamine (3.1 mL, 22 mmol), DMAP (20 mg) and methane sulfonyl chloride (1.1 mL, 15 mmol). After 25 min, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3.3 g (100%) of N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide as a yellow solid which required no further purification. 1H NMR (400 MHz, DMSO) δ 7.7 (d, 1H), 7.45 (d, 1H), 7.4 (m, 4H), 7.15 (t, 1H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:42][N:43]1[CH2:48][CH2:47]N[CH2:45][C:44]1=[O:49].[CH3:50]CN(CC)CC>CN1C(=O)CCC1.C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]2[S:21][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=[C:8]4[C:6]3[N:7]=[C:2]([CH:50]4[CH2:47][CH2:48][N:43]([CH3:42])[C:44](=[O:49])[CH2:45]4)[CH:3]=[CH:4][CH:5]=3)=[N:18][N:19]=2)=[CH:25][CH:26]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(F)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Reactant: CN1CCNCC1=O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(C5CCN(C)C(=O)C5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 150 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-fluoropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (300 mg, 0.512 mmol) and 1-methylpiperazin-2-one (117 mg, 1.024 mmol) in NMP (5 mL) followed by Et3N (214 μL, 1.537 mmol). The reaction was stirred and heated in an oil bath at 150° C. for 60 h, and the mixture was diluted with DCM and washed with H2O, brine, dried, filtered and concentrated to give the crude product. MS (ESI, pos. ion) m/z: 680 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[NH:13][C:12](=[S:34])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC(c2ccc(OC(F)F)nc2)(c2cccc(Br)c2)N1
Solvent: C1CCOC1
Product: FC(F)Oc1ccc(C2(c3cccc(Br)c3)COCC(=S)N2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholin-3-one (1.6 g, 1.0 eq) and Lawesson's reagent (2.0 g, 1.2 eq) in tetrahydrofuran (60 ml) was stirred at room temperature overnight. For the workup, the solvent was removed at reduce pressure. The crude product was purified by chromatography on silica gel using a gradient of hexane/ethyl acetate as the eluent. The (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholin-3-thione was obtained as a yellow foam (1.0 g, 83% of theory). MS (ISP): m/z=415 [M+H]+.