Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].C(N(CC)CC)C.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[C:36]1([S:42]([N:25]2[CH2:24][CH2:23][CH:22]([CH2:21][N:11]3[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])[C:10]3=[O:28])[CH2:27][CH2:26]2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCNCC2)c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCN(S(=O)(=O)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
30 mg of 3-(2-cyanophenyl)-1-(piperidin-4-yl)methyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 2 ml of chloroform. Under ice-cooling, 0.04 ml of triethylamine and 23 mg of benzenesulfonyl chloride were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, and then evaporated and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 30 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][NH:5][C:6](=O)[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH2:19][C:20]#[C:21][CH3:22])[C:14]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]3)=[N:13][C:12]=2[N:11]([CH3:37])[C:9]1=[O:10]>C(O)(=O)C>[N:1]1[C:2]2[C:3](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:4][NH:5][C:6]=1[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH2:19][C:20]#[C:21][CH3:22])[C:14]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]3)=[N:13][C:12]=2[N:11]([CH3:37])[C:9]1=[O:10]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)NCc1ccccc1N)c(=O)n2C
Solvent: CC(=O)O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC1=Nc3ccccc3CN1)c(=O)n2C
Reaction time: 2 h

Procedure:
A mixture of 280 mg of 1-[2-(2-amino-benzylamino)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine and 4 ml glacial acetic acid is heated to boiling for two hours. Then the reaction mixture is evaporated down and the flask residue is purified through a column of aluminium oxide (activity stage 11) with methylene chloride/ethyl acetate/methanol (5:5:0 to 5:4:1) as eluant. In addition to the desired 1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine, deprotected 1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine is also obtained.
Reaction SMILES: COCCS(F)(F)([F:11])(CCOC)N.[F:14][C:15]1[CH:41]=[CH:40][C:18]([C:19]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(O)[C:20]([O:22][C@@:23]23[N:30]([CH3:31])[C@@H:27]([CH2:28][CH2:29]2)[CH2:26][CH:25]=[CH:24]3)=[O:21])=[CH:17][CH:16]=1>ClCCl>[C@@:23]12([OH:22])[N:30]([CH3:31])[C@@H:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]=[CH:24]2.[F:11][C:19]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([C:18]1[CH:40]=[CH:41][C:15]([F:14])=[CH:16][CH:17]=1)[C:20]([O-:22])=[O:21]
Reactant: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reactant: COCCS(N)(F)(F)(F)CCOC
Solvent: ClCCl
Product: CN1[C@@H]2CC=C[C@@]1(O)CC2
Product: O=C([O-])C(F)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
2.94 g (0.013 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are reacted with 3.85 g (0.01 mol) of 5d analogously to Example 4, step 4.3 in 100 ml of dichloromethane. The product is recrystallised from acetonitrile in the form of its hydrochloride.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O.C(Cl)(Cl)Cl>C1C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][Cl:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(CCl)cc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 98.5 %

Procedure:
To a cooled solution of 3-[(tert-Butyldimethylsilyl)oxy]-4-methoxybenzyl alcohol 14 (9.5 g, 35.4 mmol) in benzene (50 mL) under nitrogen, thionyl chloride (6.32 g or 3.87 mL, 53.1 mmol) dissolved in benzene (5 mL) was added over 10 min and maintained the temperature at 0° C. for 2 h. The completion of reaction was checked by TLC (chloroform on silica gel plate). Ice was added to the reaction mixture and the solution was extracted with ethylacetate. The organic layer was washed with saturated bicarbonate solution and water and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded 15. Yield: 98.5%; yellow oil. 1H NMR: δ 0.16 (s, 6H, 2×CH3), 1.00 (s, 9H, 3×CH3), 3.80 (s, 3H, OCH3), 4.44 (s, 2H, CH2), 6.70-7.01 (m, 3H, Ar—H). Anal. Calcd for C14H23ClO2Si: C, 58.62, H, 8.08. Found: C, 58.69, H, 8.03.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH3:12])[CH3:11])[CH:5]=[O:6].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][C:17]2[C:18](C)([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1.[CH2:31](O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:11][N:10]([CH3:12])[C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:15]1[C:14]([CH3:13])=[CH:23][C:22]2[C:21]([CH3:24])([CH3:25])[CH2:20][CH:19]([CH3:31])[CH:18]([CH3:26])[C:17]=2[CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1Br
Reactant: CCO
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1-c1cc(C=O)ccc1N(C)C)C(C)C(C)CC2(C)C
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 3-bromo-4-(dimethylamino)-benzaldehyde (5 g, 21.92 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl) boronic acid (6.5 g, 26.30 mmol) in a mixture of toluene (50 mL), ethanol (10 mL) and water (7.5 mL) was added potassium carbonate (6.0 g, 43.83 mmol). The solution was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.438 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (8% ethyl acetate in hexane) to give 7.08 g of 4-dimethylamino-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl) benzaldehyde (92%). 1H NMR (300 MHz; DMSO) 1.22 (s, 3H); 1.28 (s, 3H); 1.29 (s, 3H); 1.31 (s, 3H); 1.69 (s, 4H); 2.07 (s, 3H); 2.64 (s, 6H); 6.93 (d, J=8.4 Hz, 1H); 7.13 (s, 1H); 7.15 (s, 1H); 7.58 (d, J=2.4 Hz, 1H); 7.75 (dd, J1=8.7 Hz, J2=2.1 Hz, 1H); 9.80 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:55]=[CH:54][C:40]([C:41]([NH:43][CH2:44][C:45]([CH3:53])([CH3:52])[CH2:46][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:42])=[CH:39][C:38]=1[O:56][CH3:57].CC(C)CC(O)C>CO>[CH:13]1([N:10]2[CH2:9][C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:7](=[O:22])[N:6]([CH3:23])[C:5]3[C:11]2=[N:12][C:2]([NH:36][C:37]2[CH:55]=[CH:54][C:40]([C:41]([NH:43][CH2:44][C:45]([CH3:52])([CH3:53])[CH2:46][N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:42])=[CH:39][C:38]=2[O:56][CH3:57])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1N
Reactant: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: CCC1(CC)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NCC(C)(C)CN4CCCC4)cc3OC)ncc2N(C)C1=O
Temperature: 120 °C
Yield: 27.5 %

Procedure:
10-chloro-2-cyclopentyl-4,4-diethyl-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 250; 111 mg, 0.33 mmol), p-toluenesulphonic acid monohydrate (155 mg, 0.81 mmol) and 4-amino-N-(2,2-dimethyl-3-pyrrolidin-1-yl-propyl)-3-methoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120° C. over the weekend. The sample was transferred to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (55 mg, 27%).
Reaction SMILES: ClCl.[CH2:3]([O:5][C:6](=[O:14])[C:7]([S:10]C(=O)C)([CH3:9])[CH3:8])[CH3:4].C([N:18]([CH2:22][CH3:23])[CH:19](C)C)(C)C.N1CCC1.[OH2:28]>C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:14])[C:7]([S:10]([N:18]1[CH2:19][CH2:23][CH2:22]1)=[O:28])([CH3:8])[CH3:9])[CH3:4]
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Reactant: CCN(C(C)C)C(C)C
Reactant: O
Agent: C1CNC1
Agent: ClCl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)S(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Chlorine gas is bubbled through a biphasic mixture of 5 g (26 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester in DCM (50 mL) and water (50 mL) at 10° C. for 10 min. After this time, the organic phase is separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude sulfinyl chloride is re-dissolved in DCM (50 mL) and N,N-diisopropylethylamine (4.58 mL, 26 mmol) and azetidine (1.5 g, 26 mmol) are introduced. The reaction is stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent heptanes, ethyl acetate) provides 4.62 g of 2-(azetidine-1-sulfinyl)-2-methyl-propionic acid ethyl ester. Yield: 80%, ES-MS: m/z 220 [M+H].
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=O.[OH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=[O:22].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:6]([O:5][CH2:3][C:2]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)=[O:22])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(=O)COC(C)(C)C)cc1
Reaction time: 16 h

Procedure:
t-Butyl bromoacetate (0.83 mL, 5.1 mmol), methyl 4-hydroxybenzoate (780 mg, 5.1 mmol) and Cs2CO3 (1.83 g, 5.6 mmol) were combined in 25 mL DMF. After 16 h, the reaction was diluted with ethyl acetate, washed with water, saturated NaHCO3, 10% KHSO4 and brine, dried (MgSO4) and concentrated providing 24-1 as a yellow oil. Rf 0.84 (silica, 50% EtOAC/hexane).
Reaction SMILES: [Li+:1].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].[C:19](OC(C)(C)C)(=[O:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CCOCC>[C:23]([O:22][C:20](=[O:21])[C:19]([O-:27])=[CH:12][C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13])([CH3:26])([CH3:25])[CH3:24].[Li+:1]
Reactant: CC(=O)c1ccco1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C([O-])=CC(=O)c1ccco1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
Part A. A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130 mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solution was cooled to −78° C. and 2-acetylfuran (14 g, 12 m mmol) was added in one portion. After 5 min, di-tert-butyl oxalate was added dropwise over 1 h as a solution in 100 mL of ether. The resulting mixture was warmed to 23° C. over a period of 3 h and was maintained at rt for 20 h. The mixture was then filtered, and the resulting beige precipitate was washed with 100 mL of ether. The filter cake was dried in a vacuum oven for 1 h to afford lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (25 g, 83%) as a cream colored solid. 1H NMR (DMSO-d6) δ 7.75 (t, 1H), 6.96 (m, 1H), 6.56 (m, 1H), 3.34 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:10]([C:11](O)=[O:12])=[C:9]([CH3:14])[O:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([O:5][C:6]1[C:10]([CH2:11][OH:12])=[C:9]([CH3:14])[O:8][N:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1onc(OCC(C)C)c1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(OCC(C)C)c1CO
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a stirred solution of 3-isobutoxy-5-methyl-isoxazole-4-carboxylic acid (146 mg, 0.73 mmol) and triethylamine (74 mg, 0.73 mmol) in tetrahydrofuran (5 mL) at −10° C. and under argon was added ethyl chloroformate (80 mg, 1.46 mmol). After 30 min, the mixture was filtered and the filter cake washed with tetrahydrofuran (4 mL). The combined filtrates were added to a solution of sodium borohydride (69 mg, 1.83 mmol) in water (2 mL) at 5° C. After 2 h the mixture was concentrated in vacuo, diluted with NaOH (2 N, 4 mL) then dried, filtered and concentrated in vacuo to give the title compound (111 mg, 82%) as a pale yellow oil. MS: m/e=186.3 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH3:33])=O)(=O)OC.O.[NH2:35][NH2:36]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:35][N:36]=[C:20]([C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:24][C:23]=2[CH3:33])[CH:19]=1
Reactant: COP(=O)(CC(=O)c1sc(-c2ccccc2)nc1C)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: Cc1nc(-c2ccccc2)sc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
orange solid. MS (EI): 361.0 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(4-Methyl-2-phenyl-thiazol-5-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:32])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:24]([CH3:25])=[N:23][N:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:21]=2)=[CH:14][CH:13]=1)[C:9]#[C:10][CH3:11])C.O.Cl>CCO>[CH3:25][C:24]1[C:20]([CH2:19][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH:8]([C:9]#[C:10][CH3:11])[CH2:7][C:6]([OH:32])=[O:5])=[CH:17][CH:16]=2)=[N:21][N:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:23]=1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2nn(-c3ccccc3)nc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC#CC(CC(=O)O)c1ccc(OCc2nn(-c3ccccc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
2N KOH(aq) (1 mL) was added to a solution of 26.2 (68 mg, 0.17 mmol) in EtOH (2 mL). The reaction was stirred at room temperature overnight and then poured into water. The aqueous mixture was acidified to pH=2 with 1N HCl(aq), and then extracted with ethyl acetate. The organic layer was washed with water, followed by brine. The organic layer was then concentrated under reduced pressure and the resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 60.3 mg (95%) of compound 26 as a colorless oil. LC/MSD m/e: 374.0 (M−H); 1H NMR (400 MHz) (acetone-d6) δ 8.05 (2H, d, J=8.0 Hz), 7.56 (2H, t, J=8.0 Hz), 7.40 (3H, t, J=8.0 Hz), 7.06 (2H, d, J=8.0 Hz), 5.28 (2H, s), 4.05 (1H, m), 2.70 (2H, m), 2.44 (3H, s), 1.80 (3H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=O.[C:11]1([C@@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[C:11]1([C:17](=[N:19][C@H:2]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)[CH3:1])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(=N[C@@H](C)c1ccc(Cl)cc1)c1ccccc1
Yield: 99 %

Procedure:
At first, zinc chloride (0.16 g, 1.1 mmol) was added to a toluene solution (100 ml) containing 16.6 g (107 mmol) of 4-chloroacetophenone (1b) as a ketone and 14.3 g (118 mmol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine. Then, the same steps as those of Example 1-7a were conducted, thereby obtaining 27.3 g of (S)-N-(1-phenylethylidene)-1-(4-chlorophenyl)-ethylamine ((S)-3ba, purity: 95%, yield: 94%).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2].[CH3:27][NH2:28]>CN(C=O)C.C(OC(=O)C)C.CCCCCC>[CH3:27][NH:28][C:1]1[C:3]([C:8]([NH:7][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([S:25][CH3:26])[N:5]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=2)[N:2]=1
Reactant: CSc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(C)cc2)cc1
Reactant: CN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1nc(-c2ccc(SC)cc2)nc(SC)c1C(=O)Nc1ccc(C)cc1
Temperature: 45 °C
Yield: 37 %

Procedure:
To a solution of 5-Cyano-1-(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine (2 g, 5.3 mmol, prepared according to the procedure disclosed in our US patent 2004/0259891) in DMF was added methylamine (0.32 g, 10.5 mmol) under stirring. The solution was slowly warmed to 45° C., and maintained at this temperature for 1 hour. The completion of the reaction confirmed by TLC using ethylacetate:hexane (1:1) as a solvent system. The resulted reaction mass was poured onto ice and filtered, the crude solid thus obtained was purified by column chromatography using ethylacetate:hexane to give the title compound, 0.8 g, yield 37%, purity 99.5% by HPLC, m.p.: 228-230° C. 1H-NMR (CDCl3) δ (ppm): 2.35 (s, 3H), 2.54 (s, 3H), 2.73 (s, 3H), 3.1-3.13 (d, 3H), 7.17-7.20 (d, 2H), 7.30-7.32 (d, 2H), 7.48-7.5 (d, 2H), 7.9 (bs, 1H), 8.35 (bs, 1H), and 8.4-8.42 (d, 2H). IR (KBr) cm−1: 3358, 3270, and 1625. MS m/z: 411.1 (M++1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.[N-]=[N+]=[N-].[CH2:9]([O:11][Si:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>P([O-])([O-])(O)=O.[Na+].[Na+].C(Cl)Cl>[CH2:9]([O:11][Si:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25]([N:1]=[N+:2]=[N-:3])(=[O:27])=[O:26])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])[CH3:10]
Reactant: CCO[Si](CCCCCCS(=O)(=O)Cl)(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCO[Si](CCCCCCS(=O)(=O)N=[N+]=[N-])(OCC)OCC
Temperature: 25 °C

Procedure:
Sodium azide (1.5 equivalent) in 4 ml of sodium hydrogen phosphate and hydrogen chloride buffer (14.4 g or Na2HPO4 to 4.4 mil conc HCl in 1 liter of distilled water) per gram of azide is added dropwise to a stirred 50 percent solution of triethoxysilylhexane sulfonyl chloride in methylene chloride containing 1 percent Aliquat 336. The mixture is stirred at room temperature for thirty minutes after the addition is complete. The layers are separated. The methylene chloride layer is washed with a saturated salt solution, dried over magnesium sulfate and the methylene chloride is evaporated. Ninety percent solids of a light yellow liquid triethoxysilylhexane sulfonyl azide of about 90 percent purity are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH2:23]([SH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([S:30][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CSCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 43, 0.100 g) and benzyl mercaptan (0.30 g) in acetonitrile (10 ml) was treated with potassium carbonate (0.46 g) and the mixture stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water the organic layer as collected, dried over magnesium sulfate and concentrated. The residue was purified by SPE (Si cartridge) eluting initially with cyclohexane:chloroform (5:1) and then cyclohexane:chloroform (1:3) to give the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]=O.COC1C2C(=CC=CC=2)C(OC)=CC=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:33](\[CH3:32])/[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Reactant: COc1c(C)c(C=O)c(OC)c2ccccc12
Product: CCOC(=O)/C(C)=C/c1c(C)c(OC)c2ccccc2c1OC

Procedure:
Compound 98a was prepared from 34 (0.506 g, 2.20 mmol) as described above for 28a to give 0.541 g (1.42 mmol, 65%) of the product as a colorless oil following flash chromatography (1:19 i-Pr2O:hexanes).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].NCCC(O)=O.O.[Br:32][C:33]1[N:38]=[C:37]([CH:39]=O)[CH:36]=[CH:35][CH:34]=1>C(O)C.C(OCC)(=O)C>[Br:32][C:33]1[N:38]=[C:37](/[CH:39]=[C:3](\[C:1]#[N:2])/[C:4]([NH:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH3:10])=[O:5])[CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Agent: NCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To the solution of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29; 116 mg, 0.35 mmol) in ethanol (2 mL) was added β-alanine (499 mg, 5.6 mmol) and water (2 mL). 6-Bromopicolinaldehyde (260 mg, 1.4 mmol) was added, and the resulting mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with sat. aqueous NaHCO3 (2×) and sat. brine, dried over sodium sulfate, and concentrated to a crude solid. Purification by flash silica gel column chromatography, eluting with 5:95 methanol/dichloromethane, afforded 33 (140 mg, 80%) as a thick yellow oil: MS (ES+) m/z=499.1 (M+H)+.