Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH:14]OS([O-])=O.[K+].[OH2:20]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)(=[O:14])=[O:20])=[CH:6][CH:7]=1
Reactant: O
Reactant: Clc1ccc(Sc2cccs2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a 0° C. solution of 2-(4-chlorophenylthio)thiophene (0.49 g, 2.2 mmol) in MeOH (8 mL) was added a solution of Oxone® 3.98 g, 6.5 mmol) in water (8 mL). The resulting slurry was allowed to warm to room temperature, stirred for 4 h, then diluted with water and extracted with CH2Cl2. The organic layer was washed with water and a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure to give 4-chloro-1-(2-thienylsulfonyl)benzene (0.69 g, 100%) as a white solid: TLC (20% EtOAc/hex) Rf 0.36; 1H NMR (CDCl3) δ 7.09-7.12 (m, 1H), 7.47-7.52 (m, 2H), 7.66-7.71 (m, 2H), 7.90-7.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][N:33](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:32][CH2:31][C:22]=1[NH:23]2.CCOC(C)=O.Cl>CO>[CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][NH:33][CH2:32][CH2:31][C:22]=1[NH:23]2
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC4)cccc1-n1cnc2ccccc2c1=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A suspension of 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (248.5 mg, 0.359 mmol) in methanol (4 mL) was treated with EtOAc (less than 1 mL) to form a clear solution. This was treated with 1 M aqueous HCl (3 mL), forming a cloudy mixture which was stirred at room temperature. After 30 min, the mixture was concentrated under vacuum, treated with NaHCO3 (aq) and EtOAc and stirred at room temperature for about 1 h. The precipitate was collected by filtration, washed with water, then with EtOAc, and dried under vacuum to provide the desired product as a white solid (145 mg, 90% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:37][CH2:38][CH3:39])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH3:3].[CH2:40](O)[CH3:41]>>[CH2:40]([O:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:37][CH2:38][CH3:39])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)[CH3:41]
Reactant: CCO
Reactant: CCCN(CCC)CCCCN(CCC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Product: CCCN(CCC)CCCCN(CCC(=O)OCC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The compound (135.4 mg) obtained in Example 51-1 was suspended in ethanol (13.5 ml) and the whole was refluxed under heating for 16 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with saturated sodium hydrogen carbonate aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off, thereby obtaining the subject compound (127.0 mg) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:34]([S:46]SC(=N)N)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].O>C(O)C.C(OCC)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:46][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])=[N:11]1
Reactant: COc1cc(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCSSC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCSC1C(=O)N(c2c(Cl)cc(Cl)cc2Cl)N=C1Nc1cc(OC)c(Cl)cc1Cl

Procedure:
15.1 g of 1-(2,4,6-trichlorophenyl)-3-(2,4-dichloro-5-methoxyanilino)-5-pyrazolone was dissolved in 500 cc of 80% ethanol (volume ratio of ethanol to water: 4:1), and 2.5 g of potassium carbonate was added. 10.4 g of S-(n-dodecylthio)isothiourea hydrochloride dissolved in 100 cc of ethanol was dropwise added over a period of 10 minutes on a steam bath with stirring under heating, and further, the mixture was stirred under heating. After cooling with flowing water, 300 cc of ethyl acetate was added, followed by washing twice with water. After drying ethyl acetate layer with anhydrous sodium sulfate, sodium sulfate was removed, the solvent was concentrated under reduced pressure, and the residue was crystallized from acetonitrile. The thus-obtained crystal was recrystallized from acetonitrile-ethyl acetate (volume ratio: 10:1) to obtain 18 g of the coupler having a melting point of 100° to 102° C. (conversion rate: 95%).
Reaction SMILES: [C:1]([N:5]([CH3:29])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]3[C:8]([C:6](=[O:7])[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:29])=[CH:9][C:10]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[C:11]32)=[CH:16][C:17]=1[O:22][CH3:23])[CH3:31]
Reactant: COc1cc2c(cc1O)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)cc(-c3cccs3)c1-2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of the product of example 52 (250 mg), bromo-acetic acid ethyl ester (81 μl) and Cs2CO3 (595 mg) in DMF (10 ml) was stirred at 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature, subsequently poured into water and extracted with dichloromethane. The organic layer was washed with an aqueous HCl solution (0.5 M), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/1 (v/v)] as eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2].[CH:23](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])([CH3:23])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(=O)CCC3
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3c(c12)C(=O)CCC3

Procedure:
0.2 g of 4-methoxymethyl-5-oxo-5,6,7,8-tetrahydro-betacarboline-3-carboxylic acid ethyl ester is refluxed in 10 ml of isopropanol with 0.1 ml of titanium tetraisopropylate for 1.5 hours under argon atmosphere. The crystals precipitated after cooling are sectioned off and rewashed with isopropanol. 0.135 g of 4-methoxymethyl-5-oxo-5,6,7,8 -tetrahydro-beta-carboline-3-carboxylic acid isopropyl ester with a melting point of 243°-245° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26](C=N[NH:29]2)=[CH:25][CH:24]=1.C[CH2:33][N:34](C(C)C)C(C)C>C(O)CCC.C(OCC)(=O)C>[NH:29]1[C:30]2[CH:31]=[C:23]([NH:22][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([Cl:1])[N:3]=3)[CH:24]=[CH:25][C:26]=2[N:34]=[CH:33]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5nc[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
To a solution of 2,4-dichloro-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.28 mmol) in n-butyl alcohol (1 mL) was added 6-aminoindazole (0.043 g, 0.32 mmol) and DIPEA (0.057 mL, 0.32 mmol) at room temperature. After heating at 80° C. for 15 h, the mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with 1N HCl, Sat NaHCO3, and brine. The organic extract was dried over Na2SO4 and concentrated to give crude N-(1H-benzo[d]imidazol-6-yl)-2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.105 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([OH:23])[CH2:21][CH3:22]>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:23])[CH2:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCO
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Product: CCOC(=O)C(c1nsc(NC(=O)OC(C)(C)C)n1)C(O)CC

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 0.76 ml (~10 mMol) of propanol for 5 days in the manner described in Example 29 and the separated into the erythro and threo forms by chromatography on silica gel using toluene/ethyl acetate 4:1.
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH2:5][CH3:6].[Br:14]Br.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:14][CH:5]([CH3:6])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: BrBr
Reactant: CCC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a CH2Cl2 solution (5 mL) of propiophenone (4.93 g, 36.82 mmol), a CH2Cl2 solution (5 mL) of bromine (6.49 g, 40 mmol) was gradually added at 15° C., followed by 1 hour of stirring. To the resulting solution, 30 mL of saturated NaHCO3 solution and 40 mL of EtOAc were added to conduct extraction. The organic layer was washed with 20 mL of a 20 wt % sodium thiosulfate aqueous solution and then with 20 mL of saturated brine, dried (MgSO4), and subjected to distillation under reduced pressure to remove the solvent. The title compound (7.7 g) was obtained as a yellow oil. LC-MS (ES) m/z=214 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:14]([NH:21][CH:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCN(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-one (2.0 g, 11.4 mmol) (from Example 123) and benzylamine (1.33 g, 12.5 mmol) were dissolved in 1,2-dichloroethane (35 mL) and acetic acid (1.36 g, 22.6 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium triacetoxyborohydride (3.14 g, 14.8 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO3 (aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane--30% ethyl acetate to give the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:38][C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:39]([Cl:38])=[O:41])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCC[C@@H](Nc2nccc(-c3c(-c4ccc(F)cc4)nc4occn34)n2)C1
Yield: 95.8 %

Procedure:
To a solution of 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine (200 mg, 0.45 mmol) and Hunig's base (145 μL, 0.90 mmol) in 10 mL DCM was added a solution of triphosgene (660 mg; 2.25 mmol) in 10 mL DCM dropwise over 10 min with stirring. The mixture was allowed to stir at ambient temperature for 1.5 hr. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with 20 mL ether and concentrated under reduced pressure yielding (3R)-3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carbonyl chloride as an off-white solid (190 mg). The solid was diluted in 10 mL DCM. To the resulting solution was added morpholine (60 μL, 0.67 mmol) and triethylamine (70 μL, 0.50 mmol). The mixture was allowed to stir at ambient temperature for 20 hr. The reaction mixture was then concentrated under reduced pressure and the residue purified by flash chromatography on silica gel (1:4, ethyl acetate:hexanes) to yield 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amine as an off-white solid (50.2 mg, 23%). 400 MHz 1H NMR (DMSO-d6) δ: 8.75 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.62-7.66 (m, 2H), 7.30-7.34 (m, 2H), 6.37 (s, 1H), 3.76 (m, 2H), 3.53 (m, 4H), 3.15 (m, 2H), 3.09 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 1.99 (s, 1H), 1.78 (br.s, 1H), 1.50-1.54 (m, 2H). LCMS: 492 [M+H].
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(O)CCCC>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([O:15][CH2:3][CH2:2][CH2:1][CH2:6][CH3:5])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Solvent: CCCCCO
Solvent: O=S(Cl)Cl
Product: CCCCCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 40.2 %

Procedure:
2 g of 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetic acid, 3 g of thionyl chloride and 30 ml of n-pentanol are treated in the same manner as described in Example 13. One g of n-pentyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained. Yield: 40.2%
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]#[N:19])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].[CH2:27]([O:29]CC)[CH3:28]>>[CH2:1]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:27](=[O:29])[CH3:28])[C:9]#[N:10])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:20](=[O:22])[CH3:21])[C:18]#[N:19])=[CH:13][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Reactant: N#CNc1ccc(Cc2ccc(NC#N)cc2)cc1
Product: CC(=O)N(C#N)c1ccc(Cc2ccc(N(C#N)C(C)=O)cc2)cc1

Procedure:
124.1 g (0.5 mol) of 4,4'-methylene-bis-(phenylcyanamide) and 510.5 g (1.0 mol+400% excess) of acetic anhydride are reacted at 73°-83° C. for 4 hours and 10 minutes, 465 ml of diethyl ether are then added and the mixture is cooled. The suspension is filtered with suction and the residue is dried at 50° C. in vacuo to give 139.6 g (84.0% of theory) of a crystalline product which, after recrystallisation from toluene, has a melting point of 134°-136° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=1[Cl:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.N1C=CC=CC=1>C(O)(C)C>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:19]#[N:20])=[CH:31][C:30]=1[Cl:36])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(C)=O

Procedure:
A mixture of 4.17 g (0.0149 moles) of the N-(4-chloro-3-cyano-7-ethoxy-6-quinolinyl)acetamide, 4.04 g (0.0173 moles) of 4-benzyloxy-3-chloro-phenylamine (example 5), and 2.0 g (0.017 moles) of pyridine hydrochloride in 85 ml of isopropanol was stirred and refluxed in an oil bath for 30 minutes. The reaction was cooled in an ice bath, and the solid was collected by filtration and washed with isopropanol, and then with ether yielding 7.26 g of crude product as the hydrochloride salt. This material was purified by chromatography of the free base on silica gel by elution with 1:39 methanol-methylene chloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].CN1CCOCC1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH2:15]([O:22][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(CCCBr)OCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
In the first step, 4-bromobutyryl chloride (13.8 g, 75 mmole) was placed in a 100 ml round bottom flask. The flask was cooled to -20° C. using a dry ice/carbon tetrachloride bath. Ethyl acetate (50 ml) containing N-methylmorpholine (7.58 g, 75 mmol, 8.2 ml) was added carefully. Using an addition funnel, benzyl alcohol (6.97 g, 6.67 ml, 6.64 mmoles) was added dropwise. After the addition the bath was removed and the mixture was stirred for 2 hours. The product was transferred to a separatory funnel using ethyl acetate (50 ml), washed once with sodium bicarbonate (10%), then twice with water, and dried with anhydrous sodium sulfate. Evaporation of solvents gave benzyl-4-bromo-butyrate as an oil (yield=91%).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[CH3:13]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[C:5]([CH3:13])[CH:6]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)c(C)c1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.67 mL bromine was added to 2 g 1-(4-fluoro-3-methyl-phenyl)-ethanone in 10 mL conc. acetic acid. The reaction was stirred for 3 h at RT and added to ice water. The precipitate was filtered, washed with water and dried to give 2.7 g desired product.
Reaction SMILES: [Br:1][C:2]([OH:12])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)(Br)CCC1CCC(=O)N1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(Br)(CCC1CCC(=O)N1)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
To a solution of 5-(3-bromo-3-hydroxy-butyl)-pyrrolidin-2-one (6.76 g, 21.6 mmol) in DMF (86 mL) was added tert-butyldimethylsilyl chloride (3.59 g, 23.8 mmol) followed by imidazole (2.95 g, 43.3 mmol) and DMAP (264 mg, 2.16 mmol). The reaction was stirred for 24 h and was quenched with saturated aqueous ammonium chloride. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated. Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) provided 5-[3-bromo-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (7.45 g). 1H NMR (CDCl3) δ7.30 (m, 2H), 7.12 (m, 1H), 7.04 (m, 1H), 5.71 (m, 1H), 3.81 (m, 1), 3.56 (m, 1H), 2.66 (m, 2H), 2.32-2.17 (m, 3H), 1.70-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.24 (d, 3H); MS 426.2, 428.2 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[N:4]([C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9])[CH2:5][C:6]#[CH:7].O>O1CCCC1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[N:4]([CH:5]=[C:6]=[CH2:7])[C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9]
Reactant: C#CCN(C(=O)c1ccco1)c1c(C)cccc1C
Solvent: O
Solvent: C1CCOC1
Product: C=C=CN(C(=O)c1ccco1)c1c(C)cccc1C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
50 g (0.2 mol) of 2,6-dimethyl-N-(2-furoyl)-N-propargyl-aniline were dissolved in 200 ml of anhydrous tetrahydrofuran, and 150 mg of potassium tert.-butylate were added. During this procedure, the temperature of the solution rose to about 50° C., the solution becoming colored. The reaction mixture was left to stand for 2 hours and then poured onto 500 ml of water. The crystalline product which had precipitated was filtered off, dried and recrystallized from ethyl acetate/petroleum ether. 24 g (48% of theory) of 2,6-dimethyl-N-allenyl-N-(2-furoyl)-aniline of melting point 138°-41° C. were obtained. (The 1H-NMR spectrum indicated complete isomerization). ##STR99##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:15](=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:15](=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[N:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(O)cccc2o1
Product: Oc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 7.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (203 mg, 1.29 mmol) and 2-(but-3-ynyl)benzo[d]oxazol-4-ol (241 mg, 1.29 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH4OH 94:5:1 to 90:8:2) to yield 25 mg (95 Ξmol, 7%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol as an orange solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]C)=[O:10])=[CH:5][CH:4]=1.CN(C=O)C>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[SH:17])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2SC)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(O)cc1)c1ccccc1S
Temperature: 25 °C
Yield: 73 %

Procedure:
To a nitrogen flushed mixture of 1.415 g (4-methoxyphenyl)(2-(methylthio)phenyl)methanone (C) (5.48 mmol) and 3 g sodium thiolate (26.6 mmol) was added 40 ml anhydrous DMF. The mixture was refluxed under nitrogen. After the mixture turned to black, the reaction was refluxed for two more hours, cooled to RT and quenched with water. The mixture was washed ethyl acetate (2×100 ml). The combined organic was brined, dried over magnesium sulfate, filtered and concentrated. Flash column (hexane:ethyl acetate 80:20) yield 0.954 g product (4.0 mmol, 73% yield).