Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Si:2]([CH3:5])([CH3:4])[CH3:3].C([O:8][P:9]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])[O:10]CC)C>>[CH3:3][Si:2]([O:8][P:9]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])[O:10][Si:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Br
Reactant: CCOP(=O)(OCC)c1ccc(F)cc1
Product: C[Si](C)(C)OP(=O)(O[Si](C)(C)C)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
Bromotrimethylsilane (15.3 mL, 0.116 mol) was added dropwise to 4-fluorophenyl-phosphonic acid diethyl ester (8.95 g, 38.58 mmol) stirred in a reaction flask chilled to 0° C. The resulting solution was allowed to warm to ambient temperature and stirred for an additional hour. The mixture was then concentrated by rotary evaporation yielding crude 4-fluorophenyl-phosphonic acid bis(trimethylsilyl) ester which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]3[C:15]([CH3:23])([C:20]([NH2:22])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:18])[C:11]3=[C:10]2[CH3:24])[CH:6]=[CH:7][CH:8]=1.C(OO)=[O:26]>CC(C)=O>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]3[C:15]([CH3:23])([C:20]([NH2:22])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:18])[C:11]3=[C:10]2[CH3:24])[CH:6]=[CH:7][CH:8]=1)=[O:26]
Reactant: CSc1cccc(-n2c(C)c3c(c2C)C(C)(C(N)=O)CC3(C)C)c1
Reactant: O=COO
Solvent: CC(C)=O
Product: Cc1c2c(c(C)n1-c1cccc(S(C)=O)c1)C(C)(C(N)=O)CC2(C)C

Procedure:
Reaction of the 2-(3-methylmercaptophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide described above in Example 1CK with one molar equivalent of performic acid in acetone at room temperature affords 2-(3-methylsulfinylphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.CN1N=NC2C1=CC=CC=2.[CH2:23]=[O:24].[CH2:25]([CH:27]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][NH:29][CH2:30][CH:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][CH3:35])[CH3:26]>O.CO>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[N:10][C:11]=1[CH:23]=[O:24].[CH2:36]([CH:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:30][NH:29][CH2:28][CH:27]([CH2:25][CH3:26])[CH2:38][CH2:39][CH2:40][CH3:41])[CH3:37]
Reactant: C=O
Reactant: Cc1ccccc1-c1c[nH]nn1
Agent: CCCCC(CC)CNCC(CC)CCCC
Agent: Cn1nnc2ccccc21
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1[nH]nnc1C=O
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Approximately 40.0 gm (0.3 mole) of tolyltriazole (commercially obtained from PMC Specialties Group, Inc. under the tradename Cobratec TT-100), 25.1 gm (0.31 mole) aqueous formaldehyde (37 wt. % solution in water), and 50 ml of methanol were charged into a 500 ml reactor equipped with a reflux condenser, thermometer, dropping funnel, and mechanical stirrer. The reaction mixture became homogeneous after stirring for about 5 minutes. Then 72.5 gm (0.3 mole) of bis(2-ethylhexyl)amine was slowly added to the reactor at a temperature less than 40° C. (moderate exotherm is observable). Thereafter, the mixture was heated to - 70° C. and maintained at reflux for 3 hrs. Then the reactants were heated at 110° C. during which methanol and water was azeotropically collected in the Dean-Stark trap. Finally, house vacuum was used to remove the trace amount of water at 110° C. for a half hour. A final filtration to remove possible unreacted tolyltriazole is optional. Small amounts of residual water could make the final product appear hazy. Approximately 115.3 gm of yellow liquid was recovered as desired product (>99% yield).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:46](O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.O>ClCCl>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(CO[C@H]2CCN(Cc3ccccc3)C[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25, diisopropylethylamine (40.5 μl) and benzyl alcohol (12.4 μl) in dichloromethane (2.0 ml), EPPA (17.3 μl) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[I:19]CI.N(OCCCCC)=O>C(#N)C>[C:7]([C:6]1[C:2]([I:19])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[S:4][C:5]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:8]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1N
Reactant: ICI
Agent: CCCCCON=O
Solvent: CC#N
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Temperature: 80 °C
Reaction time: 96 h
Yield: 46.2 %

Procedure:
To a solution of methyl 3-amino-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (3.4 g, 12.6 mmol) in ACN (110 mL) was added diiodomethane (10.5 mL, 130.2 mmol) and amyl nitrite (1.1 mL, 77.7 mmol). The reaction mixture was allowed to stir at 80° C. for 4 days and was concentrated. The residue was purified by column chromatography to give methyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (2.2 g, 46%). LCMS: (FA) ES+ 379.0. 1H NMR (400 MHz, d6-DMSO) δ: 3.76 (s, 3H), 3.72-3.75 (m, 4H) and 3.56-3.61 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH:16]([O:29][CH2:30][CH2:31]Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:16]([O:29][CH2:30][CH2:31][N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Product: O=C1OC2(CCN(CCOC(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
Reaction of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one and 2-benzhydryloxy-1-chloroethane by the method described in Example 5d provides 1'-(2-benzhydryloxyethyl)-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one as colorless crystals, m.p. 99°-100°.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:13])[NH:9][CH:10]([CH3:12])[CH3:11])=[O:5].[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](=N)OCC)=[CH:22][C:21]=1[Cl:31]>C(O)C>[Cl:31][C:21]1[CH:22]=[C:23]([C:24]2[N:6]([CH2:7][C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:13])[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[C:15]([OH:18])[CH:14]=3)[N:1]=2)[CH:29]=[CH:30][C:20]=1[F:19]
Reactant: CCOC(=N)c1ccc(F)c(Cl)c1
Reactant: CC(C)NC(=O)CNC(=O)c1cc(O)ccc1N
Solvent: CCO
Product: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(O)cc2c1=O
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 2-amino-5-hydroxy-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE II.1) (400 mg, 1.59 mmol) and ethyl 4-fluoro-3-chlorobenzimidate*HCl (INTERMEDIATE III.5) (1.14 g, 4.78 mmol) in ethanol (10 mL) was heated at reflux temperature for 1 h. The mixture was then cooled to room temperature and the resultant solid collected by filtration and washed with additional portions of cold ethanol (3×20 mL) to afford 2-[2-(3-chloro-4-fluorophenyl)-6-hydroxy-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.1) (380 mg, 0.97 mmol, 61%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][N:33]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]1)[C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1cccc(Cl)c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.1 g of 3-chlorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.06 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-chlorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CC[C@H](O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@H](O)C3)c21

Procedure:
Using Method C above, (S)-3-hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 96A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 42 mg, 71%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+].O>CO>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 8 °C
Yield: 93.5 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (806 g), potassium hydroxide (548 g), water (2400 mL) and methanol (300 mL) were refluxed for two hours with stirring and then cooled to 8° C. The mixture was extracted twice with dichloromethane. The aqueous layer was adjusted to pH 4 with 1000 mL of 10 N hydrochloric acid keeping the temperature under 15° C. Water was added to facilitate stirring. The solid was collected by vacuum filtration, washed three times with water and dried under vacuum at 50° C. to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic (645 g, 93.5% yield) acid as a yellow solid. NMR (DMSO-d6) δ 2.40, 2.43 (2×s, 2×3H, 2×CH3), 9.57 (s, 1H, CHO), 12.07 (br s, 2H, NH+COOH). MS m/z 168 [M+1].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][NH:34][CH3:35]>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:34]([CH3:35])[CH3:33])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CNC
Product: CN(C)c1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2-chloropyridine-3-carboxamide and 10 ml of 40% N,N-dimethylamine gives 700 mg of the desired product: M+ =451.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C1COCC1.CCCCCC>[CH2:29]([O:28][C:26]([N:12]1[C:11](=[O:13])[CH2:10][CH2:9][C@H:8]1[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 g (4 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 10 ml dry THF and cooled to −78° C. After the addition of 2.76 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 676 □l (820 mg, 4.8 mmol) benzyl chloroformate (Cbz-Cl) is added and stirring is continued at −78° C. for 2 h. The reaction is then quenched by addition of 12 ml saturated NH4Cl solution followed by 10 ml water and then extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer is dried over MgSO4, filtered and evaporated. The resulting residue (1.73 g) is purified on column chromatography (dichloromethane:methanol=99.5:0.5) to give (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (1-a, R1=Cbz) as off-white solid. NMR (400 MHz, DMSO-d6, □/ppm): 7.66 (m, 2 H); 7.60 (m, 2 H); 7.51-7.34 (m, 8 H); 7.26 (d, J=8.2, 2 H); 5.28 (s, 2 H); 4.37 (m, 1 H); 3.05 (dd, J=3.3, 13.1, 1 H); 2.88 (dd, J=9.0, 13.1, 1 H); 2.45 (m, 1 H); 2.28 (m, 1 H); 2.01 (m, 1 H); 1.77 (m, 1 H). MS (ESI, m/e) 386 [M+H]+, 788 [2M+NH4+]. IR (solution in CH2Cl2, □/cm−1): 3092; 2957; 1756; 1705; 1488; 1396; 1304; 1287; 1231; 1139; 1043; 952; 750.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:12]=1[CH3:13])(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+].C(OCC)(=O)C>CN(C=O)C>[N:20]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:12]=1[CH3:13])=[N+:21]=[N-:22]
Reactant: Cc1sc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1CCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a brown solution of 2-(5-methyl-2-phenylthiazol-4-yl)ethyl methanesulfonate (200 mg, 673 μmol; prepared according to WO 2001/021602) in DMF (2.5 mL) was added sodium azide (52.5 mg, 807 μmol) at RT. The mixture was heated to 60° C. and stirred for 3 h and was then allowed to slowly cool down to RT. The reaction mixture was poured into ethyl acetate (50 mL) and the organic phase was washed with water (3×25 mL) and brine (1×25 mL). The aqueous layers were back-extracted with ethyl acetate (1×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 174 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless oil (107 mg, 438 μmol, 65.1%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][C:11]([CH3:16])([CH3:15])[C:12](=[S:14])[NH2:13]>C(O)C.CCOC(C)=O>[CH3:10][CH2:11][CH2:12][CH:3]([CH3:2])[CH3:4].[C:11]([C:12]1[S:14][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:13]=1)([CH3:16])([CH3:15])[CH3:10]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)C(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(C)C
Product: CCOC(=O)c1csc(C(C)(C)C)n1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (6.20 mL, 49.40 mmol) was added very carefully to a stirred solution of 2,2-dimethylpropanethioamide (5.79 g, 49.40 mmol) in ethanol (60 mL). The solution was then heated under reflux for 16 h. After cooling, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate solution and evaporated in vacuo. Purification by silica gel chromatography (Biotage, 100 g) eluting with EtOAc: iso-hexane, 1:10 gave the sub-title compound as a yellow oil. Yield: 6.56 g
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][C:6](=[O:9])[CH2:7][Br:8].[C:13](Cl)(=[O:16])[CH2:14][CH3:15].N1C=CC=CC=1>C(Cl)Cl>[C:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][C:6](=[O:9])[CH2:7][Br:8])(=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)Cl
Reactant: O=C(CBr)Nc1cccc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Oc1cccc(NC(=O)CBr)c1
Reaction time: 0.33 h

Procedure:
The anilide, 3'-hydroxy bromoacetanilide, 6.9 g. and propionyl chloride (3.1 g., 0.033 mole) are combined in 120 ml. of methylene chloride as a solvent. Pyridine (2.6 g., 0.033 mole) is added dropwise. A slightly exothermic reaction takes place during the addition. Stirring is continued at room temperature for 20 minutes. A clear solution is obtained. The material is washed sucessively with water, dilute hydrochloric acid and again with water. The organic layer is dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting material is recrystallized from a mixture of ethylacetate and ether. There is obtained 6.5 g. of the title compound, m.p. 85°-88° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.[NH2:10][C@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[Cl:26][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@H:11]([NH:10][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][N:4]=3)=[O:9])[CH3:27])[N:14]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: Cc1cnc(C(=O)O)s1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1cnc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)s1
Yield: 54.6 %

Procedure:
5-Methyl-1,3-thiazole-2-carboxylic acid (55 mg, 0.38 mmol) was coupled with (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg, 0.38 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water) to obtain 80 mg (54%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.55 (d, 3H), 4.26 (dd, 1H), 4.45 (dd, 1H), 4.51-4.62 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.60 (dd, 1H), 7.68 (d, 1H), 7.79 (dd, 1H), 8.13 (d, 1H), 8.24 (d, HA).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O.NN>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(-c2c[nH]cn2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc(-c2c[nH]cn2)ccc1N
Yield: 100.7 %

Procedure:
4-(3-Methyl-4-nitrophenyl)-1-H-imidazole (9.2 g) was allowed to react with 85% hydrazine hydrate in methanol to give 7.9 g of 4-(3-methyl-4-aminophenyl)-1-H-imidazole, M.p. 195°-197° C. 4-(3-Methoxy-4-aminophenyl)-1-H-imidazole, M.p. 145° C. (dec.), was prepared analogously.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=O)=[CH:4][CH:3]=1.C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:8]2)=[CH:27][CH:28]=1
Reactant: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)C(=O)C1c1ccccc1
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)CC1c1ccccc1

Procedure:
1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethyl piperazine prepared according to Example 10, is reduced by following the procedure described hereinabove in Example 8a whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethyl piperazine is used. The resulting 3-phenyl piperazine compound is obtained in the form of a light yellow oil boiling at 180° C./0.01 mm. Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=[C:4]2[C:3]=1[NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][NH:13][C:3]1[C:4]2[N:5]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1CNc1c(N)ccn2c(C)c(C)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccn2c(C)c(C)nc2c1NCc1c(C)cccc1C
Temperature: 25 °C

Procedure:
7-amino-2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine (example 77) (0.16 g, 0.53 mmol) was dissolved in methylene chloride (5 ml) and acetic anhydride (60 mg) was added. The mixture was stirred over night at ambient temperature. A small amount of triethylamine was added and the solvent was removed under reduced pressure. Chromatography first with methylene chloride:methanol, 95:5 and secondly with methylene chloride:ethyl acetate, 50:50 gave after trituration with diethyl ether 87 mg (47%) as white solid.
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[CH2:13]([N:17]1[C:25]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][C:23]2[C:18]1=[N:19][C:20]([C:38]1[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=1)=[N:21][C:22]=2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[CH:14]([CH3:16])[CH3:15]>CN1C(=O)CCC1>[CH2:13]([N:17]1[C:25]([N:26]2[CH2:31][CH2:30][N:29]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:28][CH2:27]2)=[N:24][C:23]2[C:18]1=[N:19][C:20]([C:38]1[CH:43]=[N:42][C:41]([NH2:44])=[N:40][CH:39]=1)=[N:21][C:22]=2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 1 h
Yield: 51 %

Procedure:
Triethylamine (143 μl) and mesyl chloride (50 μl, 0.63 mmol) were added to 5-(9-isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (2 ml of solution of 100 mg of this compound in 1 ml of NMP) and the resulting mixture was stirred for 1 hour. Mesyl chloride (50 μl, 0.63 mmol) was further added, the resulting mixture was stirred for 1 hour, then the reaction mixture was partitioned with ethyl acetate and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (135 mg, 51%) as a pale yellow solid.