Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[F:22])[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[F:22])[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1F
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared from rac-[(4-chloro-2-fluoro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 3) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISP): 489.9 (M+H)+.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.O1CCCC1>[CH3:23][Si:24]([C:27]#[C:28][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([CH3:26])[CH3:25]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Yield: 88 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, 20 a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 0.019 g (0.1 mmol) of copper (I) iodide, 1.088 g (6 mmol) of dicyclohexylamine and 9 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.174 g (0.3 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 30 minutes. 0.925 g (5 mmol) of 4-bromobenzaldehyde and 0.589 g (6 mmol) of trimethylsilylacetylene were added, followed by stirring at 30° C. for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.890 g of 4-[(trimethylsilyl)ethynyl]benzaldehyde (yield: 88 mol % based on 4-bromobenzaldehyde). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)cc(CO)c1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Br)cc(CO)c1
Reaction time: 16 h

Procedure:
To 3-bromo-5-(hydroxymethyl)benzoic acid (7.0 g, 30 mmol) in 20% methanol/benzene (100 mL) is added trimethylsilyldiazomethane (2M in hexanes), and the reaction is stirred 16 h. The reaction is concentrated under reduced pressure to afford the title compound. ESI MS m/z 244.0 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[F:11][C:12]([F:25])([F:24])[O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:23].O>ClCCl>[F:11][C:12]([F:24])([F:25])[O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][C@@H:18]2[OH:23]
Reactant: O=C1CCc2c(OC(F)(F)F)cccc21
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@H]1CCc2c(OC(F)(F)F)cccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Triethylamine (5.23 mL, 37.2 mmol) is dissolved in dichloromethane (60 mL) and cooled to 0° C. then formic acid (1.60 mL, 42.4 mmol) is added dropwise with cooling. 4-Trifluoromethoxy-indan-1-one (US patent 2011/53974, 2.58 g, 11.94 mmol) is added and the mixture degassed with a flow of argon. Chloro([(1S,2S)-(+2-amino-1,2-diphenylethyl]-4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) complex (148 mg, 0.24 mmol) is added and the mixture is stirred overnight under argon at room temperature. Water is added, the mixture shaken and the phases separated. The organic phase is dried and concentrated under vacuum. The residue is purified by flash chromatography (20% ethyl acetate in cyclohexane) to give the title compound (yield 2.50 g).
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16](Br)=[CH:15][C:14]=3[CH3:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:22][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(Br)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2c1C[C@@H]1CCNC[C@H]21
Temperature: 20 °C
Reaction time: 15 h
Yield: 785.7 %

Procedure:
To a solution of cis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (50 mg, 0.14 mmol) in MeOH (2.0 mL) was added Pd(OH)2 (−10 mg, 20 wt %). The reaction mixture was stirred at 20° C. for 15 h under H2 atmosphere, filtered through celite and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 1/1) to give the title compound (21 mg, 1.1 mmol): MS (ES) 188.1 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1.[H-].[Na+].[CH3:15]I.O>O1CCCC1>[CH3:15][O:1][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1
Reactant: Cc1cccc2c(CO)csc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1csc2c(C)cccc12
Temperature: 50 °C

Procedure:
400 mg of 3-hydroxymethyl-7-methyl-benzo[b]thiophene are dissolved in tetrahydrofuran, mixed with 82 mg of NaH (80%) and after addition of 48 mg of methyl iodide heated for half an hour at 50° C. The reaction mixture is mixed with water, repeatedly extracted and the organic phase washed, dried and concentrated on a rotary evaporator. The residue is chromatographed over silica-gel (eluant: toluene/glacial acetic acid=95:5) to yield the title compound as an oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+:16]>>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC1c1ccccc1
Reactant: [NH4+]
Agent: O=C[O-]
Product: NC1CCCC1c1ccccc1

Procedure:
2-Phenylcyclopentanone is reacted with ammonium formate at 170° C. via the Leuckart method to afford predominantly the cis isomer of 2-phenylcyclopentylamine.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:28][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH3:27])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:28])[CH3:27])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OCC(C)O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc3sccc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3ccc(OCC(C)O)cc3)cc3sccc23)CC1
Temperature: 25 °C
Yield: 78 %

Procedure:
4-(4-Ethylpiperazin-1-yl)-6-[4-(2-t-butyldiphenylsilyloxypropoxy)phenyl]thieno[3,2-c]pyridine of 3.38 g (5.31 mmol) was dissolved in THF of 20 ml and stirred at room temperature. To the mixture was added 1.0M tetrabutylammonium fluoride/THF solution of 10.6 ml (2.0 equivalents), and the mixture was stirred for 8 hr. The solvent was evaporated, and to the resulting residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water (three times) and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (n-hexane/ethyl acetate system), to give the title compound as a colorless oil (1.65 g, yield; 78%).
Reaction SMILES: Cl.[NH2:2]/[C:3](/[C:8]#[N:9])=[C:4](\[NH2:7])/[C:5]#[N:6].[C:10]([CH2:18][C:19](=O)[CH3:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[C:5]([C:4]1[CH:3]([C:8]#[N:9])[NH:2][C:10]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[C:19]([CH3:20])[N:7]=1)#[N:6]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#C/C(N)=C(/N)C#N
Agent: Cl
Solvent: c1ccccc1
Product: CC1=CC(O)(c2ccccc2)NC(C#N)C(C#N)=N1

Procedure:
In the presence of a catalytic amount of HCl (4N=4 mol/l), 1 mol of diaminomaleonitrile was reacted with 1 mol of benzoylacetone in a solvent (benzene) at 45° C. for 6 hours to give 2,3-dicyano-5-hydroxy-5-phenyl-7-methyl-4H-1,4-diazepine (compound 1a). The diazepine compound (1a) thus obtained was reacted with 4-methoxybenzaldehyde in the presence of piperidine to give the object compound 2,3-dicyano-5-hydroxy-5-phenyl-6-(4-methoxyphenylmethylidene)-7-methyl-4H-1,4-diazepine (compound 1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])(O)=O.[Na+].[C:19](=[O:26])([O:23][CH2:24]I)[S:20][CH2:21][CH3:22]>O.C(Cl)Cl>[C:19](=[O:26])([O:23][CH2:24][O:12][C:11](=[O:13])[CH2:10][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[S:20][CH2:21][CH3:22]
Reactant: CCOP(=O)(CCC(=O)O)OCC
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(CCC(=O)OCOC(=O)SCC)OCC
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
To a mixture of 3-(diethylphosphono)propanoic acid (79, 1.0 g, 4.76 mmol) in H2O (12 mL) and CH2Cl2 (12 mL) was added NaHCO3 (1.0 g, 11.9 mmol) and TBAHSO4 (1.62 g, 4.76 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (1.17 g, 4.76 mmol) in CH2Cl2 (2 mL) was added. The biphasic reaction was stirred vigorously for 4 h 20 min and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using EtOAc as the eluent, to yield compound 80 (1.29 g, 83%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.30-1.65 (m, 9H), 2.03-2.12 (m, 2H), 2.64-2.71 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 4.06-4.14 (m, 4H), 5.82 (s, 2H). 31P NMR (162 MHz, CDCl3) δ 30.45 (s).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Br[CH:56]([CH3:58])[CH3:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH:56]([CH3:58])[CH3:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 28 %

Procedure:
The desired compound was prepared according to the procedure of Example A111, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-bromopropane as starting materials in 28% yield. LCMS for C27H33ClN7O (M+H)+: m/z=506.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:13][CH2:14][N:15]([CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: COc1ccc(CCl)cc1
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(Cc3ccc(OC)cc3)CC2)c2ccccc2)cc1
Yield: 68.6 %

Procedure:
Method as described for Example 4, using compound 6 (174 mg) and 4-methoxybenzyl chloride (78 mg) provided N,N-diethyl-4-[(N-4-methoxybenzyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide (160 mg, 68%):
Reaction SMILES: [Cl:1][C:2]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.Cl.[CH3:43]O>>[CH3:43][O:18][C:17](=[O:19])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:40])[F:41])[C:2]=2[Cl:1])[CH2:20][CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:11]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 90 %

Procedure:
To a solution of (3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid (0.5 g, 3.7 mmol) in methanol (300 ml) was added concentrated hydrochloric acid (10 ml). After the resulting mixture was heated to reflux for 2 h solvent was removed under vacuum. The residue was dissolved in water and neutralized to pH=7. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated in vacco to give the title compound as colorless oil (0.5 g, 90%). MS m/e 596.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:21])[CH:9]=[C:8]([C:10]([NH:12][CH3:13])=[O:11])[C:7]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:6]=2[O:5]1.[CH3:22]I.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1([CH3:21])[CH:9]=[C:8]([C:10]([N:12]([CH3:22])[CH3:13])=[O:11])[C:7]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:6]=2[O:5]1
Reactant: CI
Reactant: CNC(=O)C1=CC(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(C)C=C(C(=O)N(C)C)c2cc([N+](=O)[O-])ccc2O1
Temperature: 0 °C

Procedure:
To a mixture of 130 mg of 2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide, 83 μl of methyl iodide and 5 ml of dried N,N-dimethylformamide was added 21 mg of sodium hydride (60%) with stirring under ice-cooling and stirred at room temperature for 15 hours. Ice water was added to the reaction solution and it was extracted with ether. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 130 mg of 2-methoxymethyl-N,N,2-trimethyl-6-nitro-2H-1-benzopyran-4-carboxamide. Subsequently, 103 mg of a Lawesson's reagent and 8 ml of benzene were added therein and the resultant mixture was refluxed with heating for 1 hour. After the reaction solution was vacuum-condensed, the residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=3:1) to obtain 140 mg of 2-methoxymethyl-N,N,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide. Subsequently, 290 μl of iodomethane, 104 mg of cyanamide and 8 ml of dried tetrahydrofuran were added therein and 96 mg of sodium hydride (60%) was added therein with stirring under ice-cooling, and the resultant mixture was stirred at room temperature for 15 hours. Ice water was added to the reaction product and it was extracted with ethyl acetate. an organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=2:3) to obtain 125 mg of N-cyano-2-methoxymethyl-N',N',2-trimethyl-6-nitro-2H-1-benzopyran-4-amidine with a melting point of 143°-146° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15]OS(C)(=O)=O)=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33]2)=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 91.8 %

Procedure:
Following the procedure of Example 1(10), 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 91.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C(O)CC(OC(C)(C)C)=O)[C:5]([NH:18][C:19](=[O:24])[C:20]([CH3:23])(C)C)=[CH:4][N:3]=1.[H][H]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][N:3]=1)[NH:18][C:19](=[O:24])[CH:20]=[CH:23]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC(O)c1cc(Cl)ncc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc2cc(Cl)ncc2[nH]1

Procedure:
A solution of 4.63 g (13 mmoles) of 2-chloro-5-((2,2-dimethyl-1-oxopropyl)amino)-β-hydroxy-4-pyridine propanoic acid, 1,1-dimethylethyl ester in 70 ml of dioxane and 30 ml of 3N HCl in water was warmed at reflux for a period of 4 hours. The solution was diluted with 100 ml of water and cooled to give a white precipitate. The crystals were filtered, washed with water and dried in a vacuum oven to give 2.18 g (93% of theoretical) of the above-captioned compound having a melting point of 304°-306° C. The carbon, hydrogen and nitrogen content calculated for C8H5ClN2O is C, 53.20; H, 2.79; and N, 15.52 percent by weight which compares to that actually found upon analysis of C, 53.55; H, 2.79; and N, 15.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:26]([S:33](Cl)(=[O:35])=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:33]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:35])=[O:34])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)Cc4ccccc4)cc3)cc2C1=O

Procedure:
The compound of example 93 was prepared analogous to compound of example 77 by reaction of compound of example 6 with benzyl sulfonyl chloride. The compound of example 93 was used directly without isolation for the preparation of compound of example 94.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11](O)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCOCC1.CN(C)C=O.C(O)(=O)C.CC(C)=O>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Oc1ccc(/C=C/CO)cc1

Procedure:
To a cold solution (10° C.) of 10.000 (48.5 mmol) of 4-acetoxy-trans-cinnamic acid in 72 ml of anhydrous dioxane is added 7.44 ml (53.35 mmol) of triethylamine. Ethyl chloroformate (5.08 ml, 53.35 mmol) in anhydrous dioxane (10 ml) is added to the mixture over 15 minutes with stirring. The resulting mixture is stirred for further 30 minutes at 10°-12° C. and then filtered. The filtrate is dropwise added to a suspension of 2.295 g (60.624 mmol) of powdered sodium borohydride in 100 ml of anhydrous dioxane and 1.22 ml of anhydrous dimethylformamide, and the mixture stirred at 8° C. for one hour. Acetone (7 ml) is added, the mixture stirred for 30 minutes, and 3.47 ml of acetic acid added. The mixture is concentrated in vacuo to about 100 g and extracted with benzene and water. The organic layer is washed with chilled 10% aqueous sodium carbonate and water, successively, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 4-acetoxy-trans-cinnamylalcohol (I). This is recrystallized from carbon tetrachloride to give 6.673 g of colorless prisms, mp.73.5°-75° C. The mother liquor is concentrated in vacuo and 1.622 g of residue is dissolved in water and hexane. The aqueous layer is extracted with benzene and the benzene layer is washed with chilled 10% aqueous sodium carbonate and water twice, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 4-acetoxy-trans-cinnamylalcohol (I). This is recrystallized from carbon tetrachloride to give 536 mg of colorless prisms, mp. 73°-74.5° C. Total yield 7.209 g (77.3%). A portion of the product is recrystallized from ether/hexane to give an authentic specimen as prisms having mp. 75°-76° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33]Cl)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[Na]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Na]c1ncc[nH]1
Reactant: COc1cc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.8 g of 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo-[2,3-d]pyrimidine and 0.2 g of imidazolyl sodium are heated to 80° C. in 30 ml of DMF and the mixture is stirred for 5 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 122°-124° C. is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:18]=2)=[O:9])[CH2:3][CH2:2]1>[C].[Pd].CO>[O:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)[C:8]([C:10]2[N:11]=[C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[CH:18]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(c1cn2ccccc2n1)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cn2c(n1)CCCC2)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of N-(tetrahydro-2H-pyran-4-yl)-N-[3-(trifluoromethoxy)benzyl]imidazo[1,2-a]pyridine-2-carboxamide (50 mg), 10% palladium-carbon (50 mg) and methanol (15 mL) was stirred in a nitrogen atmosphere for 2 hours at room temperature. The insoluble matter was filtered off and methanol was distilled off under reduced pressure to give the titled compound (48 mg).