Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:6]=[C:5]2[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN1CCC[C@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1Cc1cn([Si](C)(C)C(C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a solution of (S)-5-bromo-3-[(N-methylpyrrolidin-2-yl)methyl]-l H-indole (Example 3c, 1.00 g, 3.41 mmol) in THF (15 mL) under argon, was added sodium hexamethyldisilazide (6.82 mL, 6.82 mmol and the resulting solution was stirred at room temperature for 20 min. The reaction mixture was cooled to 0° C. and to this was added a solution of t-butydimethylsilyl chloride (1.03 g, 6.82 mmol) in THF (4 mL) and the resulting culture was warmed to room temperature and stirred for 1 hour. The solvent as removed in vacuo and the resulting product was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The ethyl acetate extract was washed with brine (10 mL), dried (Na2SO4), filtered and the filtrate was evaporated to dryness. The crude residue was subjected to flash silica gel chromography to afford the title compound as a yellow oil (1.07 g, 79%). 13C NMR (CDCl3)δ: 140.1, 133.1, 129.8, 124.1, 121.5, 115.8, 115.2, 112.7, 66.2, 7.6, 40.9, 31.6, 30.1, 26.2, 21.9, 19.5, −3.96
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])C(O)=O.NC1C=C(C(O)=O)C(=CC=1N)C(O)=O.O[C:27]1[CH:28]=[C:29]([C:34]2C=CC(N)=C(O)[CH:35]=2)[CH:30]=[CH:31][C:32]=1N.NC1C=CC(C2C=CC(N)=CC=2)=CC=1>>[C:29]1([C:34]2[CH:35]=[N:1][C:2]3[C:10](=[CH:9][CH:8]=[CH:4][CH:3]=3)[N:11]=2)[CH:30]=[CH:31][CH:32]=[CH:27][CH:28]=1
Reactant: Nc1ccc(-c2ccc(N)c(O)c2)cc1O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Nc1cc(C(=O)O)c(C(=O)O)cc1N
Agent: Nc1ccc(-c2ccc(N)cc2)cc1
Product: c1ccc(-c2cnc3ccccc3n2)cc1

Procedure:
One proceeds in accordance with Example 1, where in place of 3,4-diaminobenzoic acid, 4,5-diaminophthalic acid is used, and in place of 3,3'-dihydroxy-4,4'-diaminobiphenyl, 4.4'- diaminobiphenyl is used. Via tetracarboxylic acid, or the corresponding acid chloride, as an intermediate stage, a copolymer with phenylquinoxaline units and o-carboxyamide groupings (-CO-NH-) is thereby obtained. When annealed to approximately 400° C., they cyclize into imide structures.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Cc1ccc(CN)o1
Reactant: Nc1ccc(F)cc1
Product: Cc1ccc(CNc2ccc3c(Nc4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=348.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 4-fluoroaniline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]=[C:12]([CH2:15][OH:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[Na+].[Na+].CI.[Cl-].[Na+]>CO.ClCCl>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:18])[C:12]([CH2:15][OH:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1nc(CO)[nH]cc1OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CI
Product: Cn1c(CO)ncc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 49.2 %

Procedure:
5-(Benzyloxy)-2-(hydroxymethyl)-4(1H)-pyrimidinone (2.3 g) are dissolved in 20 ml of absolute methanol. The solution is treated with 4.24 g (40 mmol) of sodium carbonate and 10 ml of methyl iodide and stirred at room temperature for 4 days. Now, 400 ml of dichloromethane and 100 ml of saturated sodium chloride solution are added thereto, the organic phase is separated, dried over sodium sulphate and concentrated. The residue is chromatographed of 100 g of silica gel (0.063-0.2 mm). The two products are eluted in succession with dichloromethane/methanol (9:1 v/v). There are obtained 1.2 g of 5-(benzyloxy)-2-(hydroxymethyl)-3-methyl-4(3H)-pyrimidinone as white crystals from ether, m.p. 83°-84° C. 5-(Benzyloxy)-2-(hydroxymethyl)-1-methyl-4(1H)-pyrimidinone also forms white crystals from ether, m.p. 172°-173° C. 0.6 g is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1.C(=O)(O)[O-:18].[Na+].O>CS(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1)=[O:18]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1-c1ccc(C=O)cc1
Temperature: 120 °C
Yield: 63.1 %

Procedure:
A mixture of 2-(4-bromomethylphenyl)benzonitrile (12 g) and sodium bicarbonate (26 g) in dimethyl sulfoxide (150 ml) was heated at 120° C. for 5 hours with stirring. After addition of water, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from chloroform-isopropyl ether gave colorless needles (5.77 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCOC(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(Cl)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1

Procedure:
To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (1.00 g, 3.44 mmol) and DIPEA (0.672 mL, 3.86 mmol) at room temperature (20° C.) in DCM (7 mL) was added morpholine (0.33 mL, 3.86 mmol). After 2 h the reaction was diluted with DCM and Sat. NaHCO3. The organic layer was rinsed (brine), dried (anhydrous Na2SO4) and concentrated in vacuo. The desired product was isolated by flash chromatography (silica, 50 g, 0-50% EtOAc in petroleum ether (40-60) over 25 min) as a white solid (0.63 g, 1.85 mmol, 54% yield).
Reaction SMILES: [CH:1]1[C:5]2[C:6]([Cl:10])=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.ClC(Cl)(O[C:15](=[O:21])OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[NH2:32][C:33]1[CH:34]=[C:35]([NH:40][C:41](=[O:58])[C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([N:52]3[CH:56]=[C:55]([CH3:57])[N:54]=[CH:53]3)[CH:43]=2)[CH:36]=[CH:37][C:38]=1[CH3:39]>C1COCC1>[CH3:39][C:38]1[CH:37]=[CH:36][C:35]([NH:40][C:41](=[O:58])[C:42]2[CH:47]=[C:46]([C:48]([F:49])([F:50])[F:51])[CH:45]=[C:44]([N:52]3[CH:56]=[C:55]([CH3:57])[N:54]=[CH:53]3)[CH:43]=2)=[CH:34][C:33]=1[NH:32][C:15]([N:3]1[C:4]2[N:9]=[CH:8][N:7]=[C:6]([Cl:10])[C:5]=2[CH:1]=[CH:2]1)=[O:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(N)c3)cc(C(F)(F)F)c2)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
6-Chloro-7-deazapurine (3.9 g, 25.5 mmol), triphosgene (3.80 g, 12.8 mmol), and DIEA (8.9 mL, 51 mmol) are stirred in THF (100 mL) at 0° C. for 3 hours. The THF is removed by evaporation and the residue is dissolved in THF (100 mL). The solution is mixed with N-(3-amino-4-methyl-phenyl)-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide (3.5 g, 9.3 mmol) and shaken at room temperature for 18 hours. The solvent is evaporated and the residue is purified by silica gel column chromatography (2% MeOH in CH2Cl2) to obtain 4-chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (3.4 g, yield 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.71 (s, 1H), 9.62 (s, 1H), 8.99 (s, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8.46 (d, J=4.0 Hz, 1H), 8.24 (d, J=4.0 Hz, 1H), 8.18 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.96 (d, J=4.0 Hz, 1H), 2.47 (s, 3H), 2.37 (s, 3H); ESIMS m/z 554.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:19][CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(Cc3ccccc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole(2.96 g, 10.9 mmol) in dry DMF (15 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/479 mg, 12.0 mmol) in dry DMF (15 ml) maintained under nitrogen at room temperature. After stirring for 45 minutes at room temperature benzyl bromide (1.3 ml, 10.9 mmol) was added dropwise. The reaction was stirred for a further 2 hours, diluted with ethyl acetate (75 ml), washed with brine (2×80 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate-hexane (2:7) as eluant. (3.68 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[C:23](O[C:27](=[O:29])[CH3:28])(=[O:25])C.[CH:30](O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH:10]1[N:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:13][N:14]1[CH:23]=[O:25].[CH:27]([O:29][CH:22]([CH3:21])[CH3:17])([CH3:30])[CH3:28]
Reactant: Clc1ccc(Cl)c(N=C2NCCN2OCc2ccccn2)c1
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Product: CC(C)OC(C)C
Product: O=CN1CCN(OCc2ccccn2)C1Nc1cc(Cl)ccc1Cl
Temperature: 25 °C

Procedure:
2.3 g of 2-([{2-[(2,5-dichlorophenyl)-imino]-1-imidazolidinyl}oxy]methyl)pyridine and 5.1 ml of formic acid are cooled to 5° and treated with 12.2 ml of acetic acid anhydride. The solution is warmed to room temperature and evaporated in vacuo. The residue is taken up in ether. The organic phase is washed with a saturated sodium bicarbonate solution, dried and evaporated in vacuo. The residual of oil is chromatographed on silica gel with a mixture of 4 parts of chloroform and 1 part of ethyl acetate as the elution agent. There is obtained crystalline 2-[(2,5-dichlorophenyl)amino]-1-formyl-3-(2-pyridylmethoxy)imidazolidine of melting point 91°-92° (isopropyl ether).
Reaction SMILES: N1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]2[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)C1.[F:19][C:20]([F:31])([F:30])[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.[NH:32]1C2C(=CC=CC=2)C=[C:33]1C(O)=O>>[F:19][C:20]([F:31])([F:30])[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([N:32]2[CH2:33][CH2:5][CH2:4][CH:3]2[CH2:6][O:7][C:8]2[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:28])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCOC(=O)c1ncccc1OCC1CCNC1
Product: CCOC(=O)c1ncccc1OCC1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using ethyl 3-(pyrrolidin-3-ylmethoxy)picolinate (EXAMPLE 92, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: CN1CCNCC1.BrC1SC(C=O)=CC=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[S:27][C:23]([N:20]3[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CN1CCN(c2ccc(C=O)s2)CC1
Agent: CN1CCNCC1
Agent: O=Cc1ccc(Br)s1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCN(C)CC3)s2)cc1OC
Yield: 66.9 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 1-methylpiperazine (6.01 g) was introduced into 5-bromothiophene-2-carboxaldehyde (3.82 g), to thereby yield 5-(4-methyl-piperazin-1-yl)-thiophene-2-carbaldehyde (yield: 3.71 g, 88%). The produced 5-(4-methyl-piperazin-1-yl)-thiophene-2-carbaldehyde (2.10 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.77 g) through Method A (production step 2), to thereby yield the target product (yield: 2.47 g, 67%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+].[CH3:28]N1C(=O)CCC1>>[CH2:16]([O:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:22][CH:23]=1)[CH3:28]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CN1CCCC1=O
Reactant: C=Cc1ccc(OC)nc1
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH:3]([O:9][C:10](=[O:26])[CH2:11][CH:12]([CH2:17][NH:18]C(OC(C)(C)C)=O)[CH2:13][CH:14]([CH3:16])[CH3:15])[O:4][C:5](=[O:8])[CH2:6][CH3:7].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[OH:32][C:30]([C:29]([F:34])([F:33])[F:28])=[O:31].[CH3:27][CH:2]([CH3:1])[CH:3]([O:9][C:10](=[O:26])[CH2:11][CH:12]([CH2:17][NH2:18])[CH2:13][CH:14]([CH3:15])[CH3:16])[O:4][C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)OC(OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)OC(OC(=O)CC(CN)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Compound 18 (0.196 g, 0.51 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (3.25 mL) was added in an ice water bath and maintained for 30 minutes. The solution was then warmed to room temperature and stirred for 5 hours. After concentrating and drying, 3-aminomethyl-5-methyl-hexanoic acid 2-methyl-1-propionyloxy-propyl ester TFA salt 19 (0.194 g) was obtained with a yield of 95%. 1HNMR (CD3OD, 500 MHz) δ0.88-0.92 (m, 6H), 0.94 (d, J=6.5 Hz, 3H), 1.08 (t, J=7.5 Hz, 2H), 1.20-1.28 (m, 2H), 1.60-1.69 (m, 1H), 1.95-2.02 (m, 1H), 2.16-2.23 (m, 1H), 2.29-2.46 (m, 3H), 2.89-2.98 (m, 2H), 3.27 (s, 1H), 6.59 (d, J=5 Hz, 1H); 13CNMR (CDCl3, 125 MHz) δ9.29, 9.31, 16.74, 16.84, 16.86, 22.58, 22.59, 23.25, 23.27, 23.31, 26.28, 26.32, 28.28, 32.83, 32.90, 32.95, 36.85, 36.93, 37.28, 41.80, 41.89, 42.24, 44.31, 44.34, 44.71, 49.66, 94.54, 94.57, 172.16, 172.18, 174.46. LC/MS: ESI positive mode (M+H): 288.30.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14]C)[CH:6]=[CH:7][C:8]([OH:10])=[O:9].CO[C:18]1[CH:19]=[C:20]([CH2:26][CH2:27]CO)[CH:21]=[CH:22][C:23]=1[O:24]C.[C:30](CC(O)=O)#[N:31].B(Cl)(Cl)Cl.OC1C=C(C=CC=1O)C=O>>[C:30]([C:7](=[CH:6][C:5]1[CH:11]=[CH:12][C:13]([OH:14])=[C:3]([OH:2])[CH:4]=1)[C:8]([O:10][CH2:27][CH2:26][C:20]1[CH:21]=[CH:22][C:23]([OH:24])=[CH:18][CH:19]=1)=[O:9])#[N:31]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: COc1ccc(CCCO)cc1OC
Reactant: N#CCC(=O)O
Agent: ClB(Cl)Cl
Agent: O=Cc1ccc(O)c(O)c1
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)OCCc1ccc(O)cc1

Procedure:
After the reduction of 3,4-dimethoxycinnamic acid to 3-(3,4-dimethoxyphenyl)propanol in the usual manner followed by condensation with cyanoacetic acid according to the procedure in Example 3, the product was demethylated with boron trichloride and condensed with 3,4-dihydroxybenzaldehyde to give the following compound.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1CO>>[Na:1].[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])[C:13]=1[CH3:30]
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: OCC1OCCCO1
Agent: [Na]
Product: Cc1c(OCC2OCCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 10 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 1,3-dioxan-2-ylmethanol obtained in the step (32b) to obtain the title compound (148 mg, total yield: 10%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[C:42]([CH3:47])=[CH:43][CH:44]=[CH:45][CH:46]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH3:47])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Cc1ccccc1N
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (146 mg, 0.428 mmol), EDC (115, 0.599 mmol), and HOBT (81 mg, 0.599 mmol) in DMF (8 mL) was added o-toluidine (64 mg, 0.60 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (92 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][C:7]=1[CH3:12])(=O)[CH3:4].[C:13]1(=[O:27])[O:26][C:19](C)([CH:20]([CH2:23]C)[CH2:21][CH3:22])[O:18]C(=O)CC1.Cl.[C:29](Cl)(=O)C>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:12][C:7]1[O:8][C:9]([CH3:11])=[CH:10][C:6]=1/[C:3](=[C:23]1/[C:13]([O:26][C:19](=[O:18])[C:20]/1=[C:21]([CH3:22])[CH3:29])=[O:27])/[CH3:4]
Reactant: CCC(CC)C1(C)OC(=O)CCC(=O)O1
Reactant: CC(=O)Cl
Reactant: CC(=O)c1cc(C)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)=C1C(=O)OC(=O)/C1=C(\C)c1cc(C)oc1C
Temperature: 0 °C
Reaction time: 7 h
Yield: 15 %

Procedure:
To a suspension of 700 ml of benzene with 52.8 g of sodium hydride, 118 g of a mixed solution 76 g of 3-acetyl-2,5-dimethylfuran (mfd. by Sldrich Chemical Co., Inc.) and 118 g of the diethylisopropylidene succinate obtained in Reference Example 1 (4) was added dropwise in 2 hours with stirring. After reacting for further 7 hours with stirring, the reaction solution was poured into 2 kg of ice. The water layer was separated, made acidic with 690 ml of 5M HCl, and extracted with 1.5 liters of ethyl acetate. The resulting organic layer was concentrated. To the residue, 1.85 liters of 5 w/v% ethanolic potassium hydroxide was added and reaction was carried out for 15 hours under relux. After the reaction, the reaction solution was made acidic with HCl. A precipitate produced was dissolved in chloroform. The solvent was removed from the resulting chloroform solution by distillation. To the residue, acetyl chloride was added and ring closing reaction was carried out. After the reaction, excess acetyl chloride was removed by distillation. The residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give pale yellow crystals of 2-[(E)-1-(2,5-dimethyl-3-furyl) ethylidene]-3-isopropylidene succinic anhydride of the formula: ##STR26## wherein Me is a methyl group, in yield of 15%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)[CH3:9])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[S:34])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=S)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
A mixture the product of Step A (3 g, 8.5 mmol) and Lawesson's reagent (1.7 g, 4.25 mmol) in toluene (100 ml) was refluxed for 2 h. The mixture was cooled to room temperature and then was diluted with EtOAc (100 ml), washed with 1N NaOH (2×50 ml), dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification (DCM/MeOH gradient, 0-15% MeOH) provided the desired product as a white solid (2.2 g, 71%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:30]([N:37]1[CH2:42][CH:41]2[CH:39](N2N)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH2:44]([N:46](CC)CC)C>C(#N)C>[CH2:30]([N:37]1[CH2:42][CH:41]2[CH:39]([CH:44]2[NH:46][CH2:12][CH2:11][CH:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NN1C2CN(Cc3ccccc3)CC21
Reactant: COc1ccc(C)cc1C(CCOS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C)cc1C(CCNC1C2CN(Cc3ccccc3)CC21)c1ccccc1
Temperature: 80 °C

Procedure:
The compound, toluene-4-sulphonic acid-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl ester (prepared as described in EP 0325571, 1.5 gm, 3.66 mmole, 1 eq) was dissolved in dry acetonitrile (4 ml). To the reaction mixture, 3-benzyl-3,6-diazabicyclo[3.1.0]hex-6-yl amine, 1.38 gm, 7.32 mmole, 2 eq, (prepared according to T. F. Braish et al. Synlett 1996, 1100) and triethylamine (5.1 ml) were added. The resulting reaction mixture was heated at 80° C. for 4 days. The solvents were evaporated off, from the reaction mixture under reduced pressure. The residue was dissolved in ethyl acetate, and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulphate and concentrated under high vaccum. The crude compound was purified through column chromatography using ethyl acetate in hexane solvent system.