Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:42]([O:46][C:47](=[O:62])[NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51](CN2C=CC(N)=N2)[CH:50]=1)([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([O:46][C:47](=[O:62])[NH:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH:54]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(N)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 500 mg, 1.52 mmol) was suspended in methylene chloride (7.6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (760 μL, 1.52 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (354 μL, 3.04 mmol) was added. The reaction continued to stir at 0° C. for 15 min. [3-(3-Amino-pyrazol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (437 mg, 1.52 mmol) was dissolved in methylene chloride (7 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (300 mL), washed with water (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate and concentrated in vacuo to a yellow foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 5% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded (3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-phenyl)-carbamic acid tert-butyl ester (539 mg 59%) as a pale pink powder: ESI-LRMS m/e calcd for C30H37ClN4O5S [M+] 600.22, found 601.50 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.23 (m, 2H, CH2), 1.45-1.93 (m, 8H, 4×CH2), 1.51 (s, 9H, 3×CH3), 2.15-2.30 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.8 Hz, 1H, CH), 5.11 (s, 2H, NCH2), 6.49 (brs, 1H, NH), 6.71 (d, J=2.5 Hz, 1H, Ar), 6.82 (m, 1H, Ar), 7.19-7.25 (m, 2H, Ar), 7.26-7.29 (brs, 1H, Ar), 7.31 (d, J=2.5 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz. 1H, Ar), 8.17 (brs, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(N(CC)CC)C>C(#N)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:20]([C:11]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:21])[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27]
Reactant: c1ccc(COCn2ccnc2)cc1
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(C(=O)c2nccn2COCc2ccccc2)cc([N+](=O)[O-])c1OC
Reaction time: 3 h

Procedure:
A solution of 10.0 g of 1-[(benzyloxy)-methyl]imidazole in 50 ml of acetonitrile is added dropwise within 10 minutes while cooling with ice to a solution of 13.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4 g of triethylamine in 80 ml of acetonitrile so that the temperature does not exceed 25°. The mixture is subsequently stirred for an additional 3 hours, whereupon the solvent is distilled. After treatment with water, the mixture is extracted with ethyl acetate. After two-fold washing with water, the organic phase is dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 600 g of silica gel with toluene/ethyl acetate (95:5). There is obtained 1-[(benzyloxy)methyl]imidazol-2-yl (3,4-dimethoxy-5-nitrophenyl) ketone as a yellowish oil
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9]>O.C1COCC1>[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.6 %

Procedure:
Lithium hydroxide monohydrate (19 mg, 0.45 mmol) in water (2 mL) was added to methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-phenylmethoxy-benzoate (0.11 g, 0.3 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer adjusted to pH 3 with citric acid then extracted into ethyl acetate (2×30 mL). The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound (0.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:49])[N:10]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[NH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:50]([N:52]=[C:53]=[O:54])[CH3:51]>>[CH2:1]([O:8][C:9]([N:10]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:37][CH:36]=1)[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:53](=[O:54])[NH:52][CH2:50][CH3:51])[CH:20]=2)[NH:15][C:14]=1[C:23]1[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=1)=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN(CCCCc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)c1
Reactant: CCN=C=O
Product: CCNC(=O)Oc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(OCc4ccccc4)cc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C

Procedure:
To a solution of [4-(4-benzyloxyphenyl)-butyl]-[2-[2-(3,5-dimethylphenyl)-5-hydroxy-1H-indol-3-yl]ethyl]carbamic acid benzyl ester (50 mg in 0.5 mL dry tetrahydrofuran) was added 0.035 mL of ethyl isocyanate and the mixture stirred at room temperature. Over the course of 2 weeks, additional ethyl isocyanate was added in portions and the mixture heated to reflux for several days after which time it was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) to give the title compound (20 mg).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:13](O)(=[O:15])[CH3:14].O.OS(O)(=O)=O>>[C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])(=[O:15])[CH3:14]
Reactant: OCCCCCCCCCCO
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OCCCCCCCCCCO
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 4.36 g (25 mmoles) of 1,10-decanediol in 100 ml (1.77 moles) of glacial acetic acid was mixed with 130 ml (7.22 moles) of H2O containing 0.25 ml (4.5 mmoles) of conc. H2SO4. This mixture, itself at room temperature, was then extracted continuously for two days using refluxing cyclohexane. The cyclohexane layer was then cooled to room temperature and 0.78 g (18% recovery) of crystalline 1,10-decanediol was recovered by simple filtration of this nonpolar organic phase. The cyclohexane was then removed from the filtrate under reduced pressure, affording 4.28 g (approximately 79% yield--97% based on recovered starting material of product. GC analysis showed the presence of less than 2% starting diol; the ratio of monoester to diester was 20 to 1. Hence the desired monoester was approximately 95% pure.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([B:7]([OH:9])[OH:8])=[CH:4][CH:3]=1.[NH:10]([CH2:14][CH2:15]O)[CH2:11][CH2:12]O>>[Cl:1][C:2]1[S:6][C:5]([B:7]2[O:9][CH2:15][CH2:14][NH:10][CH2:11][CH2:12][O:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: OCCNCCO
Product: Clc1ccc(B2OCCNCCO2)s1
Yield: 28 %

Procedure:
The title compound (28%, crystals) was prepared from 5-chlorothiophen-2-boronic acid and diethanolamin.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[NH:13]1[CH2:20][CH2:19][CH2:18][C@@H:14]1C(O)=O>>[CH2:19]1[C@@H:20]2[C:5](=[O:12])[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:4])[N:13]2[CH2:14][CH2:18]1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: O=C1Nc2ccccc2C(=O)N2CCC[C@H]12
Yield: 78.9 %

Procedure:
The same procedures used in the method B in Reference Example 19 were repeated except for the use of isatoic anhydride and D-proline to form the title compound. Yield 78.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:28]#[N:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:28]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:8][C:4]1[CH:3]=[C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:17][C:16]([NH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[N:15][CH:14]=2)#[N:29]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 33.6 %

Procedure:
4-(3-aminophenylamino)-6-(2-morpholinoethylamino)-1,7-naphthyridine-3-carbonitrile (111 mg, 0.29 mmol, 1 eq) was suspended in methylene chloride (10 mL). Triethylamine (44 uL, 0.32 mmol, 1.1 eq) was added and the mixture was cooled to 0° C. Methylsulfonyl chloride (24 uL, 0.31 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 12 hr. Another 44 uL triethylamine (1.1 eq) and 48 uL methylsulfonyl chloride (2.2 eq) were added and reaction mixture was stirred for 12 hr. Work-up and preparative HPLC yielded 45.5 mg product (34% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.39-2.47 (m, 4 H) 2.56 (t, J=6.82 Hz, 2 H) 2.99-3.03 (m, 3 H) 3.27-3.42 (m, 2 H) 3.55-3.61 (m, 4 H) 6.63 (t, J=6.06 Hz, 1 H) 7.00-7.04 (m, 1 H) 7.04 (s, 1 H) 7.08 (d, J=8.59 Hz, 1 H) 7.12-7.16 (m, 1 H) 7.36 (t, J=8.34 Hz, 1 H) 8.26 (s, 1 H) 8.84 (s, 1 H) 9.69 (s, 2 H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.Cl>CO.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([O:16][CH3:17])=[O:15]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: COC(=O)C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2,3,4-Trifluoroaniline (0.83 g) and methyl pyruvate (0.87 g) were dissolved in methanol (8 ml). After adding 5% Pd—C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 2 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.26 g) was obtained as slightly yellowish crystals. Various spectral data of this product was identical with those obtained in Example 5.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].[CH2:36]([N:38](C(C)C)C(C)C)C.Cl.CN>CN(C)C=O>[F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:38][CH3:36])=[O:28])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(CCc2ccccc2)CC(F)(F)C(=O)N3C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.012 g (0.19 mmole) of methylamine hydrochloride in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.056 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-278) as a white solid.
Reaction SMILES: N#N.[O:3]1[CH:7]2[O:8][CH2:9][CH2:10][CH:6]2[CH:5]([O:11][C:12](=[O:40])[NH:13][CH:14]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:15]([OH:32])[CH2:16][N:17](C(OCC2C=CC=CC=2)=O)[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:4]1>[Pd].O1CCCC1>[O:3]1[CH:7]2[O:8][CH2:9][CH2:10][CH:6]2[CH:5]([O:11][C:12](=[O:40])[NH:13][CH:14]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:15]([OH:32])[CH2:16][NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:4]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
After displacing the air with N2, palladium on charcoal (10%, 5.00 g, 47.00 mmol, 0.32 equiv) was added followed by the addition of a solution of [1-benzyl-3-(benzyloxy-carbonyl-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester (78.36 g, 148.80 mmol, 1 equiv) in tetrahydrofurane. For a few minutes vacuum was applied and replaced by H2. After stirring for 24 h at room temperature. N2 was then introduced in the flask to displace the remaining H2. The palladium catalyst was removed by filtration over a bed of dicalite under N2 and the filter was washed with tetrahydrofurane. The filtrate was evaporated under reduced pressure. (58.40 g, 148.80 mmol, quantitative). LRMS (ES+): m/z 393 [M+H]+; 1H-NMR (CDCl3) δ0.91 (d, 3H, CH3), 0.93 (d, 3H, CH3), 1.45-1.57 (m, 2H, CH2, H4), 1.58-1.83 (m, 1H, CH (isobutyl)), 2.43 (dd, 2H, CH2—N (isobutyl)), 2.66-2.81 (m, 3H, CH2—N and CH of CH2C6H5), 2.87-2.96 (m, 1H, CH, H3a), 3.06 (dd, 1H, CH of CH2C6H5), 3.51-3.57 (m, 1H, CH2, H5), 3.67-3.75 (m, 2H, CH and CH2, H2), 3.81-3.93 (m, 2H, CH—OH and CH2, H5), 3.94-4.00 (m, 1H, CH2, H2), 5.01-5.08 (m, 1H, CH, H3), 5.10 (d, 1H, NH), 5.64 (d, 1H, CH, H6a), 7.16-7.31 (m, 5H, C6H5).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNCC1
Reactant: O=C(CBr)c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(CN1CCCCC1)c1cccc(F)c1

Procedure:
A mixture of 2-bromo-1-(3-fluoro-phenyl)-ethanone (5.0 g; 23.04 mmol; 1.0 eq.), piperidine (2.30 ml; 23.04 mmol; 1.0 eq.) and DIEA (4.89 ml; 27.65 mmol; 1.20 eq.) in CHCl3 (100 mL) was heated for reflux overnight. The mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The separated organic layer was dried over MgSO4, filtered and concentrated. The residue was purified through flash chromatography on silica gel to afford the title compound. LC-MS: 222 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:12]/[C:13]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-hydroxy-4-methoxybenzaldehyde (1.1 g, 7.3 mmol) and 3,4,5-trimethoxyacetophenone (1.54 g, 7.3 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with chloroform (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, the solvent concentrated under vacou. The product was purified by crystallisation from methanol. 1H-NMR (CDCl3): 7.8 (d, 1H), 7.4 (d, 1H), 7.2-7.3 (m, 3H), 7.1 (dd, 1H), 6.9 (d, 1H), 5.8 (s, 1H) 4.0 (s, 9H) 3.9 (s, 3H); Mass Spectrum m/C (M+1) 329.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]([NH2:14])=[S:13].[O-]CC.[Na+].[C:19]([CH2:21][C:22](OCC)=[O:23])#[N:20].S(=O)(=O)(O)O>CCO.O>[NH2:20][C:19]1[N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:12](=[S:13])[NH:14][C:22](=[O:23])[CH:21]=1
Reactant: NC(=S)NCc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(=O)[nH]c(=S)n1Cc1nc2ccccc2[nH]1
Reaction time: 7 h
Yield: 30.3 %

Procedure:
To a solution of N-(1H-benzimidazol-2-ylmethyl)thiourea (0.85 g, 4.1 mmol, obtained from Example 8(a)) in EtOH (10 mL) was added, dropwise, in portions during 7 h, sodium ethoxide (1M, 16.6 mL, 16.6 mmol) and a solution of ethyl cyanoacetate (1.76 mL, 16.6 mmol) in EtOH (10 mL) while the reaction was stirred at 80° C. After cooling to r.t. water (200 mL) was added followed by 2M sulphuric acid, the mixture was concentrated until precipitation occurred. The formed solid was collected by filtration, washed with water and dried to give the title compound (0.34 g, 30%) as a solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[N:10]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:2]([O:4][CH2:5][Cl:6])=[O:3])[N:10]=1)=[O:3]
Reactant: OCc1cccc(CO)n1
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCCl)OCc1cccc(COC(=O)OCCl)n1
Yield: 95 %

Procedure:
The reaction of the compound of the formula (II) with the compound of the formula (III) is carried out at a temperature between -30° C. and +10° C., preferably at about -5° C. This reaction will be described in detail hereinafter. At least 2 moles of chloromethyl chloroformate of the formula (III) [as calculated for 2,6-bis(hydroxymethyl)pyridine of the formula (II)] are dissolved in the desired solvent, preferably in chloroform, and a solution containing an organic base, preferably pyridine, in the same molar amount as the compound of the formula (III) in the same solvent is added at a temperature lower than 10° C., preferably at about -5° C., under stirring. The suspension obtained is stirred for about 20 minutes while care is taken to avoid any increase of the temperature. Then, 2,6-bis(hydroxymethyl)pyridine of the formula (II) is added to the above mixture at the same temperature at such a rate that the temperature reaches at most -5° C. The suspension is stirred for about 20 minutes to give a brown solution. After washing this solution with water and evaporation, a practically pure product with 95 to 97% of 2,6-bis(chloromethyloxy-carbonyloxymethyl)pyridine content is obtained. The product obtained after washing with water and making free of the solvent can be used without any purification or, if desired, may be further purified by chromatography on a silicagel column or on an other adsorbent, e.g. on a synthetic resin.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]4[S:22][C:23]([CH:25]=O)=[CH:24][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]4[S:22][C:23]([CH2:25][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:24][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCN(c2ccc(-n3cnc4cc(C=O)sc4c3=O)cc2)CC1
Reactant: C1CCNC1
Product: CN1CCCN(c2ccc(-n3cnc4cc(CN5CCCC5)sc4c3=O)cc2)CC1

Procedure:
3-[4-(4-Methylperhydro-1,4-diazepin-1-yl)phenyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-6-carbaldehyde was reacted with pyrrolidine by method BA. The product with the molecular weight of 423.58 (C23H29N5OS) was obtained in this way; MS (ESI): 424 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]1([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:16][CH2:15]CCC1>>[CH:1]1([CH2:6][CH2:7][CH2:8][C:19]([CH:18]2[CH2:15][CH2:16][CH2:11][CH2:17]2)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: O=C(O)CCC1CCCC1
Product: O=C(CCCC1CCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where 3-cyclopentyl propionic acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([C:12]([F:15])([F:14])[Cl:13])[N:10]([OH:11])[C:3]=12.[OH-].[NH4+:17]>>[NH2:17][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([C:12]([F:15])([F:14])[Cl:13])[N:10]([OH:11])[C:3]=12
Reactant: On1c(C(F)(F)Cl)nc2nccc(Cl)c21
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ccnc2nc(C(F)(F)Cl)n(O)c12

Procedure:
7-Chloro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo-(4,5-b)pyridine is reacted with ammonium hydroxide to obtain 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine which is oxidized to the corresponding 7-nitro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. Also, the 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine is treated with sodium nitrite and subsequently sodium cyanide to obtain the corresponding 7-cyano-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. On treatment with 70 percent sulphuric acid the corresponding 7-carboxy-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine is prepared. On further treatment with SF4 and HF, there is obtained 7-(trifluoromethyl)-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine.