Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CC[N:11]([C:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:20][C:19]([CH3:32])=[C:18]([C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[O:34])[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH:11]1[CH2:14][CH2:9][CH:10]([NH:11][C:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)=[CH:20][C:19]([CH3:32])=[C:18]([C:33]([N:35]3[CH2:36][CH2:37][CH:38]([N:41]4[CH2:42][CH2:43][CH2:44][CH2:45]4)[CH2:39][CH2:40]3)=[O:34])[N:17]=2)=[O:15])[CH2:9][CH2:10]1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NC2CCNCC2)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 150.7 %

Procedure:
A solution of 0.20 g (0.31 mmol) of 4-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (example 59) in 10 ml of MeOH was treated with 0.39 ml (1.56 mmol) of HCl in dioxane (4 molar) and the reaction mixture was then stirred at RT. After 18 hours, it was evaporated, poured into crashed ice, the pH was adjusted to 8-9 with sodium carbonate solution and the mixture was then extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 95:5 to 4:1) to give 0.127 g (75%) of the title compound as light yellow solid. MS: 544.3 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[NH:7][C:8]1[C:9]2[N:10]=[CH:11][N:12]([C:22]=2[N:23]=[CH:24][N:25]=1)[C@@H:13]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]1[OH:15].[H][H]>[Pt].C(O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[C:9]2[N:10]=[CH:11][N:12]([C:22]=2[N:23]=[CH:24][N:25]=1)[C@@H:13]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]1[OH:15]
Reactant: [H][H]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4C=CC[C@@H]4O)ncnc32)[C@H](O)[C@@H]1O
Agent: [Pt]
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@@H]4O)ncnc32)[C@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
A mixture of N-(cis-2-hydroxycyclopent-4-enyl)adenosine (1.6 g), 5% platinum on charcoal (0.3 g) and ethanol (80 ml) was stirred in the presence of hydrogen for 20 h. The resulting mixture was filtered and the filtrate was evaporated. The residue was dissolved in methanol (50 ml) and the solution was evaporated to yield the title compound (1.2 g) as a foam.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.N1(O)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.C(N(CC)C(C)C)(C)C.C1(NN)C=CC=CC=1.Cl.[N:42]1[CH:47]=[CH:46][C:45]([CH2:48][C:49](O)=[O:50])=[CH:44][CH:43]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[C:17]1([NH:16][NH:15][C:49](=[O:50])[CH2:48][C:45]2[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: NNc1ccccc1
Product: O=C(Cc1ccncc1)NNc1ccccc1
Reaction time: 16 h
Yield: 19.6 %

Procedure:
N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.06 g, 10.76 mmol, 2.02 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (1.45 g, 10.76 mmol), N,N-diisopropylethylamine (4.69 mL, 26.9 mmol), and phenyl hydrazine (970 mg, 8.97 mmol) were added to a solution of 4-pyridylacetic acid hydrochloride (1.23 g, 8.97 mmol) in dimethylformamide (10 mL). After 16 h, the reaction was worked up with dichloromethane and saturated sodium bicarbonate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (99% dichloromethane→12% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (400 mg). MS 228.5 (M+1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][C:32]([F:46])([F:45])[CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:46][C:32]([F:45])([CH2:31][O:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[CH2:33][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)COS(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 135 °C
Yield: 67.8 %

Procedure:
Diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 3.5 g, 13.6 mmol), 2,2-difluoropropane-1,3-diyl bis(4-methylbenzenesulfonate) (6.0 g, 14.3 mmol) and K2CO3 (3.9 g, 28.5 mmol) are mixed in DMF (36 mL) and the reaction mixture is separated into 3 fractions. Each fraction is heated in a microwave reactor at 135° C. for 1 h. The 3 fractions are combined, and water (300 mL) and EtOAc (300 mL) are added. The aqueous layer is separated and extracted with EtOAc (3×100 mL). The organic layers are combined, washed with water (3×200 mL), dried (Na2SO4) and concentrated. The crude compound is purified by flash column chromatography using EtOAc in heptane to afford the title compound (4.7 g, 59% pure, 38% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>CO.CC(O)=O.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:17])[CH:12]=[C:11]([CH3:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1cccc(OCc2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Br)cc(OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-benzyloxy-6-methyl-phenylamine (3.4 g, 16 mmol) in MeOH/AcOH (50 mL/20 mL) is cooled to 0° C. then a solution of Br2 (0.82 mL, 16 mmol) in AcOH (10 mL) is added dropwise. After the addition, the solution is stirred at RT overnight. The solvent is removed under reduced pressure and the residue adjusted to pH>8 with aqueous K2CO3 solution. The suspension is extracted with EtOAc and the combined organic layers are washed with water, brine, then dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (hexanes/EtOAc=10:1 to 5:1) to give the title compound as a red solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1.Cl>CO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:12]1([CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCNC1
Product: O=C1CC2(CCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15.8 g, 73.8 mmol), cyclopentanone (12.35 g, 147 mmol) and pyrrolidine (12 mL, 140 mmol) in MeOH (300 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromospiro[chroman-2,1′-cyclopentan]-4-one (23 g, 100%). 1H-NMR (CDCl3): 1.64 (m, 4H), 1.72 (m, 2H), 2.03 (m, 2H), 2.78 (s, 2H), 6.78 (m, 1H), 7.48 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylsulfonylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:17]=[CH:16][C:8]([CH:9]=[CH:10][C:11](OCC)=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>>[CH:1]([O:4][C:5]1[CH:17]=[CH:16][C:8](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(OC(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)Oc1ccc(/C=C/CO)cc1

Procedure:
According to the same manner as that described in Reference Example 10, ethyl 4-isopropoxycinnamate was reduced with diisobutyl aluminum hydride to give (E)-3-(4-isopropoxyphenyl)-2-propenol as an oil. This oil was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane (1:4, v/v)) (yield: 83%).
Reaction SMILES: FC(F)=C(C1C=CC(OC)=C(C=1)C=O)C(F)(F)F.N[C@H]1CCCN(C(OC(C)(C)C)=O)[C@H]1C1C=CC=CC=1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH2:49][C@H:48]([NH:52][CH2:53][C:54]2[CH:59]=[C:58]([CH:60]([C:65](F)([F:67])[F:66])[C:61]([F:64])([F:63])[F:62])[CH:57]=[CH:56][C:55]=2[O:69][CH3:70])[C@@H:47]1[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH2:49][C@H:48]([NH:52][CH2:53][C:54]2[CH:59]=[C:58]([C:60]([C:61]([F:62])([F:63])[F:64])=[C:65]([F:66])[F:67])[CH:57]=[CH:56][C:55]=2[O:69][CH3:70])[C@@H:47]1[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(=C(F)F)C(F)(F)F)cc1C=O
Product: COc1ccc(C(=C(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 79 and Compound 12 in the same manner of Compound 13.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]1[CH:23]=[CH:22][C:14]2[S:15][C:16]([C:18](OC)=[O:19])=[CH:17][C:13]=2[CH:12]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[F:10][C:11]1[CH:23]=[CH:22][C:14]2[S:15][C:16]([CH2:18][OH:19])=[CH:17][C:13]=2[CH:12]=1
Reactant: COC(=O)c1cc2cc(F)ccc2s1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc2cc(F)ccc2s1
Temperature: -10 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
DIBAL-H (59.4 mL, 59.41 mmol) was added to a solution of methyl 5-fluorobenzo[b]thiophene-2-carboxylate (I-50a: 2.5 g, 11.882 mmol) in THF (75 mL) at −70° C. and the resulting reaction mass was stirred at −10° C. for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was quenched with methanol at −70° C. and concentrated under reduced pressure. The crude residue obtained was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 1.8 g of the product (83.33% yield).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[NH:17][C:18]([N:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7])=[O:19]
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (5.52 g.; 0.041 mole) is converted to free base in benzene in the usual manner. Then 9.08 g. (0.041 mole) of 2,4,6-trichlorophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added with stirring. The reaction mixture is stirred for 2 hours and the solvent is evaporated in vacuo to give a solid residue of 1-(2,4,6-trichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 160°-162° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:3][C:4]=1[CH3:10])=[O:7]
Reactant: CNC(=O)OC(C)(C)C
Reactant: Cc1cc(Br)ccc1C=O
Product: Cc1cc(CNC(=O)OC(C)(C)C)ccc1C=O

Procedure:
The title compound was prepared from crude 4-bromo-2-methylbenzaldehyde (D91) and 1,1-dimethylethyl methylcarbamate (D83) using a method similar to that described for D84 in Description 84. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.76 (1H, d), 7.28 (1H, dd), 7.19 (1H, d), 3.31 (3H, s), 2.66 (3H, s), 1.49 (9H, s).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:17]2[C:18](=[O:38])[C:19]([O:36]C)=[C:20]3[C:25]([CH2:24][CH2:23][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=4)[C:21]3=[O:35])=[C:16]2[C:15](=[O:39])[N:14]([CH3:40])[CH2:13][CH2:12][CH2:11]1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[CH2:26][N:22]1[CH2:23][CH2:24][C:25]2[C:20](=[C:19]([OH:36])[C:18](=[O:38])[N:17]3[C@@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][CH2:13][N:14]([CH3:40])[C:15](=[O:39])[C:16]3=2)[C:21]1=[O:35]
Reactant: COc1c2c(c3n(c1=O)[C@@H](COCc1ccccc1)CCCN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCC[C@H](CO)n2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (6R)-6-[(benzyloxy)methyl]-11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (167 mg, 0.29 mmol) in dichloromethane (2.9 mL) was cooled to 0° C. and treated with boron tribromide (295 mg, 1.18 mmol). The cooling bath was removed and the mixture stirred at room temperature for 30 minutes. The reaction was quenched by the addition of MeOH followed by 1 N aqueous HCl. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[NH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][N:33]([CH3:35])[C:31]([CH2:30][NH:29][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13])=[O:32]
Reactant: CN(C)C(=O)CN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 33.3 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (40.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 492; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, m), 7.88-7.84 (2H, m), 7.51-7.49 (1H, m), 7.37-7.28 (2H, m), 7.19-7.18 (1H, m), 4.18-4.15 (2H, m), 4.11-4.09 (2H, m), 3.03 (3H, s), 2.87 (3H, s), 1.29-1.23 (3H, t), —NH proton signal was not observed.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-fluoro-2-methylnitrobenzene (15.5 g), imidazole (6.8 g), and sodium carbonate (11.1 g) was heated at 100° for 24 hours in dimethylformamide (DMF). The mixture was then concentrated in vacuo, the residue was acidified to pH1 with 4M hydrochloric acid, and the resulting solution was extracted with chloroform (2×25 cm3). The aqueous phase was basified to pH10 with 2.5M sodium hydroxide solution and the mixture was extracted with chloroform (3×100 cm3). The dried (MgSO4) organic extracts were evaporated to give a solid which was recrystallised from ethyl acetate to afford 1-(3-methyl-4-nitrophenyl)imidazole, m.p. 112°-115°, (10.0 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[C:14]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH3:17])=[O:15]>C(#N)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:18]/[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCN(CC)c1ccc(/C=C/C(=O)OC)cc1
Yield: 76 %

Procedure:
A solution of 4-(diethylamino) benzaldehyde (10 g) and carbomethoxymethylenetriphenylphosphorane (20 g) in dry acetonitrile (100 ml) was stirred at reflux under nitrogen for 24 h. The solvent was evaporated and the residual oil was treated with ER (100 ml). The precipitate was filtered, the filtrate was concentrated to an oil and the ER treatment was repeated. After filtration and evaporation the resulting orange oil was purified by [FCS] eluting with cyclohexane/EA/triethylamine 80:20:1) to give the title compound (10.0 g). T.l.c. (cyclohexane/EA/triethylamine 80:20:1) Rf 0.33.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:5]1[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2)c(C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1nc(-c2ccc(Cl)cc2)c(CBr)o1
Yield: 100 %

Procedure:
2-Ethyl-4-(4-chlorophenyl)-5-methyloxazole (6.6 g) was brominated with N-bromosuccinimide (5.4 g) in carbon tetrachloride (90 ml) in the presence of azobisisobutyronitrile (0.3 g) in the same manner as Example 5-(2). The procedure gave an oil of 5-bromomethyl-4-(4-chlorophenyl)-2-ethyloxazole, yield 100%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:5]([N:7]([CH:19]([CH3:22])[CH2:20][CH3:21])[C@@H:8]([C:16](O)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].COC(=O)[C@@H](CC1C=CC=CC=1)N.C([BH3-])#N.[Na+].CC1C=C(C=C(C)C=1)C(Cl)=O.Cl.C[O:57][C:58](=[O:71])[C@H:59]([CH2:61][C:62]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[NH:64][CH:63]=1)[NH2:60]>CN(C1C=CN=CC=1)C.C(C(C)=O)C>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[C:5]([N:7]([CH:19]([CH3:22])[CH2:20][CH3:21])[C@@H:8]([C:16]([NH:60][C@H:59]([C:58]([OH:57])=[O:71])[CH2:61][C:62]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[NH:64][CH:63]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CCC(C)N(C(=O)c1cc(C)cc(C)c1)[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: CCC(C)=O
Product: CCC(C)N(C(=O)c1cc(C)cc(C)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Following the procedure described in example 12 and starting from N-(3,5-dimethylbenzoyl)-N-(1-methylpropyl)-(D)-phenylalanine (prepared by reductive alkylation of (D)-phenylalanine methyl ester with ethylmethylketone in the presence of sodium cyanoborohydride followed by N-acylation with 3,5-dimethylbenzoyl chloride in the presence of DMAP and hydrolysis of the methyl ester moiety according to example 1 and (L)-tryptophan methyl ester hydrochloride gives N-(3,5-dimethylbenzoyl)-N-(1-methylpropyl)-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 540 (M+H)+.
Reaction SMILES: [N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:21][N:22]1CCNCC1.N1CCCCC1>>[CH3:21][N:22]1[CH2:5][CH2:6][N:1]([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1
Solvent: C1CCNCC1
Product: CN1CCN(N2NC=C(c3ncc([N+](=O)[O-])n3C)S2)CC1

Procedure:
The preparation of the above compound is carried out in the manner described for the 2-piperidino derivative (Example 28), an equivalent of 1-methylpiperazine replacing the piperidine. The crude product is purified by recrystallization from 2-methoxyethanol and melts at 242°-244° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.Br[CH:14]([OH:17])[CH2:15][CH3:16]>CCO>[OH:17][CH2:14][CH2:15][CH2:16][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCC(O)Br
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCCCO)cc1

Procedure:
An aqueous solution of NaOH (1 mol) and KI (0.05 mmol) was added to a solution of 4-hydroxybenzoic acid (0.5 mmol) and 400 mL EtOH solution under a nitrogen atmosphere and stirred. After stirring for 30 minutes, an EtOH solution including bromopropanol (0.55 mmol) was dropped thereinto, and then, reacted for 24 hours after elevating to 80° C. A solvent was removed from a reaction product and hydrochloric acid-treatment was carried out. A solid phase was isolated through filteration, and 4-(3-hydroxypropoxy)benzoic acid as a compound of Formula 4 was synthesized.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:6]=[N:7][C:8](Cl)=[N:9][CH:10]=1>CN(C)C=O.O>[Br:4][C:5]1[CH:6]=[N:7][C:8]([C:1]#[N:2])=[N:9][CH:10]=1
Reactant: Clc1ncc(Br)cn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium cyanide (2.30 g, 46.6 mmol) was dissolved in dimethylformamide (60 ml) and treated with 5-bromo-2-chloropyrimidine (6.0 g, 31.1 mmol). The resulting mixture was stirred at room temperature for 18 hours, diluted with water and extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, dried (magnesium sulphate), filtered and concentrated in vacuo. The crude product was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:4) to afford the title compound (D38).