Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]([CH2:35][CH2:36][OH:37])[C:28](=O)[O:29]C(C)(C)C)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:35][CH2:36][O:37][C:28]3=[O:29])[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N(CCO)C(=O)OC(C)(C)C)no2)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N3CCOC3=O)no2)cc1C#N
Reaction time: 20 h
Yield: 29 %

Procedure:
To a stirred solution of (R)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate INT-22 in DMF (1 mL) was added NaH (6 mg, 0.15 mmol, of a 60% solution in mineral oil). After stirring for 20 h, the reaction mixture was diluted with EA and washed with NaHCO3. The combined aqueous extracts were back-extracted with EA. The combined organic extracts were dried over Na2SO4, concentrated, and purified by column chromatography (EA/hexanes) to provide 11.9 mg (29%) of (R)-2-isopropoxy-5-(3-(1-(2-oxooxazolidin-3-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 154. LCMS-ESI (m/z) calculated for C22H22N4O4: 430.5. found 431.1 [M+H]+, tR=3.72 min. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.2 Hz, 1H), 8.34 (dd, J=8.9, 2.2 Hz, 1H), 8.14 (t, J=4.4 Hz, 1H), 7.42 (m, 2H), 7.13 (d, J=9.0 Hz, 1H), 5.72-5.57 (m, 1H), 4.80 (dt, J=12.2, 6.1 Hz, 1H), 4.35 (qt, J=15.7, 7.8 Hz, 2H), 3.56-3.39 (m, 2H), 3.25 (dtd, J=24.4, 8.6, 7.1 Hz, 2H), 2.65-2.48 (m, 1H), 2.10 (ddt, J=13.7, 9.0, 7.1 Hz, 1H), 1.48 (d, J=6.1 Hz, 6H). Compound 155 was made in an analogous fashion.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:17]N1C(=O)CCC1=O.C1(C(F)(F)F)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:17][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Temperature: 78 °C
Reaction time: 16 h

Procedure:
To a mixture of 3′-fluoro-4′-methylbiphenyl-2-carbonitrile (110 g), N-bromosuccinimide (97.3 g) and benzotrifluoride (1.0 L) was added azobisisobutyronitrile (1.71 g), and the mixture was heated to an internal temperature of 78° C. and stirred for 16 hr. The reaction mixture was cooled to around 40° C., and the insoluble material was removed to give a solution of 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluoride.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([CH2:17][OH:18])[O:15][C@H:12]([O:13][CH3:14])[C@H:11]([O:19][CH2:20][O:21][CH3:22])[C@H:10]1[O:23][CH2:24][O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=[O:41])C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:8][CH2:9][C@H:16]1[O:15][C@H:12]([O:13][CH3:14])[C@H:11]([O:19][CH2:20][O:21][CH3:22])[C@@H:10]([O:23][CH2:24][O:25][CH3:26])[C@@H:17]1[OH:18])(=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCO[C@@H]1[C@@H](OCOC)[C@@H](OC)O[C@H](CO)[C@H]1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCO[C@H]1[C@@H](OC)O[C@H](COC(=O)c2ccccc2)[C@@H](O)[C@@H]1OCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a stirred solution of methyl 4-O-benzyl-2,3-di-O-methoxymethyl-α-D-glucopyranoside (D. B. Berkowitz et al., J. Org. Chem. 1993, vol. 58, page 6174) (1.1 g, 2.96 mmol) in methylene chloride (10 mL) was added triethyl-amine (3.4 mL, 24.5 mmol), and benzoyl chloride (1.4 mL, 12.0 mmol). The reaction was stirred at room temperature for approximately 30 min and then diluted with EtOAc (100 mL) and washed with 0.5 N aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The aqueous layers were reextracted with EtOAc (100 mL) and the organics were combined, dried over Na2SO4, and then concentrated in vacuo. The crude product was taken up in ethanol (7 mL) and Pd/C-Degussa type (100 mg) was added. The reaction was stirred under an atmosphere of hydrogen for 12 h and then filtered through celite and concentrated in vacuo. The product was purified by flash chromatography (gradient 33% to 50% EtOAc/petroleum ether) to afford 2 (0.70 g, 61%) as a colorless oil: Rf=0.25 (40% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 8.06 (d, J=7.2 Hz, 2H), 7.56 (t, J=7.2 Hz, 1H), 7.44 (t, J=7.2 Hz, 2H), 4.84 (d, J=3.6 Hz, 1H), 4.7-4.8 (m, 4H), 4.65 (dd, J=2.3, 11.9 Hz, 1H), 4.57 (dd, J=5.3, 11.9 Hz, 1H), 4.23 (br s, 1H), 3.91 (ddd, J=2.3, 5.3, 9.5 Hz, 1H), 3.71 (dd, J=9.5, 9.5 Hz, 1H), 3.61 (dd, J=3.6, 9.5 Hz, 1H), 3.50 (dd, J=9.5, 9.5 Hz, 1H), 3.46 (s, 3H), 3.45 (s, 3H), 3.39 (s, 3H); 13C NMR (CD3COCD3, 67.5 MHz) δ 167.0, 134.2, 131.5, 130.5, 129.7, 100.1, 98.8, 98.1, 81.0, 79.2, 71.4, 70.7, 65.2, 56.1, 55.7, 55.5; HRFABMS calcd for C18H27O9 (M+H+) 387.1655, found 387.1656.
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([NH:21][C@H:22]([CH2:29][CH3:30])[CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:8][C:9]=2[NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.N[C@@H](CC)C(O)C(C)(C)C>CCCCO.CS(C)=O>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([NH:21][C@@H:22]([CH2:29][CH3:30])[CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:8][C:9]=2[NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Agent: CC[C@H](N)C(O)C(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (3RS,4R)-4-{9-Isopropyl-6-[(pyridin-3-ylmethyl)-amino]-9H-purin-2-ylamino}-2,2-dimethyl-hexan-3-ol (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4S)-4-amino-2,2-dimethyl-hexan-3-ol (43 mg, 2.81 eq, 0.29 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 5.4 mg (13%). (53% de 4S,3R: 47% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.99-1.03 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.57 & 1.59 (2×d, 6H, J=6.79 & 6.79 Hz, —CH(CH3)2), 1.70-1.93 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.55 (d, 1H, J=2.05 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.77-3.90 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.58-4.70 (m, 1H, —CH(CH3)2), 4.82-4.94 (m, 2H, —HNCH2-Pyr), 5.31-5.45 & 6.12-6.34 (m, 1H, —NHCH(CH2CH3)CH (C(CH3)3)OH), 7.26-7.40 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (s, 1H, Pyr-H), 7.75 (d, 1H, J=7.42 Hz, Pyr-H), 8.46-8.81 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (70). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.
Reaction SMILES: [CH3:1][O:2]CC1C=CC(COC)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C1C2[C:28](C3C=CC(O)=CC=3)([C:30]3C=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[C:27]3C(=CC=CC=3)C=2C=CC=1>C1(=O)OCCC1>[CH3:34][C:33]([CH2:32][CH2:31][CH2:30][CH2:28][CH3:27])=[O:36].[CH3:1][OH:2]
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: COCc1ccc(COC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C1CCCO1
Product: CCCCCC(C)=O
Product: CO
Reaction time: 0.17 h

Procedure:
8.75 g (0.05 mol) of α,α′-dimethoxy-p-xylene, 26.66 g of aluminum chloride, and 200 g of γ-butyrolactone are introduced into a 1 l 4-neck flask mounted with a mechanical stirrer, a condenser, a 300 ml dropping funnel, and a nitrogen gas-introduction tube with inflowing nitrogen gas, and sufficiently stirred. After 10 minutes, a solution in which 35.03 g (0.10 mol) of 4,4′-(9-fluorenylidene)diphenol is dissolved in 200 g of γ-butyrolactone is slowly dripped for 30 minutes and reacted for 12 hours. After completing the reaction, the acid is removed using water and condensed by an evaporator. Then it is diluted using methylamylketone (MAK) and methanol to provide a solution of MAK/methanol=4/1 (weight ratio) in a concentration of 15 wt %. The solution is introduced into a 31 separate funnel and added with n-heptane to remove a low molecular body including a monomer. A polymer (Mw=10,000, polydispersity=2.0) represented by the following Chemical Formula 1A is provided.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.Br[CH2:37]C1C=CC=CC=1C.C([O:47][C:48](=[O:59])[C:49](SC1SC(N)=NC=1)([CH3:51])[CH3:50])C>>[CH3:50][C:49]([S:16][C:13]1[S:12][C:11]([NH:10][C:9]([N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[CH3:37])[C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[N:15][CH:14]=1)([CH3:51])[C:48]([OH:59])=[O:47]
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1COCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-methyl-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=N)C.[O:27]=[C:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[N:30][N:29]1[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>ClCCl.CN(C)C1C=CN=CC=1.O>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:41](=[O:42])[CH2:40][CH2:39][CH2:38][N:29]1[C:28](=[O:27])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[N:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CS1
Reactant: O=C(O)CCCn1nnc2ccccc2c1=O
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CCCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of the compound obtained from step c above (2.1 g) in dichloromethane (25 mL) cooled to 0° C., 4-dimethylaminopridine (0.334 g) and triethylamine (5.7 mL) were added. After stirring the reaction mixture for 10 minutes, 1-β-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (3.9 g) and 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (3 g) were added, and the reaction mixture was stirred at room temperature for 14 hours. Dichloromethane and water were added to the reaction mixture. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 25% ethyl acetate in hexane as eluant to afford the title compound (4.4 g). Mass (m/z): 409.16
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:30])[C:21]4[C:26]([CH2:27]O)=[CH:25][C:24]([Cl:29])=[CH:23][N:22]=4)[CH:15]=[CH:16][C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2.COCCN(S(F)(F)F)CCOC.C(=O)(O)[O-]>C(Cl)Cl.C1COCC1>[NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([N:19]4[CH2:27][C:26]5[C:21](=[N:22][CH:23]=[C:24]([Cl:29])[CH:25]=5)[C:20]4=[O:30])[CH:15]=[CH:16][C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2
Reactant: NC1=N[C@@](c2cc(NC(=O)c3ncc(Cl)cc3CO)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC1=N[C@@](c2cc(N3Cc4cc(Cl)cnc4C3=O)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-3-(hydroxymethyl)picolinamide (Example 420, 60 mg, 0.136 mmol) in DCM (2 mL) was cooled 0° C. under nitrogen atmosphere. A solution of Deoxo-fluor, (50 w % in THF, 0.150 mL, 0.408 mmol) was added dropwise and the reaction mixture was allowed to stir at rt for 25 min. The reaction mixture was poured into aqueous saturated bicarbonate solution and extracted with EtOAc. The crude material was absorbed onto a plug of silica gel and purified by chromatography, eluting with a gradient of 20% to 100% EtOAc in hexane, to provide the title compound as white solid. MS m/z=423 [M+H]+.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1(OC)[CH:38]=[CH:37][C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[Cl:49])(=[O:42])=[O:41])=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:30]1.[O:52]1C=CC(B(O)O)=[CH:53]1>>[Cl:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[S:40]([CH2:39][C:36]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:52][CH3:53])[C:29]([C:23]2[CH:27]=[CH:26][O:25][CH:24]=2)=[CH:38][CH:37]=1)(=[O:41])=[O:42]
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)C1=C(CS(=O)(=O)c2ccccc2Cl)C=CC(Br)(OC)C1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2Cl)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(2-chlorobenzenesulphonylmethyl)-3-methoxybenzoate, (Intermediate 98) and furan-3-yl boronic acid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4](O)[CH:3]=1)[OH:2].[Si:9](Cl)(Cl)(Cl)[Cl:10]>>[Cl:10][Si:9].[C:1]1([OH:2])[CH:8]=[CH:7][CH:6]=[CH:4][CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: Cl[Si](Cl)(Cl)Cl
Product: Oc1ccccc1
Product: [Si]Cl
Reaction time: 5 h

Procedure:
About 0.5 mol of fine granular hydrated silica, 0.5 mol of resorcinol and 1 mol of silicon tetrachloride are slowly added while agitating and keeping the temperature below the boiling temperature of the mixture for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing a phenol chlorosilicon acid resinous product. To this resinous product about 0.5 mol of phenol is added while agitating for 1 to 2 hours, thereby producing an organic silicon acid resinous product. Hydrogen chloride evolves from the mixture.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.O=[C:20]([CH3:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:27])[NH:8][C:7]([C:3]2[S:2][CH:6]=[CH:5][N:4]=2)=[N:9]1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccccc1Cl
Reactant: N=C(N)c1nccs1
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1Cl
Yield: 55.2 %

Procedure:
Thiazole-2-carboximidamide hydrochloride (11.63 g, 71.1 mmol) was reacted with 2-chlorobenzaldehyde (10 g, 71.1 mmol) and ethyl 3-oxobutanoate (11.1 g, 85.3 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (14.2 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].[CH2:15](N)[CH2:16][NH2:17]>>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[NH:17][CH2:16][CH2:15][N:12]=1
Reactant: NCCN
Reactant: N#CCc1ccccc1OC(F)(F)F
Product: FC(F)(F)Oc1ccccc1CC1=NCCN1

Procedure:
2-(2-Trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-trifluoromethoxy-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): yellow powder; MS (ISP): 245.0 ((M+H)+.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([C:14]([OH:16])=O)[N:13]=1)[CH3:2].[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:14]([C:12]2[N:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])[O:10][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:16])=[CH:30][CH:31]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCc1ccccc1-c1nc(C(=O)O)c(C(F)(F)F)o1
Product: CCc1ccccc1-c1nc(C(=O)Nc2ccc(N(C)CCOC)nc2)c(C(F)(F)F)o1

Procedure:
With a procedure similar to example 16 above, 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H23F3N4O3 (m/e) 448, obsd 449 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>O>[CH:25]([O:24][C:22]([NH:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:7])[CH3:8])[C:3]([OH:5])=[O:4])=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)SC(C)(C)[C@H](N)C(=O)O
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)OC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reaction time: 6 h
Yield: 64 %

Procedure:
2-(R)-Amino-3-isopropylsulfanyl-3-methyl-butyric acid (17 mmol; crude material obtained from D-penicillamine and isopropyl iodide) was dissolved in 40 mL of water and 40 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Isopropyl chloroformate (22 mL; 1 M solution in toluene) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 11) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a yellow oil, which was purified by HPLC (RP-18; pH 2.3; H2O/CH3OH 3/7) to give 3.0 g (64%) of the title compound as a colorless oil. (−)-APCI-MS: 276 ([M−H]−).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N)C(F)=C(F)C(F)=C([NH2:28])C=1F.Cl.Cl.CO[C:35]1[C:39](OC)=[N:38][S:37](=[O:42])[N:36]=1>CO>[NH2:28][C:35]1[C:39]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[N:38][S:37](=[O:42])[N:36]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CO
Product: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(3-piperidinomethylphenoxy)propylamine (from the dihydrochloride, 4.0 g; 12.4 mmoles) in 40 ml of methanol was added dropwise over a period of 50 minutes to a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.01 g; 12.4 mmoles) in 200 ml of methanol that had been cooled to 0° in an ice-water bath. After 15 minutes, anhydrous ammonia was bubbled into the solution for 5 minutes and the solution then was stirred at ambient temperature for 17 hours. The reaction mixture was evaporated under reduced pressure and the residue chromatographed by flash chromatography on 100 g of silica gel (230-400 mesh) using methanol-acetonitrile. The appropriate fractions were combined and evaporated to give 4.18 g of product. Recrystallization from 95% aqueous ethanol yielded the title compound, mp 155°-157° (dec.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:39][CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-(2-piperazin-1-yl-ethyl)-acetamide (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C37H47Cl2N6O3 [(M+H)+] 693.3081, observed 693.3082.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38](O)=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][C:42]1NN=[N:44][N:43]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1(C)C=CC=CC=1>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]2[CH2:11][C@@H:10]([C:38]3[O:39][C:42]([CH3:41])=[N:43][N:44]=3)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1nnc([C@@H]2C[C@H](N(CC(C)C)C(=O)c3cnc(C(C)(C)C)nc3NCc3ccco3)CN(C(=O)OC(C)(C)C)C2)o1
Temperature: 100 °C
Reaction time: 14 h
Yield: 58.3 %

Procedure:
(3R*,5S*)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (120 mg) and 5-methyl-1H-tetrazole (22 mg) were suspended in toluene (3 ml), DCC (60 mg) was added and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-75:25) was concentrated under reduced pressure to give the object compound (74.7 mg).