Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]([C:14](O)=[O:15])[CH:12]3[CH2:17][CH2:18][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:24][C@H:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH3:26])=[O:15])[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:18][CH2:17]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)C1C2CCC(CC2)N1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2C3CCC(CC3)N2Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 35.2 %

Procedure:
The title compound (D155) (12 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (D111) (22.5 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (17 mg). (Reaction time: 2 hrs; 60° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([O:15][CH:12]1[CH2:13][CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2CCC(O)CC2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C2CCC(OS(C)(=O)=O)CC2)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 75 parts of 4-(4-methoxyphenyl)cyclohexanol and 1000 parts of pyridine are added dropwise 62 parts of methanesulfonyl chloride (exothermic reaction: temperature rises to 40° C.). Upon completion, the whole is heated to 65° C. and stirring is continued for 2 hours, while meantime the mixture is allowed to cool to room temperature. The reaction mixture is evaporated and 1000 parts of water are added to the residue. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 80.5 parts of 4-(4-methoxyphenyl)cyclohexyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][C:12](=[O:19])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>Br>[Br:20][CH:13]1[C:12](=[O:19])[C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:18]=[CH:17][C:16]=2[CH2:15][CH2:14]1
Reactant: BrBr
Reactant: COc1ccc(-c2ncc3c(n2)C(=O)CCC3)cc1
Agent: Br
Product: COc1ccc(-c2ncc3c(n2)C(=O)C(Br)CC3)cc1

Procedure:
2-(4-Methoxy-phenyl)-6,7-dihydro-5H-quinazolin-8-one (300 mg; 1.2 mmol) in 48% HBr (30 ml) is treated drop-wise with Br2 (189 mg; 1.2 mmol) dissolved in 48% HBr (0.8 ml). The reaction mixture is heated to 350 C for 10 minutes, poured on NaHCO3/water (20 g/100 ml) and extracted with TBME three times. The organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as brown-yellow crystals. 1H-NMR (400 MHz; DMSO-d6): 9.08 (s, 1H); 8.33 (d, 2H); 7.10 (d, 2H); 5.22 (m, 1H); 3.84 (s, 3H); 3.07 (m, 2H); 2.73 (m, 1H); 2.45 (m, 1H). MS (m/z) ES+: 335, 333 (MH+); 255 (80).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10]>CO.[Rh]>[CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[OH:10]
Reactant: OC1Cc2ccccc2C1
Agent: [Rh]
Solvent: CO
Product: OC1CC2CCCCC2C1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 13.4 g (10.0 mmol) of 2-indanol in 100 mL of dry methanol was added 3.0 g of 5% Rh on carbon under a stream of argon. The solution was shaken in a Parr hydrogenation apparatus under hydrogen at 60 psi and 20° C. for 8 h. The mixture was filtered through Celite 545, rinsing with methanol, and the filtrate concentrated and distilled to give 4.2 g (30%) of (2 alpha and 2 beta 3a alpha, 7a alpha)-octahydro-1H-inden-2-ol, bp 130°-131° C. (18 mm); TLC Rf 0.68, 0.60 (SiO2, ethyl ether, molybdophosphoric acid-dark blue).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[C:13]=2[F:21])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[C:13]=2[F:21])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC=C(c2ccc(C#N)c(F)c2F)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#N)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 mol of 4-(4-pentylcyclohex-1-enyl)-2,3-difluorobenzonitrile (prepared according to Example 1a)-1c)), 1.0 g of palladium/active carbon (1%) and 150 ml of toluene is hydrogenated to saturation at room temperature. After filtering and removing the solvent, the residue is dissolved in 150 ml of dimethyl sulfoxide, 12 g of potassium tert.-butoxide are added and the mixture is stirred at room temperature for 2 hours. Acidifying and customary working up gives 4-(trans-4-pentylcyclohexyl)-2,3-difluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[O:13]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]([C:23]2[CH:24]=[CH:25][C:20]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:21][CH:22]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: O=Cc1c(Cl)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Yield: 34 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-phenoxyphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-phenoxyphenyl)-1H-indole-3-carboxaldehyde (34% yield) as a cream solid. ESI/MS 348 (M+H), 389 [(M+1+CH3CN) adduct], RT=3.74 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH:14]=[N:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: Nc1ccncc1O
Product: CN(C)C=Nc1ccncc1O

Procedure:
A solution prepared from of 4-amino-3-pyridinol (1.10 g) and 10 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 30 minutes. At the end of this time, the reaction mixture was concentrated under reduced pressure and the residue was passed over a short column of florisil, eluting with 5% methanol/ethyl acetate. The eluate was concentrated and the residue and recrystallized from ethyl acetate/pentane to afford 0.91 g of analytically pure product, m.p. 121°-123°.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:7]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][C:31]1[N:32]=[CH:33][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:35][CH:36]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:48][C:45]2[CH:46]=[C:47]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][N:39]=[C:38]3[NH:37][C:34]2[CH:33]=[N:32][C:31]([CH3:30])=[CH:36][N:35]=2)=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:7]=1
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: CCOC(COc1cnc(F)c(Cl)c1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(COc1cnc(Oc2ccc3ncnc(Nc4cnc(C)cn4)c3c2)c(Cl)c1)OCC
Temperature: 25 °C
Yield: 53 %

Procedure:
3-Chloro-5-(2,2-diethoxyethoxy)-2-fluoropyridine (460 mg, 1.74 mmol) and potassium tert-butoxide (160 mg, 1.4 mmol) were added to an N,N-dimethylacetamide suspension (0.9 ml) of 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol (180 mg, 0.71 mmol), and reacted under a nitrogen atmosphere at 200° C. for 30 minutes, using microwaves. The reaction solution was cooled to room temperature, then diluted with chloroform. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain 6-{[3-chloro-5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)quinazoline-4-amine (187 mg, yield: 53%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C3CCCCO3)=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[CH:3]=1.Cl>ClCCl.O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:17]([NH:19][OH:20])=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[CH:3]=1
Reactant: C[C@@](CCn1ccc(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@](CCn1ccc(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NO)S(C)(=O)=O
Yield: 104.1 %

Procedure:
(2R)-4-[4-(4-chloro-2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1188 mg impure material, 1 mmol) was dissolved in 3 mL of dichloromethane. To this solution was added 1 mL of 4M HCl in dioxane and 1 mL of water. The reaction was monitored for completion by LCMS. Upon completion, the reaction mixture was concentrated and redissolved in a minimal amount of dimethylsulfoxide and water and loaded onto a 5 g c18 guard-column. This material was purified on a 75 g c18 column with 10-40% acetonitrile in water with 0.1% trifluoroacetic acid. The desired material was concentrated yielding 434 mg (88%) of a light yellow solid. LCMS m/z 417.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.10-2.23 (m, 1H) 2.37-2.47 (m, 1H) 3.11 (s, 3H) 3.69-3.82 (m, 1H) 4.04-4.19 (m, 1H) 6.44-6.52 (m, 1H) 6.58 (s, 1H) 7.42 (dd, J=8.29, 1.85 Hz, 1H) 7.56-7.67 (m, 2H) 7.77 (d, J=7.02 Hz, 1H) 11.12 (br. s., 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=3)[CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)C(=O)N=C2C=CC(Br)=CN21
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C(=O)N=C2C=CC(c3cccc(Cl)c3)=CN21
Yield: 63.1 %

Procedure:
To a round-bottom flask was added 6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (60 mg, 0.25 mmol), 3-chlorophenylboronic acid (39 mg, 0.25 mmol), potassium carbonate (69 mg, 0.25 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), dioxane (5 mL) and water (1 mL). The mixture was heated at reflux until the starting material was consumed monitored by HPLC-MS. The solution was cooled and water was added. The reaction mixture was extracted twice with ethyl acetate and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography eluting with 5% methanol/dichloromethane to provide the desired product as an off-white solid (43 mg, 63%). 1H NMR (CDCl3) δ 7.84 (dd, J=1.8 and 9.1 Hz, 1H), 7.74 (s, 1H), 7.46-7.27 (m, 5H), 1.64 (s, 6H); MS (m/e): 273 (MH+); HRMS: calc'd MH+ for C15H13ClN2O 273.0794. Found 273.0800.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[NH:31]1C=CC=C1C=O>>[NH:31]1[CH:3]=[CH:30][CH:29]=[C:6]1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccc[nH]1
Product: O=C(NCCNCc1ccc[nH]1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using pyrrol-2-carboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.54 (1H, br. s.) 10.31 (1H, s) 8.00-8.07 (2H, m) 7.77 (1H, d, J=5.42 Hz) 7.47 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.22, 2.59 Hz) 6.81 (1H, d, J=5.42 Hz) 6.57-6.62 (1H, m) 6.43 (1H, dd, J=3.44, 1.88 Hz) 5.88 (1H, q, J=2.64 Hz) 5.82-5.86 (1H, m) 3.61 (2H, s) 2.63 (2H, t, J=6.47 Hz)
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]([N:6]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3nc(CC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Yield: 50.9 %

Procedure:
A solution of the compound (100 mg, 0.23 mmol) obtained in step 8, 4-methoxyphenylboronic acid (51.6 mg, 0.34 mmol), tripotassium phosphate (96 mg, 0.45 mmol), S-Phos (6.51 mg, 0.02 mmol) and palladium(II) acetate (1.8 mg, 8.02 μmol) in toluene (1.5 mL) was stirred under an argon atmosphere at 90° C. for 18 hr. The reaction mixture was purified by silica gel column chromatography (solvent gradient; 50% ethyl acetate/hexane→5% methanol/ethyl acetate) to give the title compound (55 mg, 0.117 mmol, 52%) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:23]([C:29]2[N:33](COCC[Si](C)(C)C)[C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)([OH:28])[C:24]([F:27])([F:26])[F:25])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(O)C(F)(F)F)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2)C.Cl.CO>>[CH2:1]([C:3]1[C:4]([C:23]([C:29]2[NH:33][C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)([OH:28])[C:24]([F:26])([F:27])[F:25])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Solvent: CO
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.16 g, 1.69 mmol) and HCl in MeOH (1.25 M, 13.59 mL, 16.99 mmol) was allowed to stir at 60° C. for 0.5 h. The reaction mixture was cooled to rt and concentrated. The residue was dissolved in a small amount of EtOAc, and then diluted with heptanes. The precipitated solid was collected on a Kiriyama funnel, washed with hexane, dried under reduced pressure to give the title compound. MS (ESI+) m/z 553.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[S:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=2[N:26]=[N:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:31]3[CH:30]=[CH:29][C:28]4[S:24][N:25]=[N:26][C:27]=4[CH:32]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1ccc2snnc2c1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3ccc4snnc4c3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with benzo[1,2,3]thiadiazole-5-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=495.0.
Reaction SMILES: F[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:23])[CH:14]=3)[CH:9]=[N:8]2)=CC=1.C1(CCN2C(=O)N(C3SC(C(OCC)=O)=C(C)C=3)C=N2)CC1>>[CH:24]1([CH2:5][CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([OH:20])=[O:19])=[C:15]([CH3:23])[CH:14]=3)[CH:9]=[N:8]2)[CH2:25][CH2:2]1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Agent: CCOC(=O)c1sc(-n2cnn(CCC3CC3)c2=O)cc1C
Product: Cc1cc(-n2cnn(CCC3CC3)c2=O)sc1C(=O)O
Yield: 96 %

Procedure:
Following the procedure as described in Example 30, making variations as required to replace ethyl 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate with ethyl 5-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a colorless solid in 96% yield: NMR (300 MHz, DMSO-d6) δ 12.96 (br s, 1H), 8.72 (s, 1H), 7.26 (s, 1H), 3.81 (t, J=6.5 Hz, 2H), 2.46 (s, 3H), 1.62-1.52 (m, 2H), 0.75-0.60 (m, 1H), 0.40-0.32 (m, 2H), 0.05-−0.05 (m, 2H); MS (ES−) 292.3 (M−1).
Reaction SMILES: N[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Br
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc2nc(Br)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (3 g, 16 mmole) was suspended in 150 ml of water and brought into solution with 2 ml of HBr. Sodium nitrite (3.3 g, 55 mmole) was then added and the mixture was stirred at room temperature for 1 hr. Excess CuBr2 was then added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was extracted with ethyl acetate (3×100 ml), dried with MgSO4, concentrated, and crystallized from ethyl ether to give 1.13 g (26%) of 2-bromo-5,6-dichlorobenzimidazole (7). 1H NMR (DMSO-d6) δ 7.81 ppm (s, 2H), 13.62 (s, 1H). GC/MS: m/e 266, 185, 158, 150, 133, 124, 107, 97, 88, 73; 62; 52, 37.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C.O>[N:12]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(N2CCNCC2)ncn1
Yield: 56.6 %

Procedure:
A solution of 4-chloro-6-(trifluoromethyl)pyrimidine (1.0 g, 5.48 mmol), piperazine (2.36 g, 27.4 mmol), and triethylamine (2.29 mL, 16.4 mmol) in DMF (20 mL) was stirred at 100° C. for 5 h. The reaction solution was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (10% MeOH/5% Et3N/EtOAc) to yield the desired product (720 mg, 56.6%). LCMS calculated for C9H2F3N4: (M+H) 233.1; found 233.1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:12])[CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].Cl[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:12])[C:6]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOc1ccc(OCCl)cc1
Reactant: COC(=O)C(C)C(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(OCC(C)(C(=O)OC)C(=O)OC)cc1

Procedure:
11.5 g of sodium hydride (55% in oil) are suspended in 150 ml of tetrahydrofurane under nitrogen atmosphere. 29.6 g of methyl-malonic acid dimethyl ester are added during 20 minutes while maintaining the temperature at +25° C. by cooling. Stirring is continued until the gas evolution ceased. 37.8 g of 1-Chlormethoxy-4-ethoxy-benzene are then added over a period of 20 minutes maintaining the temperature at around +30° C. After 1.5 hours the mixture is cooled to +5° C. and 25 ml of ammonium chloride is added carefully, then poured into water and extracted with ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate, filtered and the solvent evaporated. Flash chromatography (eluant: hexane/ethyl acetate 95:5) yielded 41.6 g of a slightly yellow powder.
Reaction SMILES: C(N(CC)CC)C.[N+](C1C=C[C:14]([O:17]C=O)=CC=1)([O-])=O.Cl.[NH2:21][C@H:22]([C@@H:46]([OH:57])[CH2:47][C@H:48]([C:50](=[O:56])[NH:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH3:49])[CH2:23][C@@H:24]([CH:43]([CH3:45])[CH3:44])[CH2:25][NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41]>ClCCl>[CH2:52]([NH:51][C:50]([C@H:48]([CH3:49])[CH2:47][C@H:46]([OH:57])[C@@H:22]([NH:21][CH:14]=[O:17])[CH2:23][C@@H:24]([CH:43]([CH3:45])[CH3:44])[CH2:25][NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[O:56])[CH2:53][CH2:54][CH3:55]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1cccc(OC)c1OCCCOC)C(C)C
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](CNC(=O)c1cccc(OC)c1OCCCOC)C(C)C)NC=O
Reaction time: 0.5 h

Procedure:
Triethylamine (0.034 ml) and formic acid 4-nitrophenyl ester (28 mg) are added at room temperature, with stirring, to a solution of (2S,4S,5S,7R)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-octyl)-3-methoxy-2-(3-methoxypropoxy)-benzamide hydrochloride (Example 6a) (67 mg) in dichloromethane (4 ml). The resulting reaction solution is stirred for a further 30 minutes and is then concentrated by evaporation. The residue is purified by FC (18 g of silica gel; eluant E, then ethyl acetate-hexane-methanol 5:5:1). (2S,4S,5S,7R)-N-(7-Butylcarbamoyl-4-formylamino-5-hydroxy-2-isopropyl-octyl)-3-methoxy-2-(3-methoxypropoxy)-benzamide is obtained in the form of a white foam: Rf (L)=0.58. HPLC Rt =13.2 min. MS(FAB) m/e 552 (M+ +1).