Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:35]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.80 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.00 g) in chloroform (10 ml), and then tetradecanoyl chloride (1.42 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.3 ml) was added to a solution containing the residue (2.29 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.18 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (1.38 g) as pale brown wax.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[C:18]([NH:23]C(OCC3C=CC=CC=3)=O)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([NH2:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(=Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Yield: 94.7 %

Procedure:
A mixture of 5-(2-benzyloxycarbonylamino-2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester (524 mg, 1.16 mmol) and 10% palladium on carbon (60 mg) in methanol (20 mL) was shaken for 4.5 h under 50 psi hydrogen gas using a Parr hydrogenator. The reaction mixture was evacuated and purged with nitrogen. Then, the reaction mixture was filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (351 mg, 95%). 1H-NMR (CDCl3, 500 MHz) δ 8.12-8.10 (m, 2H), 7.55 (br s, 1H), 7.37 (dd, J=8.9, 1.5 Hz, 1H), 3.77-3.75 (m, 1H), 3.70 (s, 3H), 3.19 (dd, J=13.7, 5.5 Hz, 1H), 2.99 (dd, J=13.7, 8.0 Hz, 1H), 1.72 (s, 9H). Mass spec.: 320 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](Cl)=[O:13])=[C:5]2[Cl:15].[OH-].[NH4+:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:17])=[O:13])=[C:5]2[Cl:15]
Reactant: O=C(Cl)c1cnc2ccc(Br)cc2c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1cnc2ccc(Br)cc2c1Cl
Yield: 95 %

Procedure:
DMF (1.506 mL, 19.37 mmol) was added to 6-bromo-4-oxo-1H-quinoline-3-carboxylic acid (51.93 g, 193.72 mmol) and thionyl chloride (353 mL, 4843.07 mmol) at r.t. and the resulting solution stirred at 70° C. for 2 h under an inert atmosphere. The resulting solution was evaporated to dryness and the residue azeotroped with toluene to afford 6-bromo-4-chloroquinoline-3-carbonyl chloride (62.13 g). The 6-bromo-4-chloroquinoline-3-carbonyl chloride was dissolved in DCM (420 mL) and added portionwise to ammonium hydroxide (251 mL, 1937.23 mmol) at 0° C. over 15 minutes. The organic solvent was removed under reduced pressure and the solid collected by filtration, washed with water, Et2O and then dried to afford the desired material (52.8 g, 95%) as a white solid. NMR Spectrum: 1H NMR (500 MHz, DMSO-d6) δ 8.00-8.11 (3H, m), 8.24 (1H, s), 8.45 (1H, s), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=287.
Reaction SMILES: O[CH:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[NH:5][C:4]([CH3:17])=[C:3]1[CH2:18][C:19]([O:21][CH3:22])=[O:20].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC1=C(C)Nc2c(-c3ccccc3)cnn2C1O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1c(C)nc2c(-c3ccccc3)cnn2c1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
To methyl 2-(7-hydroxy-5-methyl-3-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.5 g, 1.68 mmol) was added POCl3 (1 mL). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid were filtered and washed with water, then dissolved in ethyl acetate. The organic solution was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound (0.48 g, 90%). 1H-NMR (500 MHz, MeOD) δ ppm 2.66 (3H, s), 3.77 (3H, s), 4.04 (2H, s), 7.26 (1H, s), 7.42 (2H, s), 8.09 (2H, s), 8.57 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.[CH3:39][C:40]1[N:41]=[CH:42][NH:43][CH:44]=1.C([O-])([O-])=O.[K+].[K+].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(#N)C>[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52].[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([N:43]2[CH:44]=[C:40]([CH3:39])[N:41]=[CH:42]2)[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: Cc1c[nH]cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cn(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 80 °C
Yield: 23 %

Procedure:
In a 10 mL sealed cap glass vial, tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50 mg, 0.091 mmol), 4-methyl-1H-imidazole (22.43 mg, 0.273 mmol) and K2CO3 (50.3 mg, 0.364 mmol) were dissolved in ACN (2 mL). The cap was sealed and the mixture was reacted at 100° C. for 16 h. The reaction mixture was subsequently filtered through a Buchner funnel to remove un-dissolved solids. The solids were washed with ACN (2×5 mL) and the filtrate was evaporated to give a residue, which was treated with TFA (4 mL) and heated at 80° C. for 1 h to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The resulting residue was reconstituted in DMSO (5 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-65% gradient, 0.035% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (7.2 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.65 (m., 8H), 3.65-3.79 (m, 5H), 4.15 (s, 2H), 6.40 (d, 1H), 6.51 (d, 1H), 6.73 (m, 1H), 6.97 (d, 1H), 7.26 (d, 1H), 8.68 (br s, 1H). [M+H] calc'd for C17H21FN6O, 345. found, 345.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.C(=O)([O-])[O-:15].[Ca+2].O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:15])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1ccc(CO)cc1

Procedure:
To a stirring solution of 15 in dioxane (0.4 M) at room temperature under nitrogen was added calcium carbonate (5.5 eq) and H2O (0.8 M). The reaction was refluxed overnight then vacuum filtered. The dioxane was removed under reduced pressure. The reaction mixture was diluted with H2O then extracted with dichloromethane (3×). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (77%) 1H NMR (400 MHz, CDCl3) δ 7.33 (d, 2H), 7.27 (d, 2H), 4.67 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 1.78 (br s, 1H).
Reaction SMILES: Cl.[CH2:2]1[C@H:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31].O>CN(C=O)C>[F:31][C:30]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:20]=1[CH2:19][N:3]1[CH2:4][C@@H:5]2[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][C@@H:6]2[CH2:2]1
Reactant: OCC1C[C@H]2CNC[C@H]2C1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1C[C@@H]2CN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethanol hydrochloride (0.79 g) and potassium carbonate (1.53 g) in DMF (15 ml) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (1.5 g). The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:21](=[O:22])[CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:24])([F:12])[F:25])=[CH:19][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(C(F)(F)F)cc2)c(C)[nH]1
Yield: 33 %

Procedure:
5-Methyl-4-[2-(4-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (117) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/−40° C. Purification: prep/HPLC. Yield: 33%. 1H (CDCl3, 400 MHz): δ 10.5 (NH, broad s), 7.56 (2H, d), 7.34 (2H, d), 7.32 (1H, s), 4.37 (2H, q), 4.15 (2H, s), 2.59 (3H, s), 1.38 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 193.3, 161.5, 141.0, 139.0, 130.9, 125.5, 128.6, 121.4, 120.6, 114.0 61.0, 46.5, 14.5, 14.0 ppm. LC/MS: 98%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.[CH:35](/[S:43](Cl)(=[O:45])=[O:44])=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[Cl:27][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][S:43](/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNS(=O)(=O)/C=C/c4ccccc4)c3Cl)c2n1
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg) and triethylamine (0.04 ml) in dichloromethane (2 ml) was added a solution of (E)-styrenesulfonyl chloride (48 mg) in dichloromethane (1 ml) in an ice-water bath. After being stirred for 30 minutes under ice-cooling, the reaction mixture was partitioned into dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-((E)-styrylsulfonylglycyl)amino]benzyloxy]-2-methylquinoline (78 mg) as an amorphous powder.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:1](/[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)\[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C(N)=N/O)CC1
Temperature: 80 °C

Procedure:
A solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.5 g, 2.378 mmol) in ethanol (12 mL) was treated with hydroxylamine (50% in water, 0.51 mL, 8.32 mmol). The reaction was heated at 80° C. for 1.5 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The concentrate was dried to constant weight in a vacuum oven at 60° C. to provide the title compound. DCI(+) m/z 244.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Br[C:26]1[S:27][C:28]([CH3:31])=[N:29][N:30]=1.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.O>[CH3:31][C:28]1[S:27][C:26]([N:16]2[CH2:15][CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:30][N:29]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: Cc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4nnc(C)s4)CC3)c(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg), 2-bromo-5-methyl-1,3,4-thiadiazole (EXAMPLE 87, Step 1, 323 mg) and potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL) is stirred under N2 at 100° C. for 2 hrs, cooled to ambient temperature, diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic phase is washed with water (20 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which is then chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf =0.44 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 193-195° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[C:10]=2Cl)=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[Cl:22]C1C=C(CC#N)C=CC=1Cl>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:22])=[C:11]([Cl:16])[CH:10]=2)=[C:4]([C:18]([F:20])([F:21])[F:19])[N:3]=1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(C(F)(F)F)n1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(N)c(-c2ccc(Cl)c(Cl)c2)c(C(F)(F)F)n1

Procedure:
This compound was made in an analogous manner to the compound of Example 4, from 3,4-dichlorophenylacetonitrile (Aldrich) mp. 252°-254.5° C.: TLC (SiO2 ; methanol/chloroform, 1:9) Rf=0.38.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (17 mg, 60%), MS (ISP) m/z=453.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (24 mg, 0.0595 mmol) and 4-fluorobenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH:16]([F:18])[F:17])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9][CH2:8]1.[Br:19][C:20]1[S:21][C:22]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[Br:19][C:20]1[S:21][C:22]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[C:23]([C:25](=[O:26])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH2:15][CH:16]([F:18])[F:17])[C:6]=2[N:7]2[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9][CH2:8]2)[N:24]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Reactant: Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Product: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Yield: 69 %

Procedure:
Following the procedure for Intermediate 7 starting with 1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-ol and 2-bromo-5-(tert-butoxycarbonylamino)-thiazole-4-carboxylic acid afforded tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a colorless solid (265 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.14 (s, 1H), 8.02 (s, 1H), 6.18 (tt, J=55.9, 4.5 Hz, 1H), 4.38-4.27 (m, 2H), 3.33-3.12 (m, 5H), 2.20 (br s, 1H), 2.35-1.58 (m, 4H), 1.70-1.48 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1>>[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: c1ccc2c(c1)CCNC2
Product: Nc1cc(N2CCc3ccccc3C2)ccn1

Procedure:
Following the general method described in example 24, 4-bromo-pyridin-2-yl-amine (H. J. den Hertog, Recl.Trav.Chim.Pays-Bas, 1945, 64, 85) was reacted with 1,2,3,4-tetrahydro-isoquinoline. The crude product was chromatographed (SiO2 with CH2Cl2/CH3OH/NH4OH=200/10/1) and crystallized to yield the title compound as an off-white crystalline material. Mp. 160-161° C. (CH3CN), MS: m/e=226 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[CH3:28][C:29]1[C:33]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)=[C:32]([CH3:37])[O:31][N:30]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1noc(C)c1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 3,5-dimethyl-4-isoxazolylboronic acid were the coupling partners.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12](C(OC(C)(C)C)=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:15][CH:14]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)c1ccccc1CN(C(=O)OC(C)(C)C)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1CNc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
To a solution of 7.00 g of 2-[(tert-butoxycarbonyl-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-amino)-methyl]-benzoic acid ethyl ester in 40 ml of dichloromethane was added 9.6 ml of trifluoroacetic acid and stirring was continued at 22° C. for 2.5 h. The mixture was partitioned between aqueous saturated Na2CO3 and dichloromethane, the organic layer was dried and evaporated. The residue was purified by chromatography (SiO2, n-hexane/AcOEt 4:1) to give 3.14 g of the title compound as a pale yellow oil. MS: (M+H)+ 457.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(2,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.70 (1H, br s), 10.79 (1H, br s), 10.19 (1H, br s), 8.18 (0.45H, s), 8.13 (0.55H, s), 7.43-7.36 (1H, m), 7.29-7.21 (2H, m) 7.08-7.05 (1H, m), 4.02 (2H, s), 3.44-3.37 (2H, m), 3.31 (3H, s), 3.26-3.20 (2H, m); HRMS calcd for C19H17F2N3O4+H+: 390.1265. Found 390.1255.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:15]C)=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)#N.[ClH:17]>>[ClH:17].[ClH:17].[CH3:1][NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[NH:15]
Reactant: CNC(=NCCSCc1nccs1)NC#N
Agent: Cl
Product: CNC(=N)NCCSCc1nccs1

Procedure:
Hydrolysis of N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine by treating with concentrated hydrochloric acid at 100° for 4 hours gives N-methyl-N'-[2-(2-thiazolylmethylthio)ethyl]guanidine dihydrochloride.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][CH:37]=[CH:36]3)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29](OC)=[O:30])[CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl>[NH:38]1[C:39]2[C:35](=[CH:34][C:33]([N:21]([CH2:22][C:23]3[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[CH:27][CH:28]=3)[CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:41][CH:40]=2)[CH:36]=[CH:37]1
Reactant: COC(=O)c1cccc(CN(c2ccc3[nH]ccc3c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1cccc(CN(c2ccc3[nH]ccc3c2)C2CCNCC2)c1
Reaction time: 3 h
Yield: 8.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-[(1H-indol-5-yl)-(3-methoxycarbonyl-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.453 mmol) in DCM (2.0 mL). The reaction mixture was stirred for 3 hours, the solvent was then evaporated under reduced pressure and the residue was dissolved in DCM, a mixture of MeOH/NH4OH (9.5/0.5) was then added. The resulting mixture was filtered through a celite and silica pad and the filtrate was evaporated under reduced pressure. The residue was dissolved in THF (5.0 mL) and a solution of lithium aluminum hydride (1.0 M in THF, 1.81 mL, 1.81 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes and it was then quenched by addition of Na2SO4.10H2O. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to give 13.2 mg (9% yield) of (3-{[(1H-indol-5-yl)-piperidin-4-yl-amino]-methyl}-phenyl)-methanol, MS=336 [M+H]+.