Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH:6]1([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:13](O)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:6]1([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:13]([N:4]([O:3][CH3:2])[CH3:5])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution (80 mL) of N-methoxymethanamine hydrochloride (2.20 g) in N,N-dimethylformamide was added triethylamine (3.10 mL) for neutralization, and 3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]propanoic acid (5.95 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (5.80 g) and 1-hydroxybenzotriazole (4.10 g) were added under ice-cooling. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, and washed with water, 1N aqueous hydrochloric acid solution and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (6.07 g, yield 89%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 340 (MH+).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.C(O)(=O)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[N:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=4)=[N:11][C:10]=3[CH:12]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(-c2nc3cc(NCc4ccncc4)ccc3o2)cc1
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To 2-p-tolylbenzo[d]oxazol-5-amine (500 mg, 2.32 mmol) in 1,2-dichloroethane (20 mL) at room temperature was added acetic acid (142 μL, 2.32 mmol) and isonicotinaldehyde (222.5 μL, 2.29 mmol) and the mixture was stirred for 1 h. Sodium triacetoxyborohydride (707 mg, 3.35 mmol) was then added and the mixture was stirred at room temperature for 24 h. The mixture was then diluted with dichloromethane and the organic layer was washed with saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate:hexanes 20:80 to afford 328 mg (47%) of the title compound (LCMS RT=6.27 min, MH+ 316.1)
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:20])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH2:14][C:15]([O:17]CC)=[O:16])([CH:12]=[CH2:13])[CH2:5]1.O.Cl>CO>[CH3:3][C:4]1([CH3:20])[CH2:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]([CH2:14][C:15]([OH:17])=[O:16])([CH:12]=[CH2:13])[CH2:5]1
Reactant: C=CC1(CC(=O)OCC)CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CC1(CC(=O)O)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A solution of NaOH (1.03 g, 25.8 mmol) and acetate 16 (1.3 g, 5.15 mmol) in methanol (26 ml) was refluxed for 3 h. The mixture was cooled to room temperature and poured into water (100 ml). The aqueous phase was acidified by conc. aqueous HCl and extracted with hexane (330 ml). The combined organic phases were washed with brine and dried over CaCl2, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 17 (0.7 g, 71%) as a colorless solid with m.p. 92-94° C. 1H-NMR (CDCl3, TMS): 0.92 (6H, s, 3,5-CH3); 1.02 (6H, s, 3,5-CH3); 1.00-1.30 (4H, m, 4-CH2 and 2,6-CH); 1.90 (2H, d, 14 Hz, 2,6-CH); 2.27 (2H, s, CH2C═O); 5.11 and 5.13 (total 2H, both d, 11 and 18 Hz, ═CH2); 5.99 (1H, dd, 18 and 11 Hz, ═CH) and 10.80 ppm (1H, br s, COOH).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][C:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[C:53]([CH3:62])[O:52][N:51]=1>CN(C=O)C>[CH3:49][C:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)=[C:53]([CH3:62])[O:52][N:51]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1noc(C)c1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(3,5-dimethyl-isoxazol-4-yl)-phenylamine (0.012 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 61% yield: LCMS (ESI) m/z 377 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:3][C:4]=1[O:10][CH3:11])=[O:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OCC(=O)OC(C)(C)C)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 218 %

Procedure:
A mixture of 4-hydroxy-2-methoxybenzaldehyde (5.23 g; 34.4 mmol), t-butyl bromoacetate (4.9 mL; 30.3 mmol) and K2CO3 (15.1 g; 108.9 mmol) in 50 mL of DMF was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered, and partitioned between ethyl acetate and 1 N HCl. The organic phase was washed (sat. NaCl) and dried (MgSO4), and concentrated to give 17.59 g of t-butyl 4-formyl-3-methoxyphenoxyacetate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7](=[O:20])[C@H:8]([CH:17]([CH3:19])[CH3:18])[NH:9]C(OC(C)(C)C)=O)[CH3:2]>Cl.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7](=[O:20])[C@H:8]([CH:17]([CH3:19])[CH3:18])[NH2:9])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 5.82 gm (14.8 mMol) N-benzyl-N-[N′-tert-butoxycarbonyl-(S)-valinyl]glycine ethyl ester in 20 mL 4N hydrogen chloride in dioxane was stirred at room temperature under a nitrogen atmosphere over night. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase was extracted again with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to provide 4.2 gm (97%) of the desired compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C

Procedure:
To a solution of methyl 3-cyano-4-methoxy-benzoate (1.5 g, 7.9 mmol) in CH3OH/H2O (25 mL; 1:1), was added LiOH (2.5 g, 60.0 mmol). The reaction mixture was refluxed for 2 h, cooled at rt and 6M HCl was added dropwise until pH 2 was obtained. The precipitate was collected, washed with H2O (3×20 mL), dried in vacuo to afford 3-cyano-4-methoxy-benzoic acid. MS (ESI) 178 (M+H)+. To a 100 mL round-bottom flask with 3-cyano-4-methoxy-benzoic acid (1.4 g, 7.8 mmol), was added SOCl2 (15 mL) dropwise. The reaction was refluxed for 1 h and was cooled to rt. The excess of SOCl2 was removed in vacuo and the oily acid chloride was dissolved in THF (15 mL). The resulting solution was added dropwise to a mixture of 2-aminophenol (1.3 g, 11.7 mmol), triethylamine (1.3 g, 11.7 mmol) and THF (30 mL) at 0° C. The reaction was warmed up to rt and stirred an additional 3 h. The precipitate was removed by filtration and the filtrate was concentrated and dried in vacuo. The dark brown solid residue was dissolved in toluene (20 mL) and p-toluenesulfonic acid (6.0 g, 46.8 mmol) was added. The reaction was refluxed overnight, cooled to rt, and EtOAc (300 mL) was added. The EtOAc solution was washed with brine (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, CHCl3:CH3OH 8:1) to afford 5-(1,3-benzoxazol-2-yl)-2-methoxy benzonitrile. MS ESI) 251(M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[NH:14][CH:13]=[N:12][N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].O1CCCC1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[S:3][C:4]([C:10]2[N:14]=[CH:13][N:12]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8]
Reactant: C1=COCCC1
Reactant: N#Cc1c(Br)sc(-c2nnc[nH]2)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Br)sc(-c2ncn(C3CCCCO3)n2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
2,4-Dibromo-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.80 g, 2.4 mmol) was placed in a 500 mL round bottom flask and tetrahydrofuran (50 mL, 600 mmol) was added. To the resulting solution were added dihydropyran (1.31 mL, 14.4 mmol) and p-toluenesulfonic acid monohydrate (0.683 g, 3.59 mmol). The mixture was stirred for 3 h at rt. The solution was then poured into 20 mL water and extracted with 40 mL ethyl acetate twice. The combined organic layers were evaporated in vacuo. The residue was purified by column chromatography using 0-35% EtOAc in hexane to afford a solid product (0.842 g, yield 84%). LCMS: (AA) ES+, 417, 419, 421. 1H NMR (300 MHz, CDCl3) δ: 8.38 (s, 1H), 5.55-5.60 (m, 1H), 4.06-4.10 (m, 1H), 3.68-3.78 (m, 1H), 2.15-2.28 (m, 1H), 2.01-2.13 (m, 2H), 1.66-1.80 (m, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=O)[CH2:7]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl>C(O)C>[ClH:23].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=[N:22][NH:21][C:18]([NH2:20])=[NH:19])[CH2:7]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccco1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccco1)C2
Yield: 95.5 %

Procedure:
A mixture of 7-(2-furyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (227 mg), aminoguanidine hydrochloride (122 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was refluxed for 2 hours. The reaction solution was cooled, and precipitated crystals were filtered and washed with ethanol to give 7-(2-furyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 69) (305 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[O:34])=[CH:3][CH:4]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N2-(4-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.022 g, 0.07 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)phenyl isocyanate (0.030 mL, 0.2 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm to room temperature and left stirring for 1 hour. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to afford AD75. ESI-MS m/z [M+H]+ found 495.5, calculated 495.2.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)[C:9]2[CH2:8][CH2:7][C:6]3[O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[C:5]=3[C:4]=2[N:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH2:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[C:4](=[C:5]4[CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]5[O:25][C:6]4=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3c2CCC2=C3C3CCCCC3O2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2CC[C@@H](N)C2)c2ccc3c(c2n1)C1CCCCC1O3
Reaction time: 16 h

Procedure:
A solution of the product from Example 7A (28 mg, 0.065 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.2 mL) at ambient temperature and stirred for 16 hours. The mixture was diluted with dichloromethane (20 mL), and basified with sodium hydroxide (1 N). The organic layer was separated, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluting with ammonium hydroxide/methanol/dichloromethane (0.8/8/92) to provide the dehydrogenated material as the major product and title compound: 1H NMR (CD3OD) δ 1.00-1.18 (m, 1H), 1.27-1.41 (m, 1H), 1.45-1.58 (m, 1H), 1.62-1.75 (m, 2H), 1.92-2.07 (m, 3H), 2.11-2.24 (m, 1H), 2.24-2.39 (m, 2H), 3.38-3.52 (m, 1H), 3.74-3.92 (m, 2H), 3.98-4.12 (m, 1H), 4.10-4.24 (m, 2H), 6.87 (d, 1H), 8.08 (d, 1H); MS (DCl/NH3) m/z 326 (M+H)+.
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[C:10]([CH:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](OCC)=[O:15])(=O)[CH3:11]>CCO>[CH3:7][C:6]1[NH:9][C:14](=[O:15])[C:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:11])[N:8]=1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nc(C)[nH]c1=O
Yield: 26.9 %

Procedure:
A mixture of NaOEt (0.069 mol) in EtOH (prepared from 1.6 g of Na in 100 mL of EtOH), acetamidine hydrochloride (6.5 g, 0.069 mol), and diethyl 2-acetylsuccinate (15.0 g, 0.069 mol) was heated under reflux for 16 h. The mixture was concentrated, taken up in water (50 mL), and acidified with 2N HCl (12 mL). The aqueous mixture was extracted with CH2Cl2, and the extracts were dried (MgSO4) and concentrated. Trituration with ether gave 3.9 g (27%) of product as a white solid, mp 175°-177° C.
Reaction SMILES: CCO.[Br:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+:14]([O-])=O)[C:6]=1[S:17][C:18]#[N:19].Cl.N>[Fe].O>[Br:4][C:5]1[C:6]2[S:17][C:18]([NH2:19])=[N:14][C:7]=2[CH:8]=[C:9]([NH2:11])[CH:10]=1
Reactant: N#CSc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)c2sc(N)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a stirred mixture of EtOH (8.37 L) and water (8.37 L) at rt was added (2-bromo-4,6-dinitro-phenyl)thiocyanate (549 g, 1.81 mol) followed by addition of Fe powder (2.02 kg, 36.11 mol) and drop wise addition of HCl (12N, 527 mL) over 30 min. The resulting reaction mixture was stirred at rt for 20 min then heated to 80° C. for 45 min. After completion of the reaction (by TLC) the reaction mixture was cooled to rt and basified to pH 8-10 by addition of aqueous ammonia solution. The resulting solution was passed through celite bed, washed with EtOAc and the combined filtrate evaporated under reduced pressure. To the resulting residue was added water (8 L) then extracted with EtOAc (2×4 L). The combined organics were washed with brine, dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (412 g, 93%). 1H NMR (DMSO-d6): δ 5.16 (br s, 2H), 6.50 (d, J=2.0 Hz, 1H), 6.53 (d, J=1.60 Hz, 1H) and 7.44 (br s, 2H). LCMS: 243.86 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.O.[CH3:30][N:31](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[OH:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[O:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: CN(C)C=O
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)oc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (276 mg, 0.62 mmol), Zn(CN)2 (110 mg, 0.94 mmol), Pd2(dba)3 (57 mg, 0.062 mmol) and dppf (68.8 mg, 0.124 mmol) in DMF (6 mL) was stirred at 100° C. for 2 h. The reaction mixture was cooled to rt, poured into water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 15:1 DCM/MeOH to give 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile as a light yellow solid (62 mg, 25.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.83 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.41 (s, 1H), 7.14 (m, 2H), 5.54 (s, 2H), 4.68 (d, J=4.8 Hz, 1H), 3.34 (br s, 2H), 1.91 (br s, 2H), 1.62 (br s, 2H), 1.22 (br, 4H). LCMS (ESI) m/z 389 (M+H)+.
Reaction SMILES: CN1C=CC=C1C=O.C(N1C=CN=C1C=O)C1C=CC=CC=1.[CH2:23]([O:25][CH:26]([O:43][CH2:44][CH3:45])[C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:42])[CH:34]=[CH:35][C:36]2[N:37]([CH3:41])[CH:38]=[CH:39][CH:40]=2)=[CH:29][CH:28]=1)[CH3:24].C(N1C=CN=C1C=CC(C1C=CC(C=O)=CC=1)=O)C1C=CC=CC=1>>[CH2:23]([O:25][CH:26]([O:43][CH2:44][CH3:45])[C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:42])[CH:34]=[CH:35][C:36]2[CH:40]=[CH:39][CH:38]=[CH:41][N:37]=2)=[CH:29][CH:28]=1)[CH3:24]
Reactant: CCOC(OCC)c1ccc(C(=O)C=Cc2cccn2C)cc1
Agent: Cn1cccc1C=O
Agent: O=Cc1ccc(C(=O)C=Cc2nccn2Cc2ccccc2)cc1
Agent: O=Cc1nccn1Cc1ccccc1
Product: CCOC(OCC)c1ccc(C(=O)C=Cc2ccccn2)cc1

Procedure:
By the same method N-methylpyrrole-2-carbaldehyde and 1-benzyl imidazole-2-carbaldehyde are converted to 4-[3-(1-methyl-2-pyrrolyl)-2-propenoyl]benzaldehyde diethyl acetal and 4-[3-(1-benzyl-2-imidazolyl)-2-propenoyl]benzaldehyde.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37]>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH2:15][CH2:14][CH2:13][CH:12]2[C:10]([N:9]([CH2:8][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=2)[C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: CCn1cc(CN(C(=O)C2CCCc3ccc(O)cc32)c2ccc(C(C)C)cc2)cn1
Reactant: CN(C)CCCl
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(OCCN(C)C)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 30.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 7-[2-(dimethylamino)ethoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH:21][C:22](=[O:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17](=[O:20])(=[O:19])[OH:18])=[CH:12][CH:11]=2)[S:6][CH:7]=1)[CH3:2].[OH-].[Na+].N(C)(C)C.COS(O[Na:49])(=O)=O>CO.O>[CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH:21][C:22](=[O:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17](=[O:18])(=[O:19])[O-:20])=[CH:12][CH:11]=2)[S:6][CH:7]=1)[CH3:2].[Na+:49]
Reactant: CCc1csc([C@H](Cc2ccc(NS(=O)(=O)O)cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)n1
Reactant: COS(=O)(=O)O[Na]
Agent: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1csc([C@H](Cc2ccc(NS(=O)(=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4-((S)-2-(4-ethylthiazol-2-yl)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)ethyl)-phenylsulfamic acid (75) (150 g, 0.272 mmol) in methanol (1.2 L) was added 50% NaOH (11.3 g, 0.272 mol, 1.0 equiv.) at room temperature. The resulting mixture was stirred at rt for 30 min and then concentrated under reduced pressure to give the crude product, which contained a small amount of Me3N and MeOSO3Na. To a stirred slurry of the crude product (75 g) in H2O (150 mL) was added aq. NaOH (2 g, 0.05 mol; in 50 mL H2O) in dropwise at room temperature. The slurry was continued to stir for 20 min, filtered and washed with water (10 mL) and ethyl ether (50 mL). Then the filter cake was dried under reduced pressure at 50° C. to give 62 g (83%) of the desired compound. LC/MS (M−1): 531; H-NMR (300 MHz, CD3OD) δ: 7.21-6.98 (m, 10H), 5.40-5.36 (t, 1H, J=6.9 Hz), 4.38-4.34 (t, 1H, J=7.5 Hz), 3.61 (s, 3H), 3.24-3.23 (m, 1H), 3.11-3.01 (m, 2H), 2.81-2.74 (m, 3H), 1.31-1.26 (t, 3H, J=7.5 Hz); HPLC: 98.5%.