Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[BH4-].ClCCl>CO>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:1][C@@H:2]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN[C@H](Cc2c[nH]c3ccccc23)c2nc(-c3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (36.3 mg, 0.12 mmol) and p-anisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA-400) was then added and the slury was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and evaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H) 2.26 (s, 1H). LC/MS: m/z=423 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][NH:5][C:6](=[O:15])[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[OH:3][N:2]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([NH:5][CH3:4])=[O:15]
Reactant: CNC(=O)C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Hydroxylamine hydrochloride (5.96 g, 2.5 eq.) was added to a solution of N-methyl-2-oxo-2-phenylacetamide (5.6 g, 34.3 mmol) in pyridine (25 ml). After stirring for 10 h at room temperature, the excess pyridine was removed in vacuo and the residue was taken up in 250 ml of dichloromethane. The organic phase was washed with 200 ml of water and then again with aqueous hydrochloric acid (0.1 M, 250 ml). The precipitated solid was filtered off, giving 2-(hydroxyimino)-N-methyl-2-phenylacetamide as a yellow solid (2.31 g, pure Z isomer). The filtrate was concentrated by evaporation in vacuo. This gave 4.50 g of 2-(hydroxyimino)-N-methyl-2-phenylacetamide (Z/E=mixture of isomers) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[C:3]([O:7][CH3:8])=[N:4][NH:5][CH:6]=1.CC1C=CC(S(O[CH:20]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=N1>CN(C=O)C>[O:24]1[C:23]2([CH2:28][CH2:29][CH:20]([N:5]3[CH:6]=[C:2]([I:1])[C:3]([O:7][CH3:8])=[N:4]3)[CH2:21][CH2:22]2)[O:27][CH2:26][CH2:25]1
Reactant: COc1n[nH]cc1I
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cn[nH]c1
Solvent: CN(C)C=O
Product: COc1nn(C2CCC3(CC2)OCCO3)cc1I
Temperature: 100 °C

Procedure:
A solution of 4-iodo-3-methoxy-1H-pyrazole (0.783 g, 3.50 mmol), 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (1.20 g, 3.84 mmol), and Cs2CO3 (1.71 g, 5.24 mmol) in anhydrous degassed DMF (26.1 mL) was heated to 100° C. for 3 h. From LCMS, there was still starting material (pyrazole) therefore the reaction mixture was charged with an additional 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (0.437 g, 1.40 mmol) and Cs2CO3 (0.683 g, 2.10 mmol) and heated to 100° C. for an additional 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (25 mL) and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×25 mL), brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in 1.29 g of a crude orange oil/solid mixture. The crude was crystallized from MeOH and the white crystals were filtered through a fritted funnel resulting in the title compound as white crystals. 1H NMR (400 MHz, CD3OD): δ=1.63-1.74 (m, 2H), 1.81-1.89 (m, 2H), 1.98-2.07 (m, 4H), 3.87 (s, 3H), 3.91-3.99 (m, 4H), 4.00-4.09 (m, 1H), 7.48 (s, 1H). MS (ES+): m/z 365.05 [MH+]. HPLC: tR=3.98 min (polar—5 min, ZQ3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N:17]1[C:21]([CH3:22])=[N:20][C:19]([NH2:23])=[N:18]1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.O>[CH3:16][N:17]1[C:21]([CH3:22])=[N:20][C:19]([NH:23][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:18]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cc1nc(N)nn1C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cn(-c2ccc(Nc3nc(C)n(C)n3)cc2C#N)cn1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile (50 mg, 0.19 mmol), 1,5-dimethyl-1H-1,2,4-triazol-3-amine (45 mg, 0.40 mmol), sodium phenoxide (66 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (3 mg, 0.003 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene=Xanthphos (7 mg, 0.012 mmol) in 5 ml of dioxane was heated to 80° C. under argon for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and the product purified by chromatography on silica gel using dichloromethane/methanol 9:1 v/v as an eluent. The title compound was obtained as a yellowish solid (6 mg, 11%). MS ISN (m/e): 292.3 (100) [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>N1C=CC=CC=1.C(Cl)Cl>[CH2:12]([O:11][C:9]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
4-Aminopyridine (17.34 grams) (184.3) was dissolved in dry pyridine (217 ml.) and cooled to 0° C. over 30 minutes. Ethyl chloroformate (17.2 ml.) (180.7 mmoles) was added and the solution was stirred at 0° C. for 1 hour and then at 25° C. for 40 hours. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and water. The CH2Cl2 was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2% (10% saturated NH4OH in MeOH)—CH2Cl2 to give the title compound (Yield: 10 grams, 33%, M+ 166).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:5][S:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][Cl:3])=[CH:9][CH:8]=1
Reactant: CSc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of thionyl chloride (47.6 g) in methylene chloride is slowly added to a solution of 4-(methylthio)benzyl alcohol (50.0 g) in pyridine (37.2 g) such that the temperature never exceeds 25° C. After the addition is complete the mixture is stirred an additional 2 hours at room temperature, then washed with water, dried, and the solvents removed. The resulting red oil is mixed with hexane which is decanted and evaporated to give 49.6 g of 4-(methylthio)benzyl chloride as a yellow oil, suitable for use in the reaction described next below.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:10][C@H:9]1[C:17](=[O:35])[N:18]([CH2:20][C:21](=[O:34])[N:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[CH3:23])[CH3:19])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:33][O:32][C:30](=[O:31])[C:27]1[CH:28]=[CH:29][C:24]([N:22]([C:21](=[O:34])[CH2:20][N:18]([C:17]([C@@H:9]2[CH2:10][C@@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:12][NH:8]2)=[O:35])[CH3:19])[CH3:23])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)[C@@H]2C[C@@H](SC(C)=O)CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)[C@@H]2C[C@@H](SC(C)=O)CN2)cc1
Yield: 116.2 %

Procedure:
2.92 g (5.7 mmol) (2S,4R)-4-Acetylsulfanyl-2-[[[(4-methoxycarbonyl-phenyl)-methyl-carbamoyl]-methyl]-methyl-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester in 60 ml CH2Cl2 were treated with 15 ml TFA at 0° C. until no starting material could be detected. The solution was concentrated, dissolved in toluene and evaporated 3 times yielding 2.7 g (93%) (2S,4R)-4-[[[(4-Acetylsulfanyl-pyrrolidine-2-carbonyl)-methyl-amino]-acetyl]-methyl-amino]-benzoic acid methyl ester.trifluoro-acetate salt as brown foam, MS 408 (MH+).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9](=[CH:12][CH:13]=2)[C:10]#[N:11])=[CH:4][CH:3]=[N:2]1.CS(O[CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)(=O)=O>>[NH2:23][CH2:22][CH2:21][N:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9](=[CH:12][CH:13]=2)[C:10]#[N:11])=[N:1]1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1C#N
Product: N#Cc1ccc(-c2ccn(CCN)n2)cc1C#N

Procedure:
The title compound was prepared from 4-(1H-pyrazol-5-yl)phthalonitrile (0.38 g) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (0.61 g) using the method of Example 37(c). Yield 0.050 g (as HCl-salt). 1H-NMR (400 MHz; d4-MeOH): δ 3.50 (t, 2H), 4.54 (t, 2H), 6.94 (d, 1H), 7.81 (d, 1H), 7.98 (d, 1H), 8.28 (dd, 1H), 8.49 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[CH3:27])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[CH3:26][O:25][C:23](=[O:24])[C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:18]([CH3:27])[CH:19]=1
Reactant: COC(=O)c1ccc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OCCN2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4-[2-(4-Methoxycarbonyl-2-methyl-phenoxy)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E40.1 (200 mg, 0.53 mmol) was dissolved in 4M HCl solution in dioxan (5 ml). The mixture was stirred for 30 min at room temperature, concentrated in vacuo and azeotroped with toluene to yield the title compound (185 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[N:13][C:12]([C:18]([OH:20])=O)=[CH:11]3)=[CH:5][CH:4]=1.Cl.[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH2:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH:45][C:18]([C:12]1[N:13]=[CH:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:22][CH:21]=1)=[CH:17][CH:16]=2)=[O:20])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1
Reactant: O=C(O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Yield: 26.9 %

Procedure:
A solution of 6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid (0.050 g, 0.149 mmol) in DMF (2.0 mL) was treated with 2(S)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.051 g, 0.164 mmol), HBTU (0.062 g, 0.164 mmol), and DIEA (0.112 mL) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using Hexanes:EtOAc 88:12 to give 0.025 g of 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-{[6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1F.[CH3:16][CH:17]([S-:19])[CH3:18].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:19][CH:17]([CH3:18])[CH3:16]
Reactant: CC(C)[S-]
Reactant: N#Cc1ccc(C2OCCCO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(C#N)ccc1C1OCCCO1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (5.51 g, 27 mmol) and sodium 2-propanethiolate (2.90 g, 26.6 mmol, purity 90%; 1 eq.) were initially charged in DMF (125 ml). Potassium carbonate (9.19 g, 66.5 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at 100° C. for 4 h. TLC control then showed complete conversion. The reaction mixture was concentrated and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 4:1). The title compound was isolated as a solid (6.72 g, 96% of theory).
Reaction SMILES: [Cl:1]C(OCC)=O.[CH3:7][O:8][N:9]=[C:10]([C:15]#[C:16][CH2:17]N1CCOCC1)[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[Cl:1][CH2:17][C:16]#[C:15][C:10](=[N:9][O:8][CH3:7])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: CON=C(C#CCN1CCOCC1)C(=O)OC
Solvent: C1CCOC1
Product: CON=C(C#CCCl)C(=O)OC

Procedure:
1.4 ml of ethyl chloroformate are added to a solution of 12.1 g of methyl 2-methoxyimino-5-morpholin-4-ylpent-3-ynoate in 25 ml of THF. The mixture is now heated for 20 hours at 70°. After evaporation, the residue is chromatographed on silica gel (ether/hexane 1:2). This gives 8.2 g of colourless crystals of the title compound of melting point 64-67°.
Reaction SMILES: BrC1C=C(C=CN=1)C([O:7][CH2:8][C@@H:9]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([Br:29])[CH:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[OH-].[Li+]>CO>[Br:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][N:26]=1)[C:22]([NH:21][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:8][OH:7])=[O:30]
Reactant: COc1ccc(C[C@@H](COC(=O)c2ccnc(Br)c2)NC(=O)c2ccnc(Br)c2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@@H](CO)NC(=O)c2ccnc(Br)c2)cc1OC
Reaction time: 15 h
Yield: 37.6 %

Procedure:
To a suspension of (2S)-1-(2-bromoisonicotinoyloxy)-2-(2-bromoisonicotinoylamino)-3-(3,4-dimethoxyphenyl)propane (4.68 g) in methanol (100 ml) is added a 1 M lithium hydroxide (8.1 ml), and the mixture is stirred for 15 hours. The reaction mixture is concentrated under reduced pressure to remove the methanol, and the residue is extracted with methylene chloride. The extract is washed, dried, and concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:acetone=5:1) to give (2S)-2-(2-bromoisonicotinoylamino)-3-(3,4-dimethoxyphenyl)-1-propanol (1.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]O)[N:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:11])[N:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(Br)n1
Solvent: ClCCl
Product: BrCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-6-(hydroxymethyl)pyridine (10.00 g, 53.2 mmol) in CH2Cl2 (150 mL) at 0° C. was added PBr3 (10.03 mL, 106 mmol) dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding saturated NaHCO3 dropwise while stirring. Solid K2CO3 was also added to attain a pH>7. The mixture was separated, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (0-20% ethyl acetate/hexanes) to afford the title compound as a colorless solid. LRMS (APCI) calc'd for C6H6Br2N [M+H]+: 250, Found: 250.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[N:20]=2)[N:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:46])[CH2:44][CH3:45]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[N:20]=2)[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:43](=[O:46])[CH2:44][CH3:45])=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CCC(=O)Cl
Reactant: CN1CCN(C(=O)CCc2cccc(CSc3nc(N)c(C#N)c(-c4ccc(N)cc4)n3)n2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(-c2nc(SCc3cccc(CCC(=O)N4CCN(C)CC4)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
The compound of Example 56 (150 mg) and triethylamine (0.5 mL) were dissolved in 10 mL of acetonitrile, and 0.1 g of propionyl chloride was added dropwise to the mixture and the mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was dissolved in chloroform. Thereto water was added, the organic layer was washed with water (twice), then brine (once), and dried over magnesium sulfate. After the solvent was removed under reduced pressure, the resulting oil was purified by chromatography on silica gel (methylene chloride-methanol-aqueous ammonia=90:10:1) to give 50 mg of N-[4-(6-amino-5-cyano-2-{6-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]pyridin-2-ylmethylsulfanyl}pyrimidin-4-yl)phenyl]propionamide as a light yellow powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16][CH3:17])=[C:5]([C:13](O)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[C:1]([C:3]1[C:4]([O:16][CH3:17])=[C:5]([C:13]([Cl:21])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(C#N)cc2c(c1C(=O)O)CCCC2
Solvent: ClCCl
Product: COc1c(C#N)cc2c(c1C(=O)Cl)CCCC2
Reaction time: 2 h

Procedure:
A stirred mixture of 3-cyano-2-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.110 g, 0.476 mmol) and dry CH2Cl2 (2 mL) was treated with oxalyl chloride (51.9 μl) and dry N,N-dimethylformanide (˜5 μL) at ambient temperature. After 2.0 h, the solvent was evaporated in vacuo. The residue was dissolved in dry CH2Cl2 and used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6])#[CH:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6])[CH3:2]
Reactant: C#Cc1cc(N)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(N)ccc1F
Yield: 68.5 %

Procedure:
To a solution of 3-ethynyl-4-fluoroaniline (220 mg, 1.62 mmol) in ethyl acetate (10 mL) was added 10% palladium on carbon (wet). The resulting mixture was subjected to an atmosphere of hydrogen for approximately 1 h. The palladium on carbon was removed by filtration through celite. The filtrate was concentrated in vacuo to provide 3-ethyl-4-fluoroaniline (154 mg, 1.11 mmol, 69% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): 6.77 (dd, 1H), 6.50 (dd, 1H), 6.45-6.41 (m, 1H), 3.47 (br s, 2H), 2.57 (q, 2H), 1.19 (t, 3H); MS (EI) for C8H10FN: 140 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:19]([O:23][CH2:24][CH2:25][NH2:26])([CH3:22])([CH3:21])[CH3:20]>C(O)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:26][CH2:25][CH2:24][O:23][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CC(C)(C)OCCN
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OCCNc1ccc2ncc(Br)n2n1
Yield: 2.6 %

Procedure:
A solution of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (216 mg, 1.0 mmol), triethyl amine (0.35 mL, 2.5 mmol) and 2-(tert-butoxy)ethanamine (180 mg, 1.5 mmol) in isopropanol (2 mL) was heated at 65° C. for overnight. The mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to give brown solid as crude in quantitative yield for further synthesis. 20 mg was further purified by Prep HPLC to give pure 3-bromo-N-(2-(tert-butoxy)ethyl)imidazo[1,2-b]pyridazin-6-amine as white solid (8 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.57 (d, J=9.85 Hz, 1H), 7.42 (s, 1H), 6.76 (d, J=9.60 Hz, 1H), 4.56 (s, 1H), 3.67 (t, J=5.94 Hz, 2H), 3.53 (t, J=5.94 Hz, 2H), 1.24 (s, 9H) LRMS (ESI) m/e 315.0 [(M+H)+, calcd for C12H18BrN4O 314.2].
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:11](=[O:36])[CH2:12][N:13](C(OCC1C=CC=CC=1)=O)[C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>C(O)C.[C].[Pd].CO>[ClH:44].[C:1]([NH:9][CH:10]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:11](=[O:36])[CH2:12][NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C[C@H](NCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
1-[N-[3-(Benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, phneylmethyl ester (1.0 g.) is dissolved in absolute ethanol (30 ml.) and 1N hydrochloric acid (2.25 ml.). Palladium-carbon catalyst (10%, 200 mg.) is added and the solution is stirred under an atmosphere of hydrogen overnight. The catalyst is filtered off and the solution is evaporated. The crude product (700 mg.) is combined with 300 mg. of crude product from a previous small scale reaction and passed through a column of LH-20 (1 inch×15 inch) in methanol. The fractions containing the desired product are pooled, evaporated, dissolved in water and filtered. The clear aqueous solution is lyophilized to give 800 mg. of 1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline, monohydrochloride; [α]D25 =-59.6 (c=1.4, methanol); m.p. 98°-130° (dec.). Tlc (silica gel, n-butanol/acetic acid/water, 4:1:1) Rf =0.44.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:32]>O>[Ag+:32].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:22])[C:5]([C:23]([O-:25])=[O:24])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(O)CC3)c(F)c21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCn1cc(C(=O)[O-])c(=O)c2cc(F)c(N3CCC(O)CC3)c(F)c21
Yield: 93 %

Procedure:
To a stirred solution of 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxy-1-piperidinyl)-4-oxoquinoline-3-carboxylic acid (235 mg), sodium hydroxide (26.7 mg), and water (3 ml), a solution of silver nitrate (113 mg) and water (2 ml) was added. The precipitate was filtered off, washed with water, and dried to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxy-1-piperidinyl)-4-oxoquinoline-3-carboxylic acid silver salt (284 mg), mp 181°-184° C. (decomp.).
Reaction SMILES: [O-2].[O-2].[O-2].[Al+3].[Al+3].O[CH2:7][CH:8]1[CH:13]([CH3:14])[CH:12]2[CH2:15][CH:9]1[CH2:10][CH2:11]2.C=C1C(C)C2CC1CC2>>[CH3:7][C:8]1[CH:9]2[CH2:15][CH:12]([C:13]=1[CH3:14])[CH2:11][CH2:10]2
Reactant: CC1C2CCC(C2)C1CO
Agent: C=C1C2CCC(C2)C1C
Agent: [Al+3]
Agent: [O-2]
Product: CC1=C(C)C2CCC1C2

Procedure:
Into an atmospheric reaction tube of the flow type made of quartz and having an outer diameter of 20 mm and a length of 500 mm, 20 g of γ-alumina (manufactured by NIKKI CHEMICAL Co., Ltd.; “N612N”) was placed. The dehydration was conducted at a reaction temperature of 285° C. at a weight hourly space velocity (WHSV) of 1.1 hr−1, and 490 g of a dehydration product of 2-hydroxymethyl-3-methylbicyclo[2.2.1]heptane containing 2-methylene-3-methylbicyclo[2.2.1]heptane and 2,3-dimethyl-bicyclo[2.2.1]hept-2-ene was obtained.