Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:12]1([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cccc(N)c1
Reactant: O=C1CCCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cccc(NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Under ice cooling, 45 ml of acetic acid was added dropwise over 1 hour to 300 ml of a dichloroethane suspension of 8 g of sodium borohydride. To said mixture were added slowly a solution of 17.48 g of m-anisidine and 16 ml of cyclohexanone in 50 ml of dichloroethane, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was poured into an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed, dried and then purified by silica gel column chromatography [ethyl acetate-hexane (1:5)] to afford 29.37 g of cyclohexyl-(3-methoxyphenyl)-amine as an oil. IR (Neat) (cm-1): 3400, 2920, 2850, 1615, 1510, 1500, 1450, MS (m/z): 205 (M+), 162.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:12](N)=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[K+]>C(O)CO.O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:16][CH2:15][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:12]([OH:25])=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Solvent: CC(=O)O
Product: Cc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1

Procedure:
A solution of 1-benzyl-4-(3-methylphenylamino)-isonipecotamide (4.5 g, 13.9 mmol) and potassium hydroxide (3. g, 53.5 mmol) in ethylene glycol (35 mL) was heated under reflux. The resulting mixture was diluted with water and neutralized with acetic acid. The white solid precipitated was filtered, washed with chloroform to provide 1-benzyl-4-(3-methylphenylamino)piperidine-4-carboxylic acid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2ccco2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (61.0 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH2Cl2 was added 2-furoyl chloride (95%, 35.1 mg, 1.2 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 13 (75 mg, 93%). LRMS 285 (M-100)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22](C(F)(F)F)[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:32]1([CH:35]=O)[CH2:34][CH2:33]1.C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:32]1([CH2:35][N:11]2[CH2:10][CH2:9][N:8]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:2]([F:7])([F:6])[F:1])[N:17]=[C:16]([C:30]#[N:31])[N:15]=3)[CH2:13][CH2:12]2)[CH2:34][CH2:33]1
Reactant: O=CC1CC1
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1nc(-c2ccccc2C(F)(F)F)cc(N2CCN(CC3CC3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-(piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (67 mg) in methanol (2 ml) was added cyclopropane carboxaldehyde (13 μl), acetic acid (0.5 ml) and resin-bound cyanoborohydride (1 mmol/g, 89 mg). The reaction mixture was stirred at room temperature for 16 hrs. Resin was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in methanol and purified using the prep-HPLC to give 4-(4-cyclopropylmethyl-piperazin-1-yl)-6-(trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt as a white solid (10 mg).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:31]=[N:32][CH:33]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cncc(F)c1
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1) and (5-fluoropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.04 min, m/z=451.3 [M+H]+, m/z=449.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H) 3.44-3.51 (m, 2H) 3.56 (q, J=5.40 Hz, 2H) 4.68 (t, J=5.14 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.82-7.87 (m, 2H) 7.87-7.93 (m, 1H) 8.12 (d, J=2.38 Hz, 1H) 8.58 (d, J=2.76 Hz, 1H) 8.61 (t, J=1.69 Hz, 1H) 8.75 (d, J=2.38 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C1N=C[N:22](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([NH2:22])=[O:19])=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2ccc(C(N)=O)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68 %

Procedure:
To a room temperature solution of 7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (141 mg, 0.54 mmol) in 10 mL of THF is added N,N-carbonyldiimidazole (105 mg, 0.65 mmol). The solution is heated at reflux for 1 hour and cooled slightly. Aqueous NH4OH (2.5 mL) is added and the reaction mixture is stirred at room temperature for 40 minutes then partitioned between 1:1 hexane:ethyl acetate and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is recrystallized from hexane and ethyl acetate to provide 7-methoxy-1-(1 methylethoxy)-2-naphthalenecarboxamide in 68% yield; mp 172°-174° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C([NH:33][CH2:34][C:35](O)=[O:36])(OC(C)(C)C)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:35](=[O:36])[CH2:34][NH2:33])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:25]
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CN)CCc3ccccc3C2)cc1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a mixture of 2-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (100 mg, 0.3 mmol) from Example 8 and N-Boc-glycine (52 mg, 0.3 mmol) in DMF (1.0 mL) was added Et3N (61 mg, 0.6 mmol) and TBTU (96 mg, 0.3 mmol). The mixture was stirred overnight and the precipitates were collected by filtration(130 mg) and dissolved in dichloromethane (10 mL) and TFA (5.0 mL). The mixture was concentrated under reduced pressure and ethyl acetate (20 mL) were added and the resulting solution was washed with 1N NaOH. The organic phase was dried over MgSO4 and then concentrated under reduced pressure to give 2-(2-amino-acetylamino)-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:30](=[O:31])[N:29]([CH3:32])[C:11]3[N:12]([CH3:28])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH2:20][C:21](=O)[CH2:22][O:23][CH2:24][CH3:25])=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:30](=[O:31])[N:29]([CH3:32])[C:11]3[N:12]([CH3:28])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:41]([CH2:39][CH3:40])[N:42]=[C:21]([CH2:22][O:23][CH2:24][CH3:25])[CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: CCOCC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Reactant: CCNN
Agent: O=C(O)C(=O)O
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n(CC)n1

Procedure:
The process is carried out as in Example 37 above, with compound A, 1-[3-(4-fluorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-ethoxy-butane-1,3-dione and ethylhydrazine oxalate.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=[O:22])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CCC=O)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
A solution of dimethyl sulfoxide (5.1 mL) in dichloromethane (10 ml) was added to a stirred solution of oxalyl chloride (3.0 mL, 36 mmol) in dichloromethane (40 ml) at −78° C. over 30 min. Upon completion of the addition, the mixture was stirred at −78° C. for 5 min, followed by addition of a solution of 4-methoxybenzenepropanol (3.0 g, 18 mmol) in dichloromethane (20 ml) at −78° C. over 30 min. The resulting mixture was stirred at −78° C. for 40 min. Next, triethylamine (15 mL, 110 mmol) was added dropwise over 10 min. The resulting mixture was allowed to warm to 0° C. and stirred at this temperature for 1 hour. It was diluted with dichloromethane (30 mL) and quenched with water (15 mL). The organic extracts were separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes (gradient: 3 min: 0/100 to 23 min: 20/80) to afford the desired product (1.50 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[N:4][CH:3]=1.[CH:15]1([Mg]Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(OCC)C.[Cl-].[NH4+]>C1COCC1.O>[CH:9]1([C:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][N:4]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cnc(C(=O)c2ccccc2)o1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C(O)(c2ccccc2)C2CCCCC2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (5-methyl-oxazol-2-yl)-phenyl-methanone (intermediate 2) (3.0 g, 16 mmol) in 32 mL dry THF at 0° C. under nitrogen was treated dropwise over 10 min with a 2 M solution of cyclohexylmagnesium chloride in diethyl ether (10 mL, 20 mmol). The resulting deep yellow solution was stirred at 0° C. for about 30 min during which time a precipitate was formed, and then at RT for 1.5 h. The reaction mixture was cooled to 0° C. again and treated cautiously with satd. ammonium chloride solution (aq.). The mixture was stirred at RT for 10 min then diluted with water (10 mL). The phases were separated and the organic phase was washed with brine. The combined aqueous phase was extracted with DCM and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product, which was triturated with ether, filtered off and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4](O)([C:18]([F:21])([F:20])[F:19])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:17].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:17])[C:18]([F:20])([F:21])[F:19]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccccc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (50 ml) of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1-phenyl-α-(trifluoromethyl)-1H-pyrazole-4-acetic acid methyl ester (1.5 g, 4.5 mmol), thionyl chloride (2 ml, 22.5 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (4.41 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[C:21]2[N:22]=[C:23]([SH:25])[S:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[Cl:15][C:16]1[C:21]2[N:22]=[C:23]([S:25][CH2:2][C:3]([N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][CH2:6]3)=[O:4])[S:24][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Sc1nc2c(Cl)cccc2s1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: O=C(CSc1nc2c(Cl)cccc2s1)N1CCCc2ccccc21
Yield: 72 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4-chlorobenzo[d]thiazole-2-thiol as the nucleophile to yield 22 as a white solid (72%): MS m/z: 375 (M+H)+. Anal. Calcd. For, C18H15ClN2OS2: C, 57.67; H, 4.03; N, 7.47; S, 17.11; Cl, 9.46. Found: C, 57.79; H, 4.08; N, 7.48; S, 17.33; Cl, 9.41.
Reaction SMILES: [NH2:1][C:2](=[O:27])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6]>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:1][C:2](=[O:27])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([OH:14])=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)O)cc1N(CC(N)=O)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Benzyl 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoate (220 mg, 0.561 mmol) was dissolved in MeOH (20 ml) and CHCl3 (5 ml), then Pd/C 5% (119 mg, 0.056 mmol) was added. The solution was shaken under hydrogen atmosphere at 30 psi on a Parr apparatus for 30 minutes. The catalyst was filtered off and the solvent removed under vacuum to give 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoic acid (150 mg, 89% yield).
Reaction SMILES: [N:1]1([CH:7]([CH3:25])[CH2:8][C:9]2[C:10](=[O:24])[NH:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[N:1]1([CH:7]([CH3:25])[CH2:8][C:9]2[C:10](=[O:24])[NH:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C2=C(CC(C)N3CCCCC3)C(=O)NCCC2)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(CC1=C(c2cccc(O)c2)CCCNC1=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solution of 6.15 g of 3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone in 60 ml of methylene chloride, cooled in a dry ice-acetone bath, is added slowly to 120 ml of a similarly precooled 10% solution of boron tribromide in methylene chloride. The mixture is allowed to warm to room temperature and stirred for four hours. It is again cooled in an ice bath, 120 ml of 3 N aqueous sodium hydroxide are added and stirring at room temperature is continued for 30 minutes. The aqueous layer is separated and the methylene chloride solution is washed with 60 ml of water. The combined aqueous solution is neutralized to pH=9-10 with 6 N hydrochloric acid and the precipitate collected, to yield the 3-(2-piperidinopropyl)-4-(3-hydroxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 218°-220°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:33][NH:32][C:24](=[O:31])[C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NNC(=O)c1ccncc1
Solvent: CCO
Product: CC(=NNC(=O)c1ccncc1)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
To a solution of example 208 (0.065 g, 0.214 mmol) in ethanol (1.5 ml), isonicotinic hydrazide (0.050 g, 0.428 mmol) was added refluxed for 12 h. The reaction mixture was concentrated and the residue was washed with water, ethyl acetate and dried under vacuum to afford the title compound as a single isomer and as a pale yellow solid (0.070 g, 77%). M.P.: 239-241° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.24 (s, 1H), 8.88 (dd, J=4.1, 2.5 Hz, 1H), 8.77 (s, 2H), 8.60 (brs, 1H), 8.37 (d, J=8.0 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.82 (d, J=7.1 Hz, 2H), 7.71 (m, 1H), 7.54 (dd, J=8.3, 4.2 Hz, 1H), 6.18 (s, 2H), 2.55 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:38])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[C:25]([C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[OH:37])=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:18][CH:17]=1)=O)(C)(C)C.Cl.[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46].C(N(CC)CC)C>C1COCC1.O1CCOCC1.ClCCl>[OH:37][C:31]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=1[C:25]1[C:24]([C:23]#[C:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:14]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[S:45]([C:41]3[S:40][CH:44]=[CH:43][CH:42]=3)(=[O:47])=[O:46])=[O:38])=[CH:21][CH:20]=2)=[CH:28][N:27]([CH3:29])[N:26]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3S(=O)(=O)c3cccs3)cc2)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a solution of compound 3 (8.72 g, 16.95 mmol) in THF (100 mL) was added a solution of 4 M HCl in dioxane (200 mL). The reaction mixture was stirred at rt and monitored with TLC and LC-MS. When all the starting material 3 was reacted, the reaction mixture was concentrated to dryness. 2-Thiophenesulfonyl chloride (3.10 g, 16.95 mmol) and dry dichloromethane (˜200 mL) were added to above residua. Triethylamine (12.0 mL, 86.1 mmol) was then slowly added to above mixture while cooling with an ice-water bath. The final mixture was stirred at rt overnight. It was then washed with brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated and purified with silica column chromatography eluting with dichloromethane-ethyl acetate (v/v 9/1), then hexanes-ethyl acetate (v/v 1/1). The product was recrystallized from hot methanol to give the title compound (23, 5.93 g) as light yellow solid in 62.4% yield. 1H NMR (CDCl3, 500 MHz) δ 10.48 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 7.67 (m, 2H), 7.61 (s, 1H), 7.58 (d, 2H, J=8.0 Hz), 7.50 (d, 2H, J=8.5 Hz), 7.14 (t, 1H, J=4.0 Hz), 7.07 (d, 1H, J=8.0 Hz), 6.94 (d, 1H, J=8.0 Hz), 4.66 (d, 1H, J=5.0 Hz), 4.07 (br d, 1H, J=13.5 Hz), 3.93 (s, 3H), 3.17 (t, 1H, J=13.0 Hz), 2.36 (m, 1H), 2.34 (s, 3H), 1.67-1.45 (m, 3H), 1.29 (m, 2H). LCMS (ESI) m/z 561.14 (MH+, 100); HPLC: tR=5.82 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3[nH]ccc23)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc3[nH]ccc23)CC1
Reaction time: 8 h
Yield: 70.8 %

Procedure:
4-Hydroxy-4-(1-H-indol-4-yl)-piperidine-1-carboxylic acid tert-butyl ester 4-5 (1.0 g, 3.17 mmol) was combined with pyridine (20 mL) and phosphorus oxychloride (0.7 mL, 7.4 mmol) at room temperature under nitrogen, and was stirred overnight. The reaction was partitioned between ethyl acetate (55 mL) and water (55 mL). The ethyl acetate layer was washed with water (2×30 mL) and brine (55 mL), then dried (MgSO4), filtered and concentrated to afford (670 mg, 71%) of 4-(1H-Indol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 4-6.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25](=O)[O:26]C4C=CC([N+]([O-])=O)=CC=4)[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:26])[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)N2CCOCC2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
To a solution of 4-nitrophenyl 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenylcarbamate (55.5 mg, 0.115 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added morpholine (0.0500 mL, 0.573 mmol) and triethylamine (0.0500 mL, 0.359 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 33.4 mg (67%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)morpholine-4-carboxamide. LCMS (ESI): RT (Min)=4.234, M+H=431.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.17 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 3.66-3.53 (m, 4H), 3.47-3.37 (m, 4H), 2.21 (s, 3H), 2.15-2.00 (m, 1H), 0.98-0.67 (m, 4H).