Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH2:10][Cl:11].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:11][CH2:10][C:5]1[C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccnc1CCl
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a stirred solution of methyl-2-(chloromethyl)nicotinate (20 g, 108 mmol) in DCM (300 mL) was added m-CPBA (20.5 g, 119 mmol) at 0° C. After it was stirred at room temperature for 16 hours, the reaction mixture was washed with a mixture of satd. aq. Na2SO3 and NaHCO3 solution. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give the crude title product (20 g, yield 92%), which was used in the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:36])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccc(F)cc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(4-fluorobenzoyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.035 g, 0.085 mmol) and ammonium acetate (0.0655 g, 0.850 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.21 mL, 0.21 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H23ClFN4O (M+H)+: m/z=413.2; Found: 413.2.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[C:22]1([C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:22]1([C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Yield: 82.6 %

Procedure:
A mixture of pyridine (15 ml), diphenyl phosphite (2.34 g, 10 mmole), imidazole (0.68 g, 10 mmole) and triphenylmethanol (2.08 g, 8 mmole) was refluxed for 3 hours. Pyridine was removed under reduced pressure, and the residue was extracted with dichloromethane. The extract was washed with a 5% aqueous hydroxide solution and water in order, dried and evaporated. Recrystallization of the residue (2.23 g) from acetonitrile gave 2.05 g of 1-triphenylmethylimidazole as colorless needles. Yield, 82.7%. M.P., 221°-223° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([Br:14])[C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].CI.CC(=O)OCC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[C:4]([Br:14])[C:3]=1[O:15][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Br)cc(S(F)(F)(F)(F)F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(Br)cc(S(F)(F)(F)(F)F)cc1Br
Yield: 107.1 %

Procedure:
450 mg of 2,6-dibromo-4-pentafluorosulfanylphenol, 329 mg of K2CO3 and 186 mg of CH3I were stirred at RT in 5 ml of anhydrous DMF for 24 hours. Subsequently, the reaction mixture was poured onto 100 ml of EA and extracted 3 times with 30 ml each time of water. Drying was effected over MgSO4 and the solvent was removed under reduced pressure to obtain 500 mg of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[Cl:44][CH2:45][C:46](Cl)=[O:47]>C1COCC1>[Cl:44][CH2:45][C:46]([NH:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)=[O:47]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 400 mg, 0.87 mmol) was stirred in dry THF (5 mL) and DIPEA (0.3 mL, 1.765 mmol) was added followed by the dropwise addition of chloroacetyl chloride (104 μL, 1.258 mmol). After 45 mins, a further quantity (69 μL) of chloroacetyl chloride was added and stirring was continued for 18 hrs. The reaction mixture was partitioned between EtOAc and water, the organic layer washed with saturated brine and then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with 65% EtOAc in cyclohexane to give title compound (334 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:12]=[CH:11][C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: C=CC(=O)O
Reactant: N#Cc1ccc(Br)cc1
Product: N#Cc1ccc(C=CC(=O)O)cc1
Yield: 78.6 %

Procedure:
A Heck reaction of 4-bromobenzonitrile and acrylic acid gave 4-cyanocinnamic acid. The acid was reduced to the corresponding alcohol with ethyl chloroformate and then sodium borohydride. Yield 78.6%
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:22][O:23][C:24]=3[CH3:25])=[O:19])[CH2:14][CH2:13]2)[C:9]([Cl:34])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:35][N:36]([CH3:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:34][C:9]1[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:22][O:23][C:24]=3[CH3:25])=[O:19])[CH2:16][CH2:17]2)=[CH:11][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([N:36]([CH3:35])[CH3:46])=[CH:45][CH:44]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1N
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1NC(=O)c1ccc(N(C)C)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69.4 %

Procedure:
The reaction mixture of methyl 2-amino-5-chloro-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate (27.5 mg, 0.057 mmol), 4-(dimethylamino)benzoyl chloride (52.1 mg, 0.284 mmol), N,N-dimethylpyridin-4-amine (0.693 mg, 5.67 μmol) and 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (78 mg, 0.284 mmol) in DCE (1.5 mL) was stirred at 80° C. for 6 hours. The product was purified by preparative HPLC (0.1% TFA MeOH/H2O) to give 25 mg (49% yield) of methyl 5-chloro-2-(4-(dimethylamino)benzamido)-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate. 1H-NMR (CDCl3, 400 MHz): δ 12.06 (1H, s), 8.53 (1H, s), 8.05-7.99 (3H, m), 7.59 (1H, dd, J1=7.5 Hz, J2=1.5 Hz), 7.53-7.46 (1H, m), 7.15-6.99 (4H, m), 3.95 (3H, s), 3.84 (2H, s), 3.82 (3H, s), 3.28 (2H, s), 3.15 (6H, s), 2.59 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[OH:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH2:21][CH2:22]2)[CH:34]=[CH:35][C:36]=1[OH:37]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCOCC2)CC1)C1CC1
Product: O=C(c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N1CCC(CN2CCOCC2)CC1)C1CC1
Yield: 61.7 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(morpholinomethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.065 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (34 mg, 0.200 mmol) to afford the desired product (20.3 mg, 62%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 1H), 8.29 (s, 1H), 8.04-7.98 (m, 2H), 7.71 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.4, 2.3 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 3.74-3.71 (m, 3H), 3.53 (d, J=12.7 Hz, 2H), 3.34 (s, 3H), 3.26-3.15 (m, 2H), 2.59-2.46 (m, 4H), 2.38 (d, J=6.7 Hz, 2H), 1.98 (d, J=12.9 Hz, 3H), 1.66-1.52 (m, 2H), 1.36-1.27 (m, 2H), 1.27-1.20 (m, 2H); ESI MS m/z 506 [C29H32ClN3O3+H]+; HPLC 98.0% (AUC), tR=10.44 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:14]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:14][C:3]1[C:4]2=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cnc2cc[nH]c2c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a 0° C. solution of methyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate (1.00 g, 5.68 mmol) in N,N-dimethylformamide (15 mL) was added N-chlorosuccinimide (895 mg, 5.96 mmol). The reaction was allowed to gradually warm to room temperature and stir overnight. The reaction was diluted with water (125 mL) and stirred for 20 minutes. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (1.11 g, 93%) as an orange powder. +ESI (M+H) 211.0; 1H NMR (400 MHz, DMSO-d6, δ): 11.99 (br. s., 1H), 8.92 (d, J=2.0 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.08 (d, J=3.1 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[CH:12][C:13]([CH2:17][CH2:18][CH:19]([OH:27])[CH2:20][CH2:21][NH:22][C:23]([O:25][CH3:26])=[O:24])=[C:14]([OH:16])[CH:15]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Pd]>[CH3:26][O:25][C:23]([N:22]1[CH2:21][CH2:20][C@H:19]([OH:27])[CH2:18][C@@H:17]1[C:13]1[CH:12]=[CH:11][C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][C:14]=1[O:16][CH2:2][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:24].[CH3:26][O:25][C:23]([N:22]1[CH2:21][CH2:20][C@H:19]([OH:27])[CH2:18][C@@H:17]1[C:13]1[CH:12]=[CH:11][C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][C:14]=1[OH:16])=[O:24]
Reactant: CCCCCCC(C)(C)c1ccc(CCC(O)CCNC(=O)OC)c(O)c1
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OC)c(O)c1
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OC)c(OCc2ccccc2)c1
Yield: 57 %

Procedure:
Debenzylation of 177 mg (0.377 mmole) of N-methoxycarbonyl cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol with 144 mg of 5% palladium on carbon (50% wet) by the procedure of Example 4 affords 81.3 mg (57%) of the title compound as an oil, 4.1 mg (3%) of by-product 5-(1,1-dimethylheptyl)-2-[3-hydroxy-5-(N-methoxycarbonylamino)pentyl]phenol as an oil, and 49.2 mg (35%) of a mixture of the two.
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](OCC)=[O:4].[NH3:15]>CCO>[F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([NH2:15])=[O:4]
Reactant: N
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Solvent: CCO
Product: NC(=O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91 %

Procedure:
A solution of the title compound of Step (A) (6.00 g; 30 mmol) in 50 ml of EtOH was saturated with anhydrous NH3. An exothermic reaction was observed. After stirring the reaction mixture 60 hr at room temperature, the volatiles were removed in vacuo and the solid residue was taken up in a minimal amount of hot ethyl acetate. A small amount of insoluble material was filtered off and hexane was added to the filtrate until slightly turbid. After cooling to room temperature and standing several hr, the crystals were filtered and dried to afford 4.68 g (91%) of the title compound of this step as a colorless crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3CN2CCOCC2)[N:7]([C:28]#[N:29])[CH2:6]1)=[O:4].C(N(CC)CC)C.Cl[O:38][C:39](C)(C)C.C(=O)(O)[O-]>O1CCCC1.C(OCC)(=O)C>[C:28]([N:7]1[C@H:8]2[C@@H:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[C:11]([CH:39]=[O:38])[NH:12]4)[CH2:19][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)#[N:29]
Reactant: CC(C)(C)OCl
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]2N(C#N)C1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C#N)C1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
7.89 g of 6-cyano-2-morpholinomethyl-8beta-ergoline-carboxylic acid methyl ester (20 mmol) is dissolved in 400 ml of anhydrous tetrahydrofuran, the solution is cooled to -40° C., mixed with 4 ml of triethylamine and then the solution of 3.0 ml of tert-butyl hypochloride (25 mmol) in 60 ml of anhydrous tetrahydrofuran is instilled. After 10 minutes of stirring, another 1 ml of tert-butylhypochlorite is added, stirred for 5 minutes and the solution is poured on ice. The mixture is made alkaline with bicarbonate solution and shaken with ethyl acetate. The organic phases are dried, the solvent is evaporated and the residue is crystallized from the diisopropylether, the yield is quantitative [α]D =+42.7° (0.5% in chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH2:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:24][C:25]1[CH:30]=[C:29](Cl)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>C(O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:29]3[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3cc(Cl)ncc3[N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (5.2 g, 21.0 mmol) in ethanol (60 mL) and THF (15 mL) was added NaHCO3 (5.3 g, 63.0 mmol) followed by the product of Example 1, Step 3 (4.05 g, 21.0 mmol), and the reaction mixture was stirred overnight rt. The reaction mixture was concentrated then taken up in EtOAc and H2O extracted with EtOAc, the organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude material was crystallized from EtOAc/hexane to give the title compound as a yellow solid. MS (ES+) m/e 406 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)=[C:13]([CH:17]=2)[C:14]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=2)=[O:15])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(-c2cnc(-c3cnn(C)c3)c(C(=O)O)c2)c1
Reactant: COc1ccc(CN)cc1OC
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(Cl)c3)cnc2-c2cnn(C)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3-chloro-5-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinic acid (2-2, 0.050 g, 0.153 mmol) and 3,4-dimethoxybenzylamine (0.099 g, 0.595 mmol) in dimethylformamide (1 mL) was added EDC (0.132 g, 0.686 mmol), HOBt (0.105 g, 0.686 mmol) followed by N-methylmorpholine (0.250 mL, 2.28 mmol) and the system was stirred at 25° C. overnight. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated sodium carbonate and dried over magnesium sulfate. The reaction mixture was filtered and purified via normal phase chromatography (0→5% MeOH in DCM) to afford the title compound (2-3) as a bone-colored powder. 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J=2.5 Hz, 1H), 7.99 (s, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 7.28 (m, 2H), 7.23 (s, 1H), 6.84 (s, 2H), 6.06 (m, 1H), 4.55 (d, J=6 Hz, 2H), 3.88(s, 3H), 3.87(s, 3H), 3.86(s, 3H), 2.42 (s, 3H). HRMS [M+H] C26H25ClN4O3 calc'd 477.1688, found 477.1682.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].CO>CN(C)C=O.O>[O:1]([C:8]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: OCc1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (173 mg) in N,N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (97 mg) and the mixture was stirred at room temperature for 1 hr. Sodium borohydride (38 mg) was added to the reaction mixture at room temperature, and methanol (1 mL) was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80) and crystallized from methanol-ethyl acetate, to give the title compound (44 mg) as a colorless powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH:38]=O)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.[CH:40]1([O:45][C:46](=[O:53])[C:47]2([CH2:52][CH2:51][CH2:50][CH2:49]2)[NH2:48])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH2:38][NH:48][C:47]3([C:46]([O:45][CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)=[O:53])[CH2:49][CH2:50][CH2:51][CH2:52]3)[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CC=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NC1(C(=O)OC2CCCC2)CCCC1
Product: CC(C)c1cc(C(=O)N2Cc3ccc(CCNC4(C(=O)OC5CCCC5)CCCC4)cc3C2)c(O)cc1O

Procedure:
Prepared from Intermediate F and cycloleucine cyclopentyl ester. 1H NMR (300 MHz, d3-MeOD) 6.99-7.20 (4H, m), 6.26 (1H, s) 5.01 (1H, t, J=5.7 Hz), 3.38-3.67 (3H, m), 3.09 (1H, sep, J=6.8 Hz), 2.57-2.75 (4H, m), 1.37-2.15 (16H, m), 1.10 (6H, d, J=6.9 Hz) LC/MS: purity >98%, m/z 521.25 [M+H]+
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH3:13])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][Br:15])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OC(=O)c1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid isopropyl ester (Intermediate 117, 6.12 g, 23.8 mmol) in carbon tetrachloride (120 mL) was treated with N-bromosuccinimide (4.6 g, 26.18 mmol) and 2,2′-azobisisobutyronitrile (0.6 g) and the resulting reaction mixture was refluxed overnight. It was cooled to ambient temperature, the solids were filtered off and washed with 1:1 hexane:diethyl ether, and the filtrate and washings were evaporated in vacuo to afford an oil (5.1 g, 64%) that was used as such for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Mg+2].[Cl-].[Cl-].C[CH2:13][O:14]C(C)=O>C1COCC1>[Br:1][C:2]1[C:3]([OH:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:13]=[O:14]
Reactant: CCOC(C)=O
Reactant: Oc1ccccc1Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)c1O
Reaction time: 8 h

Procedure:
A solution of 2-bromophenol (48.5 g, 0.28 mol) in 500 mL of THF was added TEA (200 mL) and then MgCl2 (100 g, 1.05 mol) was added portionwise over 90 minutes. The reaction mixture was allowed to stir overnight under a nitrogen atmosphere. The reaction mixture was neutralized with phosphoric, and then exacted with EtOAc (1000 mL). The organic layers were washed with brine (200 mL), dried over Na2SO4. The solvent was concentrated in vacuo. The residue was purified with silica gel chromatography (petrol ether/EtOAc=5:1) to give product 3-bromo-2-hydroxybenzaldehyde.