Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:21]=2)=[O:19])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:21]=2)=[O:19])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
A mixture of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]1-indolyl]butyrate obtained in Ex. 15 (44 mg) and 1N solution of sodium hydroxide (0.5 ml) in ethanol (1 ml) and 1,4-dioxane (2 ml) was stirred at room temperature for 3 hours. The mixture was then acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvent afforded 4-[3-[8-(4-isobutylphenyl)-undecanoyl]1-indolyl]butyric acid as an oil (41 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc2ccc(Cl)nc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2ccc(Cl)nc12)c1ccccc1
Yield: 88.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 2-chloroquinolin-8-amine (Intermediate 26) (70 mg, 0.39 mmol), benzenesulfonyl chloride (83 mg, 0.42 mmol) and DMAP (cat.) gave the title compound (110 mg, 88%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:8]=1.[H][H]>N1C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][N:10]=[C:9]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:8]=1
Reactant: [H][H]
Reactant: COc1ccc(CNc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2[N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: c1ccncc1
Product: COc1ccc(CNc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2N)c(OC)c1

Procedure:
19.64 g (38.10 mmol) of the compound from example 80A were dissolved in 300 ml of pyridine, 2.00 g of palladium on charcoal (10%) were added and the mixture was hydrogenated at RT and standard hydrogen pressure for 2 h. The mixture was filtered through Celite and washed through with a little pyridine, and the filtrate was concentrated by rotary evaporation on a rotary evaporator. 19.02 g (78% of theory) of the title compound were obtained.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:18](=[S:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:16](=[O:32])[C:12]32[CH2:15][CH2:14][CH2:13]3)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:17]2[C:16](=[O:32])[C:12]3([CH2:13][CH2:14][CH2:15]3)[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:10][CH:9]=3)[C:18]2=[S:19])=[CH:21][C:22]=1[C:28]([F:30])([F:31])[F:29])#[N:27]
Reactant: COC(=O)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CC(=O)O)cc3)C2=S)cc1C(F)(F)F
Yield: 95 %

Procedure:
A mixture of (4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetic acid methyl ester (46b) (0.095 g, 0.2 mmol) and a solution of sodium hydroxide (1 ml, 2M) in methanol (2 ml) was stirred at room temperature for 2 hours. The methanol was evaporated. The residue was adjusted to pH 5 by aq. 2M HCl and then the mixture was extracted with ethyl acetate (3×10 ml). The organic layer was dried over MgSO4 and concentrated to dryness to obtain (4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl)acetic acid (46c) [RD147](0.087 g, 0.19 mmol, 95%), the structure of which is illustrated in Formula 16.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: CN(C)CCCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Product: CN(C)CCCN1CC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=556.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and 3-dimethylamino-1-propyl chloride.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH:34]=[CH:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)[CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc(N3CCNCC3)c2)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4cccc(N5CCNCC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine. LCMS calculated for C26H30N5O2(M+H)+: m/z=444.2. Found 444.2.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:32][C:31]([F:34])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-formylbenzeneboronic acid (4.00 g, 26.7 mmol) and Na2CO3 (5.66 g, 53.4 mmol) in water (240 mL) was added p-dioxane (240 mL). This mixture was treated sequentially with 2-iodobenzotrifluoride (3.74 mL, 26.7 mmol) and palladium (II) acetate (540 mg, 2.40 mmol) and allowed to stir at ambient temperature for 24 hours. The solvent was evaporated in vacuo. To the residue was added EtOAc (400 inL) and water (300 mL). The aqueous layer was acidified to pH 2 with 1.0 N aq. HCl and the layers separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic extracts were combined, washed with brine (200 mL), 5% aq. Na2S2O3 (200 mL), saturated NaCl (200 mL), dried (Na2SO4), and the solvent evaporated in vacuo and the residue chromatographed (Silica gel, 20-50% CH2Cl2 in hexanes) to afford the title compound.
Reaction SMILES: C(O[C:4]1[C:5](=[O:18])[C:6](=[O:17])[C:7]=1[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])C.[NH2:19][C@@H:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:21]>C(O)C.ClCCl>[OH:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:7]1[C:6](=[O:17])[C:5](=[O:18])[C:4]=1[NH:19][C@H:20]([CH3:21])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[C@@H](N)C(C)(C)C
Reactant: CCOc1c(Nc2c(C)cccc2O)c(=O)c1=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cccc(O)c1Nc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O

Procedure:
3-Ethoxy-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-1,2-dione (0.4 g, 1.62 mmol) and (R)-2-amino-3,3-dimethylbutane (16 mL of a 0.2M solution in absolute ethanol, 3.20 mmol) in dichloromethane (4 mL) was heated at 80° C. for 4 hours. The reaction mixture was cooled, concentrated under reduced pressure, and the resulting residue was trituated with hexane:ethyl acetate (1:1) to produce a solid, which was filtered and rinsed with hexane:ethyl acetate (1:1). Chromatography with 10% methanol in dichloromethane gave (R)-3-(2-hydroxy-6-methylphenylamino)-4-(2,2,1-trimethylpropyl-amino)-cyclobut-3-ene-1,2-dione, 0.24 g (0.79 mmol, 49%).
Reaction SMILES: [Cl-].C([NH+](CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[NH:22][N:11]=[N:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(Cc2nnn[nH]2)cc1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A mixture of triethylammonium chloride (4.14 g, 30 mmol) and sodium azide (1.95 g, 30 mmol) was treated with a solution of (4-fluorophenyl)acetonitrile (1.35 g, 10 mmol) in toluene (14 ml) and the mixture was stirred and heated at 100° C. for 5 h. The cooled mixture was treated with water (10 ml) and the mixture separated. The aqueous phase was stirred and treated dropwise with concentrated hydrochloric acid until the product had precipitated from solution. The precipitated product was filtered off, washed with water and dried to yield the title compound as a white solid (1.27 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=2)=[O:9])[CH:7]=1.[BH4-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=2)[OH:9])[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
(5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanone 4c (12.7 g, 35.5 mmol) was dissolved in 100 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of sodium borohydride (2.68 g, 70 mmol) in batch in an ice bath. The reaction mixture was warmed and stirred for 30 minutes at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure after 15 mL acetone were added. The residue was dissolved in 150 mL ethyl acetate and washed with saturated sodium chloride solution (50 mL×2). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanol 4d (12.7 g, orange grease), which was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:40])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:39])[C:17]([O:33][C@H:34]3[CH2:38][CH2:37][O:36][CH2:35]3)=[C:18]([CH:32]=2)[CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:12])=[C:4]([CH3:41])[CH:3]=1.CC1(C)C[O:47][B:46](B2OCC(C)(C)CO2)[O:45]C1.CC([O-])=O.[K+]>CS(C)=O.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.Cl[Pd]Cl.[Fe+2]>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:32]=[C:14]([NH:13][C:11]([O:10][CH2:9][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([B:46]([OH:47])[OH:45])=[CH:3][C:4]=2[CH3:41])[CH3:40])=[O:12])[CH:15]=[C:16]([F:39])[C:17]=1[O:33][C@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1)[CH3:31])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(Br)ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@H]2CCOC2)c(CN(C)C(=O)OCc2ccccc2)c1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Cc1cc(B(O)O)ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@H]2CCOC2)c(CN(C)C(=O)OCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a reaction tube was added 39C (770 mg, 1.223 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (332 mg, 1.468 mmol), KOAc (300 mg, 3.06 mmol), and Pd(dppf)Cl2 (201 mg, 0.245 mmol) in DMSO (10 ml). The tube was filled with Ar, sealed and stirred at 85° C. for 2 h. The mixture was quenched with H2O, and extracted with EtOAc (3×). The combined organic layers was filtered though silica gel and concentrated. The residue was purified by prep HPLC to give 39D (405 mg, 0.681 mmol, 55.7% yield) as a tan solid. MS (ESI) m/z: 595.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CN1CCN(c2cc(Sc3ccc(Br)cc3)nc(-c3ccccc3)n2)CC1
Temperature: 160 °C

Procedure:
A well blended mixture of 2.0 g. 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine and 5.0 g. of p-bromothiophenol is heated in an oil bath maintaining the temperature at 160°C. for three hours. After being cooled to room temperature, the reaction mixture is triturated with 60 ml. of 30°/o sodium hydroxide. The product is collected on a sintered glass funnel and washed with water repeatedly. Upon recrystallization from absolute ethanol, there is obtained 4-(4-bromophenylthio)-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8](=O)[CH2:7]1)=[O:4].[CH3:44][NH:45][CH3:46].CCOC(C)=O.C([O-])(O)=O.[Na+]>CO.[Cl-].[Na+].O>[CH3:44][N:45]([CH3:46])[CH:8]1[CH2:9][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:43])[F:42])([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:37]=[CH:38][CH:39]=[CH:40][N:41]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:7]1
Reactant: O=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2,2-trifluoro-N-(3-oxo-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (20 mg, 0.035 mmol) and dimethylamine (2M in THF, 0.052 mL, 0.104 mmol) in MeOH (0.3 mL) was added Zn(BH3CN)2 (0.3M in MeOH, 0.6 mL, 0.18 mmol), and the mixture was stirred at room temperature for overnight. To the mixture was added EtOAc, sat. NaHCO3, and brine. The resulting solid was collected by filtration to give N-(3-(dimethylamino)-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-2,2,2-trifluoroacetamide (4-4) as colorless solid. HRMS (M+H)+: observed=609.2338, calculated=609.2342.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11])=O.Cl.C(OCC)C.[Na+].[Cl-]>O.[Zn]>[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCc1ccc(O)cc1F
Temperature: 25 °C
Yield: 51.7 %

Procedure:
2-Fluoro-4-hydroxyacetophenone (15.14 g, 100 mmol) and zinc dust (19.61 g, 300 mmol) were suspended in 50 mL of H2O with stirring. Concentrated HCl (37%, 50 mL, 610 mmol) were added and the mixture was heated to reflux for six h. The reaction was cooled to rt, and diethyl ether was added. The mixture was saturated with NaCl, and filtered through celite washing with diethyl ether. The filtrate was poured into brine, and the layers were separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 7.24 g (52%) of the title compound of step A. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.00 (t, J=8.8 Hz, 1H), 6.52-6.40 (m, 2H), 2.44 (q, J=7.5 Hz, 2H), 1.06 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([C:8]1[CH:7]=[C:4]([CH:5]=[O:6])[C:3]([OH:14])=[C:2]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=2)[CH:9]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Yield: 85.6 %

Procedure:
A solution of 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) (4 g, 15.56 mmol) in DME (30 mL) and water (10 mL) was purged with nitrogen for 15 minutes. Potassium carbonate (3.2 g, 23.15 mmol), 4-trifluoromethoxybenzeneboronic acid (3.2 g, 15.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.78 g, 0.675 mmol) were added and the reaction mixture heated to reflux under nitrogen overnight. The cooled reaction mixture was then filtered through celite washing through with diethyl ether. The filtrate was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give 5-(tert-butyl)-2-hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-carbaldehyde (4.5 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](N(OC)C)=[O:13])[CH:6]=[CH:5]2.[CH3:18][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](=[O:13])[CH3:18])[CH:6]=[CH:5]2
Reactant: CON(C)C(=O)c1ccc2cc(Br)ccc2n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 6-bromo-N-methoxy-N-methylquinoline-2-carboxamide (4.29 g, 14.5 mmol) in THF (100 ml) was added methyl magnesiumbromide (18.2 ml, 17.4 mmol, 0.96M in THF solution) at 0° C. dropwise and the mixture was stirred at 0° C. for 1 hour. Then, the mixture was quenched with saturated ammonium chloride aqueous solution (50 ml) and water (200 ml). After stirring for 30 min, the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation and purification through silica gel column chromatography, eluting with hexane/ethyl acetate (4:1), furnished the title compound (3.47 g, 96% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.66 (3H, s), 7.83-7.88 (1H, m), 8.02-8.20 (4H, m). MS (ESI): m/z 250, 252 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:28]C(C)([O-])C.[K+].IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH3:28])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(F)cc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To an ice-cold suspension of 0.07 g (0.17 mmol) 4-(2,5-dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-nicotinamide in 1 mL tetrahydrofuran were added 0.019 g (0.17 mmol) potassium tert-butoxide followed by 10 μl (0.18 mmol) iodomethane. The suspension was stirred at room temperature for 16 hours, poured onto 10% aqueous citric acid solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give 32 mg (44%) of the title compound as a white solid. MS (ESI): m/z=421.052 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[C:31](O)=[O:32])[CH:24]=[CH:23]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=1)[C:31]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[NH:22][CH:23]=[CH:24]2)=[O:32])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)CCNCc1ccc(C(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
4.37 g (15 mmol) of 3-(4-tert-butyl-benzylamino)-propionic acid tert-butyl ester, 2.42 g (15 mmol) of 1H-indole-7-carboxylic acid and 3.25 g (16.5 mmol) of EDC.HCl were dissolved in 50 ml DCM. The reaction mixture was stirred at rt over night, washed twice with 1N aqueous HCl solution, once with 2N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 6.25 g (97%) product as a white solid. MS (ISP) 435.4 (M+H)+.