Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](CO)([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:13][C:14](=[O:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OCC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Reaction time: 3.5 h
Yield: 81.2 %

Procedure:
A solution of EXAMPLE 283E (3.60 g, 9.5 mmol) in THF (100 mL) and water (25 mL) was cooled to 0° C. in an ice bath and treated with sodium periodate (2.42 g, 11.3 mmol). The ice bath was removed, and the mixture stirred for 3.5 h. The mixture was diluted with EtOAc (200 mL), washed with brine (3×), then dried (MgSO4). Solvent removal and drying under vacuum provided the product as a tan solid (2.68 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][C:13]([OH:16])=[CH:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][C:13](=[O:16])[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1=CN(Cc2ccc3c(c2)OCO3)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C1CCN(Cc2ccc3c(c2)OCO3)C1
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of alcohol 273 (0.78 g, 3.53 mmol) in dry DCM (40 mL) was treated with 4 Å molecular sieves (powder, 3.49 g) and 4-methylmorpholine N-oxide (NMO) (2.11 g, 18.03 mmol) and the suspension was stirred under nitrogen atmosphere for 18 h. The reaction mixture was cooled to 0° C. for the addition of solid tetrapropylammonium perruthenate (TPAP) (0.11 g, 0.31 mmol) and stirred for 30 min, then diluted with DCM, filtered through a Celite® pad, washed with saturated NaHCO3, dried over MgSO4, filtered through a pad of SiO2 (eluent: 5% MeOH in DCM) and concentrated to provide title compound 274 (0.65 g, 84% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[C:9]([C:10]#[N:11])=[CH:8][NH:7][N:6]=1.Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].O>CN(C=O)C>[C:10]([C:9]1[C:5]([C:4]([F:3])([F:12])[F:13])=[N:6][N:7]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[CH:8]=1)#[N:11]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: N#Cc1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
NaH (60% [w/w] suspension in oil, 130 mg, 3.25 mmol) was added to a solution of 3-(trifluoromethyl)-4-cyanopyrazole (520 mg, 3.23 mmol) in DMF (10 mL). The reaction mixture was stirred at RT for 1 h before adding 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.023 g, 3.23 mmol). The reaction mixture was heated at 65° C. for 4 h then allowed to cool to RT. Water (20 mL) was added and the reaction mixture extracted with EtOAc (3×20 mL). The combined EtOAc layers were washed with water (5×20 mL), brine (20 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the crude reaction mixture as a cream solid. Purification by flash chromatography (eluent 1:1 EtOAc:heptane) gave desired product (626 mg, 1.58 mmol, 49%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C:15]1([CH:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]1([CH:21]([N:23]2[CH2:24][CH2:25][N:26]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:27][CH2:28]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (400 mg, 1.80 mmol), 1-(1-phenylethyl)piperazine (342 mg, 1.80 mmol) and DIPEA (0.34 mL, 1.98 mmol) in DMF (4 mL) were stirred and heated at 80° C. for 30 minutes. The mixture was cooled to ambient temperature then applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Fractions containing pure product were evaporated to give a solid which was recrystallised from MTBE/isohexane to give 6-[4-(1-phenylethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (516 mg, 76%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20](O)[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([N:29]4[C:25](=[O:35])[C:26]5[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:28]4=[O:30])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)O)s3)s2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)s3)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 277.8 %

Procedure:
A solution of Example 24E (0.37 g, 1.025 mmol), phthalimide (0.151 g, 1.025 mmol), and triphenyl phosphine (0.537 g, 2.05 mmol) in tetrahydrofuran (5 mL) was treated with diisopropyl azodicarboxylate (0.385 mL, 1.85 mmol) and the resulting solution was stirred at 25° C. for 3 hours. The reaction was concentrated under reduced pressure on a rotary evaporator to provide 1.4 g of a yellow oil. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 20% ethyl acetate in hexanes to provide 0.49 g (98%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.76-7.98 (m, 4H) 7.51 (d, J=3.68 Hz, 1H) 7.38 (d, J=9.19 Hz, 2H) 7.14 (dd, J=3.68, 0.92 Hz, 1H) 7.01 (d, J=9.19 Hz, 2H) 5.60-5.77 (m, 1H) 4.55-4.70 (m, 1H) 1.88 (d, J=7.35 Hz, 3H) 1.27 (d, J=5.88 Hz, 6H); MS (ESI) m/z 492 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([C:27]#[CH:28])[C:14]=2[CH3:29])=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[C:19]([C:17]1[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([C:27]#[CH:28])[C:14]([CH3:29])=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=2)[CH:18]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: C#Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1c(C)c(C#Cc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
A solution of [4-(5-tert-butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 145, 0.023 g, 0.057 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 1M lithium hydroxide (0.5 mL, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.020 g, 91%).
Reaction SMILES: [Cl:1][CH:2]([CH2:5][C:6]([Cl:10])(Cl)[CH:7]=O)[C:3]#[N:4].[ClH:11]>>[Cl:11][C:7]1[C:6]([Cl:10])=[CH:5][C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: N#CC(Cl)CC(Cl)(Cl)C=O
Reactant: Cl
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
The 2,4,4-trichloro-4-formyl-butyronitrile (17.3 g) obtained according to (a) is heated, as a weak stream of hydrogen chloride is being introduced, at 80°-85° C. for 24 hours. The entire reaction mixture is subsequently distilled with steam. The yield is 10.0 g (72% of theory) of 2,3,5-trichloropyridine in the form of white crystals, m.p. 49°-50° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (170 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (323 mg).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[C:46](=O)[CH3:47].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:46]([C:39]2[C:40]([O:44][CH3:45])=[CH:41][CH:42]=[CH:43][C:38]=2[OH:37])[CH:47]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: COc1cccc(O)c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(O)c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 69 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2-hydroxy-6-methoxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 69% yield).
Reaction SMILES: [F:1][C:2]([F:14])([CH:11]([F:13])[F:12])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([CH:11]([F:12])[F:13])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(O)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 4,4,5,5-tetrafluoro-3-oxo-pentanoate (25.7 g, 0.119 mol) was dissolved in toluene (260 ml) and cooled to 0° C. Sodium borohydride (5.4 g, 0.143 mol) was added portionwise, and the mixture was allowed to reach room temperature overnight with stirring. The mixture was then cooled to 0° C. and acidified with 1M HCl. The phases were separated, the aqueous phase was extracted two times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was reduced under reduced pressure. The residue was dissolved in a minimum amount of methanol and evaporated to dryness under reduced pressure to yield 22.9 g (0.105 mol, 88%) that were used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.Cl.[N:9]([O-])=[O:10].[Na+]>O>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N:9]=[O:10]
Reactant: O=N[O-]
Reactant: Cn1nccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1ncc(N=O)c1N
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of 5-amino-1-methylpyrazole (100 g) in water (700 ml) were added concentrated hydrochloric acid (86 ml) and sodium nitrite (63.9 g) in water (200 ml) at a temperature below 10° C. The reaction mixture was stirred at 5° C. for 30 minutes. The precipitated solid was collected by filtration and dried to give 5-amino-1-methyl-4-nitrosopyrazole (117 g).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Br>CC(O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[C:13]([NH:12][C:5]2[C:6]3[N:7]([N:8]=[CH:9][N:10]=3)[C:2]([Br:1])=[CH:3][N:4]=2)[CH:14]=1)[CH3:20]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: Br
Solvent: CC(C)O
Product: CCOC(=O)c1cccc(Nc2ncc(Br)n3ncnc23)c1
Temperature: 85 °C
Yield: 98 %

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (1.39 g, 5.00 mmol) and ethyl 3-aminobenzoate (0.93 g, 5.60 mmol) are stirred in iPrOH (10 mL) and HBr (48% aq., 1.14 mL, 10 mmol) is added. The mixture is heated at 85° C. for 4 h and then cooled to rt and quenched with NaHCO3 (sat. aq., 25 mL). The resulting suspension is cooled to 0° C. and the white solid is collected by suction filtration and washed with water (10 mL). The crude product is taken up in EtOH and the solvent evaporated to afford the title compound as an off-white solid (1.79 g, 4.9 mmol) which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[Cl:19]>>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[C:13]([Cl:19])[CH:14]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc(Cl)c1C=O
Reactant: Nc1ccc(O)cc1Cl
Product: Nc1ccc(Oc2ncnc(N)c2C=O)cc1Cl

Procedure:
Using the procedure for Example 1, 4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1a was reacted with 4-amino-3-chloro-phenol Compound 10a to provide 4-amino-6-(4-amino-3-chloro-phenoxy)-pyrimidine-5-carbaldehyde Compound 26a.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26](Cl)=[O:27])=[CH:20][CH:19]=1>O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:26](=[O:27])[O:25][CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: OCCNCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N(CCO)CCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A suspension of 2,2′-azanediyldiethanol (7.3 ml, 76.09 mmol), sodium carbonate (18.33 g, 172.94 mmol), acetone (125 ml), and water (125 ml) at 0° C. was treated dropwise over a 15 minute period with Cbz-Cl (10.25 ml, 69.17 mmol). The suspension was stirred an additional 3 hours at 0° C. The suspension was diluted with water (500 ml) and extracted with CHCl3 (2×250 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with MeOH/DCM, 0→10% over 40 minutes) to give the title compound (12.5 g, yield: 76%).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]1(C)C=CC(S(OC)(=O)=O)=CC=1.[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:1][C@@H:2]([C@@H:9]([N:14]1[C:15](=[O:24])[C:16]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]2[C:18]1=[O:19])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C[C@@H]([C@H](O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CO[C@H](c1ccccc1)[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of N-[1-(S)-[α-(R)-hydroxybenzyl]-3-methylbutyl]phthalimide (30.4 g, 94.0 mmol.) in toluene (380 mL) were successively added methyl p-toluenesulfonate (19.2 g, 103 mmol.) and 60% sodium hydride (4.13 g, 103 mmol.). The resulting mixture was heated under reflux for 18 hours under stirring, cooled to room temperature, successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by middle pressure column chromatography (n-hexane/ethyl acetate=5/1), to give N-[1-(S)-[α-(R)-methoxybenzyl]-3-methylbutyl]phthalimide as a white crystalline product (25.6 g, yield: 81%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(O)(=O)C>CO.[Rh]>[CH:2]1([C:1]([OH:12])=[O:11])[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a suspension of isophthalic acid (500 g, 3 mol) in methanol (2.8) was added 5% Rhodium-on-alumina catalyst (50 g) and acetic acid (150 ml). The reaction mixture was shaken under hydrogen (50 psi) at room temperature overnight. The mixture was filtered through celite. To this solution was added fresh 5% Rhodium-on-alumina catalyst (25 g), and the mixture was shaken under 50 psi of hydrogen for another 24 hours. The final reaction mixture was filtered through celite. The solution was concentrated under vacuum to give 493 g of the title compound as a white powder (96.3% yield). m.p. 163-165° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>CC1CCCO1>[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]5([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]5[C:4]=4[N:3]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (707 mg, 2.125 mmol) and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (770 mg, 2.55 mmol) where combined in methyltetrahydrofuran (10 mL) and aqueous sodium carbonate (2 M) (2.2 mL). The reaction mixture was heated in a 50° C. oil bath and then 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (38 mg) was added. The reaction mixture was then placed in an 80° C. oil bath. After about 1 hour the oil bath was reduced to 74° C. After about 4 hours some solvent had evaporated, 6 mL de-gassed methyltetrahydrofuran was added and decreased the oil bath temperature to 70° C. After about 6 hours, solvent had again evaporated, 6 mL de-gassed methyltetrahydrofuran was added. After another hour, 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (9 mg) was added and heating continued at 70° C. for 3 hours, then cooled to room temperature and allowed to stir overnight. The reaction mixture was then diluted with 4 mL 1:1 methyltetrahydrofuran/water, stir for 15 minutes, the solids were collected by filtration, the filter cake washed with 2×3 mL portions of 1:5 water/methyltetrahydrofuran, air-dried for 1 hour, then under vacuum for 1 hour to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C([O-])(O)=O.[Na+].[I:15]I>O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([NH2:6])=[C:7]([I:15])[CH:8]=1
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cc(F)c(Cl)cc1I
Temperature: 0 °C
Reaction time: 18 h
Yield: 101846.3 %

Procedure:
To 4-chloro-3-fluoroaniline (25 g, 0.17 mmol) in 250 mL of H2O was added NaHCO3 (21.6 g, 0.25 mmol). After cooling to 0° C., iodine (43.5 g, 0.17 mmol) was added. After 18 h at rt, an additional 10.8 g of iodine was added and the reaction was stirred overnight. The reaction was extracted with DCM (4×250 mL), the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) and dried (Na2SO4). Purification by silica gel chromatography gave 47 g of Intermediate 5A. MS (ESI) m/z: 145.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([NH2:19])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[CH3:24][N:25]([CH3:27])[CH:26]=[N:19][C:4]1[C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][N:5]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 77.7 %

Procedure:
A mixture of the above 3-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (4.59 g, 15 mmol) and dimethylformamide dimethyl acetal (2.25 mL, 16 mmol) in toluene was refluxed for 1 h. The reaction mixture was evaporated and dried at HV to give the title compound as a light yellow solid (4.21 g, 78%). MS (ISP) 362 [(M+H)+]; mp 114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][C:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([CH3:37])[CH:31]=2)[C:9]2[C:10]([C:24]([O:26]CC)=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:29][C:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([CH3:37])[CH:31]=2)[C:9]2[C:10]([C:24]([OH:26])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:13]=2[CH3:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(Nc1ccc(=O)n(C)c1)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2nc(C(=O)O)c(C(Nc3ccc(=O)n(C)c3)c3ccc(Cl)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
In a 25-mL flask was introduced ethyl 4-((4-chlorophenyl)(1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.4) (140 mg, 0.269 mmol) and LiOH.H2O (33.8 mg, 0.806 mmol) in dioxane (2.5 mL) and H2O (1.0 mL). The reaction mixture was stirred for 3 hr at rt, quenched with 0.5N HCl (50 mL), and extracted with EtOAc. The combined organic layers were washed with 0.5N HCl, dried over Na2SO4, and evaporated to dryness to afford the title product (128 mg, 0.260 mmol, 97% yield) as a green solid. tR: 3.94 min (HPLC 1); tR: 0.90 min (LC-MS 2); ESI-MS: 493 [M+H]+ (LC-MS 2).