Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:7]=1[CH2:8][N:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:10]1=[O:23].CO>C(Cl)Cl>[Cl:28][C:26]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]2=[O:23])=[C:6]([F:5])[CH:27]=1
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Temperature: -40 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
According to Scheme 14 Step 1: BBr3 (4 eq, 65.6 mmol, 6.56 mL) was added to a solution of 1-(2-fluoro-4-chlorobenzyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (16.4 mmol, 5.64 g) in CH2Cl2 at −50° C. The reaction mixture was stirred 1.5 hour at −40° C., overnight at room temperature then BBr3 (20 mL) was added at −30° C. and the reaction mixture was stirred 4 hours at room temperature. The reaction mixture was cooled down to −40° C. then MeOH (50 mL) was added dropwise and the crude mixture was stirred at room temperature. After evaporation, the crude mixture was purified by silica gel chromatography (300 g SiO2) using CH2Cl2/MeOH 95/5 to afford 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (14.9 mmol, 4.80 g, 83%) as an orange solid.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][N:11]([CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[CH3:12])C1C=CC=CC=1>CO.[C].[Pd]>[C:20]([O:19][C:17]([N:15]([CH3:16])[CH2:14][CH2:13][N:11]([CH2:10][C:9]([OH:24])=[O:8])[CH3:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(CCN(C)C(=O)OC(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
534.3 mg (1.59 mmol) of {[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-methyl-amino}-acetic acid benzyl ester prepared in Process 1-A was dissolved in methanol (20 mL), and then 51 mg of 5% palladium-carbon was added, and this was stirred for 1 hour under hydrogen atmosphere at room temperature. Insoluble substances were removed by filtration, and the filtrate was concentrated to give 391.1 mg (100%) of {[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-methyl-amino}-acetic acid as a colorless viscous oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([OH:10])(=[S:9])[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20]Cl)[CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:13]=1)[CH2:20][S:9][C:7](=[O:10])[CH3:8]
Reactant: COc1ccc(Cl)cc1CCl
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1CSC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of cesium carbonate (0.55 g, 1.70 mmol) in dimethylformamide (13 mL) was added thioacetic acid (0.24 g, 3.14 mmol) followed by addition of 4-chloro-2-chloromethyl-1-methoxybenzene (0.50 g, 2.62 mmol) in one portion. The reaction was stirred in the dark at ambient temperature overnight. The reaction was diluted with ethyl acetate, washed with water, 5% aqueous sodium hydrogen carbonate, and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.58 g).
Reaction SMILES: [CH2:1]([C:3]1([CH3:11])[N:7]([CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][O:4]1)C.N(CCO)CCO.C(C(C)=O)C>CC(C)=O>[OH:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][O:4][C:3]1([CH3:11])[CH3:1]
Reactant: CCC1(C)OCCN1CCO
Solvent: CCC(C)=O
Solvent: CC(C)=O
Solvent: OCCNCCO
Product: CC1(C)OCCN1CCO

Procedure:
Part (A) of Example I is a process for making MEHEOX, i.e., 2-ethyl-3-(2-hydroxyethyl)-2-methyloxazolidine by reaction of diethanolamine with methyl ethyl ketone. Replacement of the latter ketone with acetone in molarly corresponding amount yields 3-(2-hydroxyethyl)-2,2-dimethyl-oxazolidine, herein referred to by the acronym DMHEOX, i.e., dimethyl-hydroxyethyloxazolidine. Replacement of the ketone with cyclopentanone or cyclohexanone yields 3-(2-hydroxyethyl)-2,2-tetramethylene- or 3-(2-hydroxyethyl)-2,2-pentamethylene-oxazolidine.
Reaction SMILES: C([NH:4][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1)(=O)C.[OH-].[Na+].C(O)COCCO>O>[NH2:4][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1
Reactant: CC(=O)NC12CCCC(C1)C1CCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: NC12CCCC(C1)C1CCC2C1
Reaction time: 15.5 h
Yield: 90.3 %

Procedure:
A solution comprising a mixture of 13.0 g (63 millimoles) of 1-acetylaminotricyclo [4.3.1.12,5 ] undecane of formula (II), 8.4 g (210 millimoles) of sodium hydroxide and 160 ml of diethylene glycol is refluxed under stirring for 15.5 hours. After allowing the solution to cool, the reaction solution is poured into water and is extracted with 200 ml of diethyl ether. The ether solution is washed with water and dried with anhydrous sodium sulfate. The ether is distilled out and the resulting residue is subjected to fractional distillation under reduced pressure to collect a fraction having a boiling point of 65°-66° C/1.0 mmHg. Thus 9.40 g (yield: 90.4%) of 1-aminotricyclo [4.3.1.12,5 ] undecane are obtained. After allowing the product to cool, white crystals of a melting point of 111°-113° C are obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13](I)=[C:12]([Cl:18])[CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(C1CCC(C2C=C(F)C=C(Cl)C=2)CC1)CC.OB(O)[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=1.FC1C=C(Br)C=CC=1F.COB(OC)OC.Cl.C(=O)([O-])[O-].[K+].[K+]>[Pd].CCCCCCC.C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)=[C:12]([Cl:18])[CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCCC1CCC(c2cc(F)c(I)c(Cl)c2)CC1
Agent: [Pd]
Agent: CCCC1CCC(c2cc(F)cc(Cl)c2)CC1
Agent: COB(OC)OC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCC[C@H]1CC[C@H](c2cc(F)c(-c3ccc(F)c(F)c3)c(Cl)c2)CC1

Procedure:
A mixture of 5.0 g (13.1 mmol) of 4-propylcyclohexyl-3-chloro-5-fluoro-4-iodobenzene [prepared by the same method as in the second step of Example 1 with the exception that 4-propylcyclohexyl-3-chloro-5-fluorobenzene was used in place of the 4-propoxycyclohexyl-3-chloro-5-fluorobenzene used in the second step of Example 1], 3.1 g (19.7 mmol) of dihydroxy(3,4-difluorophenyl)borane [prepared by reacting a Grignard reagent, which was prepared in turn from 3,4-difluorobromobenzene, with trimethoxyborane, and then hydrolyzing with hydrochloric acid], 3.6 g (26.3 mmol) of potassium carbonate, 0.5 g of 5% Pd-C, and 50 ml of mixed solvent of toluene/ethanol/water (1/1/1) was heated to reflux for 32 hours. After the catalyst was removed by filtration, the mixture was extracted with 100 ml of toluene. The organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduce pressure and the residue thus obtained was subjected to silica gel column chromatography (eluent: heptane) to obtain 4.4 g of a crude 4′-(trans-4-propyl-cyclohexyl)-2′-chloro-3,4,6′-trifluorobiphenyl. This product was recrystallized from a mixed solvent of ethanol/ethyl acetate to obtain 0.9 g of the subject compound. (Yield: 18.3%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][N:16]([CH2:20][CH2:21]Cl)[CH2:17][CH2:18]Cl.Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:21][CH2:20][N:16]([CH3:15])[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(c2ccc(F)cc2)CCN(C)CC1
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Methyl 4-fluorophenylacetate (24.4 g) was dissolved in dry dimethyl sulphoxide (150 ml) and added dropwise to sodium hydride (15.7 g of an 80% dispersion in oil) under nitrogen. After 20 minutes mechlorethamine hydrochloride (24 g) in dry dimethyl sulphoxide (125 ml) was added over a period of 20 minutes. The reaction was poured onto ice (200 ml) and left overnight. The mixture was extracted with diethyl ether (50×250 ml) and the combined organic solutions were extracted with 5N HCl (100 ml). The aqueous solution was treated with potassium carbonate and extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford a brown oil. The oil was purified by flash chromatography eluting with ethyl acetate graduated to 8% methanol in ethyl acetate, to afford the title compound (9.5 g). 1H NMR (360 MHz, CDCl3) δ 1.9-2.03 (2H, m), 2.07-2.19 (2H, m), 2.27 (3H, s), 2.51-2.62 (2H, m), 2.72-2.86 (2H, m), 3.65 (3H, s), 6.98-7.06 (2H, m), 7.27-7.39 (2H, m). MS (Cl+) 224 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:33]#[C:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:8][C:9]=1[N:10]([C:24]([CH:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[CH:11]1[CH2:16][CH2:15][CH:14]([S:17][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][N:19]=2)[CH2:13][CH2:12]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:36][C:35]([CH3:37])([CH3:38])[C:34]#[C:33][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:24]([CH:26]2[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])[CH:11]2[CH2:12][CH2:13][CH:14]([S:17][C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[CH2:15][CH2:16]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(Sc2nncn2C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(Sc3nncn3C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (63 mg, 0.113 eq.) was dissolved in THF (2.0 mL) in a round-bottomed flask. A solution of LiOH (14 mg, 0.34 mmol, 3.0 eq.) in water (1.0 mL) was added. The reaction was stirred at room temperature overnight. The reaction was then neutralized with 0.2 mL 2 N HCl, concentrated, and purified by reverse phase preparative HPLC to afford Example 2 (5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid, 27 mg, 44%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:15]1([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]1
Reactant: [H][H]
Reactant: O=C1C=CC(c2ccc(OCc3ccccc3)cc2)(c2ccccc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(O)cc2)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
Compound 5 (300 mg, 8.05 mmol) was dissolved in EtOAc (15 mL). Pd/C (100 mg, 10%) was added. The flask was charged with hydrogen gas (vacuum, H2, vacuum, H2) and the mixture was stirred overnight at room temperature. The crude mixture was filtered through a pad of celite (eluated with 40 mL of EtOAc) and the solvent was evaporated under reduced pressure to yield 230 mg, 99% of 6. 1H-NMR (CDCl3) δ 7.37 (td, 1H, J=8.0 Hz and 1.7 Hz), 7.25-7.17 (m, 1H), 7.19 (d, 2H, J=8.7 Hz), 7.16-7.11 (m, 1H), 7.00-6.93 (m, 1H), 6.78 (d, 2H, J=8.2 Hz), 2.82-2.72 (m, 2H), 2.67-2.56 (m, 2H), 2.51-2.37 (m, 4H), 1.43 (s, H2O/OH); 13C-NMR (CDCl3) δ 211.9, 161.4 (d, J=248 Hz), 154.2, 136.7, 132.9 (d, J=10.8 Hz), 128.7 (d, J=8.8 Hz), 128.3 (d, J=5.0 Hz), 127.9 (d, 2C, J=1.1 Hz), 124.1 (d, J=3.5 Hz), 117.0 (d, J=24.2 Hz), 115.3 (2C), 44.2 (d, J=2.7 Hz), 38.5 (2C), 35.5 (d, 2C, J=4.6 Hz); 19F-NMR (CDCl3) δ−108.6 (m).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[CH:8][CH:7]=1.[O:26]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH2:23][OH:26])[CH:19]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OCc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Reaction time: 24 h

Procedure:
5-{7-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole (Example 1c) (1 g) was added to each of three 10-liter fermentation tanks containing a culture of Aspergillus niger (A1) in soy-dextrose medium. After 24 hours, thin layer chromatography showed essentially complete conversion to a more polar product. The total fermentation brews were extracted with two volumes each of dichloromethane. These were combined and concentrated in vacuo. The concentrate was washed with 0.05N sodium hydroxide and with water, leaving an oily material upon removal of remaining solvent. Several crystallizations from ethyl acetate and from acetone yielded 330 mg of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-isoxazolemethanol, colorless needles, m.p. 122°-124° C. The structure was established by nmr, ir and uv spectra.
Reaction SMILES: OC(C)(C)C[C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C)[CH2:6][CH2:5]1.BrC1C=CC(=O)N(C(C)C)C=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]1([CH:4]2[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)n1cc(Br)ccc1=O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1NCCC(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was added 5-bromo-1-isopropylpyridin-2(1H)-one (54.2 mg, 0.25 mmol). Then catalysts of Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (1 mL, 2 M) were added. The vessel was sealed with a septum and placed into the microwave cavity. Microwave irradiation of 100 W was used, the temperature being ramped from room temperature to 120° C. Once this temperature was reached, the reaction mixture was held at this temperature for 30 min. After the mixture cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc (20 mL×4), the organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by preparative HPLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-(S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (22 mg, 21%). 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.40 (6H), 1.53 (d, 3H), 2.18-2.30 (m, 4H), 2.40 (m, 1H), 2.88 (m, 1H), 5.31 (m, 1H), 5.70 (m, 1H), 6.73 (d, 1H), 7.02 (d, 2H), 7.15 (d, 2H), 7.27-7.38 (m, 5H), 7.43 (d, 1H), 7.50 (d, 1H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Product: COc1ccc(-c2ccccc2)cc1OC1CCCC1
Yield: 46 %

Procedure:
Following the procedure of Example 1, phenylboronic acid and 3-cyclopentyloxy-4-methoxybromobenzene yielded 46% of the title compound as white needles: mp 62°-64° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1ccnc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CC(C)n1cc(Br)cn1
Product: COC(=O)c1ccnc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 2-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-isonicotinic acid methyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]5[CH:49]=[CH:48][C:31]([C:32]([NH:34][CH:35]6[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]6)=[O:33])=[CH:30][CH:29]=5)[N:26]=4)[N:21]=[N:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[NH:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:25]3[N:26]=[C:27]4[N:19]([CH2:18][C:14]5[CH:13]=[C:12]6[C:17](=[CH:16][CH:15]=5)[N:8]=[CH:9][CH:10]=[CH:11]6)[N:20]=[N:21][C:22]4=[N:23][CH:24]=3)=[CH:49][CH:48]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3cnc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1ccc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 96 h
Yield: 11.6 %

Procedure:
Trifluoroacetic acid (0.33 mL, 4.2 mmol) was added to a solution of tert-butyl 4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzamido)piperidine-1-carboxylate (72 mg, 0.13 mmol) in DCM (1.0 mL). After 96 hours, the reaction was concentrated by rotory evaporation. The residue was purified by prep-HPLC to give N-(piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzamide (7 mg, yield 25%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][N:2]1[C:6]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cn1nccc1-c1ccc(C=O)cc1
Product: Cn1nccc1-c1ccc(C=CC=O)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-5-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[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])[CH3:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[F:19][C:17]([F:20])([O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: OB(O)c1cncnc1
Reactant: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(Br)c2)cc1
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(-c3cncnc3)c2)cc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 215.1) and pyrimidin-5-ylboronic acid to afford an off-white foam. HPLC (Condition 4) tR=4.28 min, UPLC-MS (Condition 3) tR=0.84 min, m/z=442.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (m, J=4.30 Hz, 1H) 1.81-1.99 (m, 4H) 2.87 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.30, 4.70 Hz, 2H) 3.37 (m, J=7.00 Hz, 1H) 4.15-4.24 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.16 (d, J=8.99 Hz, 2H) 7.74 (d, J=8.60 Hz, 2H) 8.08 (d, J=1.95 Hz, 1H) 8.77 (d, J=1.00 Hz, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.06 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:25][CH:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)[N:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccnc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccnc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 0.67 h

Procedure:
A mixture of 2-chloro-pyrimidine-4-carboxylic acid methyl ester (0.62 g, 3.59 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.86 g, 4.31 mmol, 1.2 equiv; commercially available) and N-ethyl diisopropylamine (0.73 mL, 0.56 g, 4.31 mmol, 1.2 equiv) in acetonitrile (60 mL) was heated by microwave irradiation to 110° C. After stirring for 40 min, the reaction mixture was concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.48 g (34%) of the title compound. MS (ISP): 337.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=O.[S].[OH-].[Ca+2].[OH-]>O>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Agent: [Ca+2]
Agent: [OH-]
Agent: [S]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 100 parts of water, 2 parts of sulfur and 2 parts of calcium hydroxide was stirred at 95°C for 3 hours and then cooled to 25°C. Crystals precipitated were recovered by filteration, washed with water, then washed with a dilute hydrochloric acid to dissolving away calcium hydroxide and dried under reduced pressure to obtain 3.7 parts of crystalline 1-aminoanthraquinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2c(F)cccc2F)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2c(F)cccc2F)nc1-c1ccc(C)cc1
Yield: 69.4 %

Procedure:
This compound was prepared according to general method D from methyl 2-(2-(2,6-difluorophenyl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.033 g; 0.080 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.022 g (69%) of the title compound.