Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@H:6]([F:8])[CH2:5][N:4]1C(OC(C)(C)C)=O)#[N:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(#N)C>[C:16]1([CH3:26])[CH:17]=[CH:18][C:19]([S:22]([OH:25])(=[O:23])=[O:24])=[CH:20][CH:21]=1.[C:1]([C@@H:3]1[CH2:7][C@H:6]([F:8])[CH2:5][NH:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of Step 1 intermediate (40 g, 186.72 mmol) in acetonitrile (400 ml) was added p-toluene sulfonic acid (64.3 g, 373.33 mmol) and the solution was stirred at for 24 h at room temperature under nitrogen atmosphere. The solvent was evaporated under reduced pressure to afford a brown residue, which was triturated with petroleum ether (100 ml) to give a filterable solid. The solid was collected by filtration and dried to give 45 g of the product as an off-white solid; 1H NMR (CDCl3, 300 MHz) δ 2.31 (s, 3H), 2.37-2.65 (m, 2H), 3.76-3.87 (m, 2H), 5.10 (br s, 2H), 5.33 (br d, J=51.6 Hz, 1H), 7.19 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[O:9])[CH3:6]>CCO.O.CCOC(C)=O>[CH2:5]([O:7][C:8]([C:10]1[C:11]([O:3][CH2:2][CH3:1])=[N:12][C:13]2[C:18]([C:19]=1[CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[O:9])[CH3:6]
Reactant: CC[O-]
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(OCC)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
1.2 g (17.8 mmol) sodium ethylate was added to a solution of 5.1 g (16.1 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in EtOH (20 ml) at RT. The RS was subsequently heated to 60° C. for 4 h and then stirred for 16 h at RT. The solution was then diluted with water and EtOAc. The organic phase was separated and washed with a 4N aq. NH4Cl sol., dried over MgSO4 and concentrated in a vacuum. 5.1 g (15.6 mmol, 97%) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=O)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][NH2:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>C1COCC1>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH2:14][NH:30][CH3:29])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde (Example 73, 0.10 g, 0.26 mmol) in THF (5 ml) was added methylamine (2.0 M in THF, 0.52 mmol) and NaBH(OAc)3 (0.82 g, 0.39 mmol). The reaction was stirred for 3 hours, quenched with water, and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting crude imine was dissolved in MeOH (5 ml) and NaBH4 (0.06 g, 0.4 mmol) was added. The reaction was stirred for 10 min, quenched with aq. Na2CO3 (10 ml), and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse phase column chromatography (5-35% ACN) to give the title compound (0.05 g, 48%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.38 (m, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.02-6.98 (m, 2H), 6.00-5.52 (br s, 1H), 5.05 (s, 1H), 3.63 (s, 2H), 2.37 (s, 3H), 1.87-1.82 (m, 1H), 1.51 (d, J=6.9 Hz, 3H), 0.93-0.91 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 398. Found: [M+H]+399.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22](O)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1.[CH3:25][O:26][CH2:27]Cl>C(N(CC)CC)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1
Reactant: COCCl
Reactant: Oc1ccc2nc(-c3ccc(I)cc3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1ccc2nc(-c3ccc(I)cc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 30 mg, 0.76 mmol) was added to a DMF (2 mL) solution of 5 (225 mg, 0.64 mmol), cooled in an ice bath. After stirring at 0° C. for 1 h, chloromethyl methyl ether (100 μL, 1.33 mmol) and triethylamine (0.2 mL) were added. The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with pH 7 buffer solution (10 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash chromatography on silica gel (CH2Cl2), to give 2-(4-iodophenyl)-6-(methoxymethyl)-1,3-benzothiazole (6) (237 mg, 93.7%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([N+:12]([O-])=O)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.[C].[Pd]>[NH2:12][C:9]1[CH:8]=[C:7]([C:15](=[O:17])[CH3:16])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:10]=1[OH:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(N)c(O)c(C(C)(C)C)c1
Reaction time: 3 h
Yield: 71.7 %

Procedure:
After adding 10% palladium-carbon (50% wet) (100 mg) to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (1.00 g, 4.22 mmol) in ethyl acetate (10 ml) at room temperature, the mixture was hydrogenated for 3 hours under normal pressure. The 10% palladium-carbon was then filtered through celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,10 g) to yield the title compound (627 mg, 71.8% yield) as a light red powder from the ethyl acetate-hexane (1:4˜1:3) fraction.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1N2CCN(CC2)C1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decan-8-ol (1.0 mg, 6.3 mmol) and triethylenediamine (0.780 mg, 7.0 mmol) cooled to 0° C. in DCM (20 mL) was added p-toluenesulfonylchloride (1.31 g, 7.0 mmol) in DCM (5 mL). The reaction mixture was stirred overnight and then washed with 0.5 N HCl (20 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (2.0 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C@@H:5]1[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][C@H:6]1[OH:17].[H][H].[BrH:25]>C(O)C.[Pd]>[BrH:25].[CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C@@H:5]1[CH2:9][NH:8][CH2:7][C@H:6]1[OH:17]
Reactant: [H][H]
Reactant: Cc1cccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)c1C
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: Cc1cccc(O[C@@H]2CNC[C@H]2O)c1C
Yield: 55 %

Procedure:
A solution of 9.1 g. (0.031 mole) of trans-4-(2,3-dimethylphenoxy)-1-phenylmethyl-3-pyrrolidinol in 100 liters of ethanol was hydrogenated over 10% palladium-on-charcoal at 50 psi and 60° C. until hydrogen uptake ceased. The mixture was filtered through Celite and the filtrate was concentrated to give an oil as residue which solidified upon standing. The solid was converted to the hydrobromide and this salt was recrystallized from isopropyl alcohol-ethylacetate-diethylether to yield 4.9 g (55%) of tan needles, m.p. 152°-3° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:33]1([C:15]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]2)=[O:16])[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
10.0 g (22.1 mmol) of the compound from Example 48A, 6.84 g (66.3 mmol) of thiomorpholine and 9.17 g (66.3 mmol) of potassium carbonate were added to 150 ml of DMF and heated in 10 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 1 h. For workup, the reaction solutions were combined and filtered, and the residue was purified by means of preparative HPLC. Yield: 5.16 g (55% of theory)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22]CC)=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([OH:22])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Reactant: Oc1cc(F)ccc1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 2-bromo-5-fluorophenol, triphenylphosphine and di-tert-butyl azodicarboxylate.
Reaction SMILES: C(NC(C1C=C(S([O:16][CH2:17][C@:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:30][C:31](=[O:39])[CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=O)=O)C=CC=1)=O)C#C.[CH2:69]([O:72][C:73]1[CH:78]=[C:77]([O:79][CH3:80])[C:76]([S:81](Cl)(=[O:83])=[O:82])=[C:75]([O:85][CH3:86])[CH:74]=1)[C:70]#[CH:71].C(N)(=O)CCCC>>[CH3:80][O:79][C:77]1[CH:78]=[C:73]([O:72][CH2:69][C:70]#[CH:71])[CH:74]=[C:75]([O:85][CH3:86])[C:76]=1[S:81]([O:16][CH2:17][C:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31](=[O:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:83])=[O:82]
Reactant: C#CCOc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Reactant: C#CCNC(=O)c1cccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c1
Agent: CCCCC(N)=O
Product: C#CCOc1cc(OC)c(S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c(OC)c1

Procedure:
Prepared in a similar manner to compound 13, except from 4-(propargyloxy)-2,6-dimethoxybenzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-242-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: [OH-:1].[Na+].[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].OO>O.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C@@H:4]1([C:3]([OH:10])=[O:9])[O:1][C@@H:5]1[C:6]([OH:8])=[O:7]
Reactant: [OH-]
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H]1O[C@H]1C(=O)O
Temperature: 90 °C

Procedure:
A solution was prepared by dissolving 67 grams of sodium hydroxide in 400 ml of water. To this solution were added 130 g of maleic acid while maintaining the solution at a temperature below 98° C. An aqueous solution of hydrogen peroxide (30%) was then added, followed by the addition of a solution containing 2.0 g of sodium tungstate dihydrate in 8.0 ml of water. The solution was heated in a 90° C. oil bath for 30 minutes and then cooled to ≤60° C. A solution containing 44 g of aqueous NaOH (50% by weight) was then added to bring the pH to 7.0. The product was analyzed by NMR, giving 14.7% by weight of cis-epoxysuccinic acid and 3.9% by weight of D,L-tartaric acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)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].C(Cl)Cl>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2ccccc2F)n1
Yield: 43 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 5-fluoro-6-(2-fluorophenyl)picolinic acid in 43% yield. LC/MS=236.1 (M+H), Rt=0.72 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[C:6]([CH3:16])[CH:5]=[C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[N:3]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:26][CH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:5][C:6]=2[CH3:16])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)nc(C)c1-c1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCCCS(C)(=O)=O)nc(C)c1-c1cccc(CBr)c1
Yield: 59.3 %

Procedure:
[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]phenyl]methanol (0.30 g) synthesized according to the methods in (Reference Example 5) and (Example 11) <Step 2> and carbon tetrabromide (0.34 g) were dissolved in methylene chloride (1.8 mL) and to the resultant solution, a solution of triphenylphosphine (0.34 g) in methylene chloride (0.9 mL) was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. From the reaction mixture, the solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=3:2) to obtain the subject compound (0.21 g) as a colorless liquid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1coc(-c2ccc(CO)cc2)n1
Solvent: ClCCl
Product: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of methylene chloride at −10° C. and excess thionyl chloride was added portionwise ethyl 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylate (1 eq) and the resulting mixture was stirred at room temperature for 3 h. The solvent was removed and the residue was azeotroped with toluene, dissolved in methylene chloride, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to give a yield of 96% of the product as white crystals; m.p. 115-117° C. 1H NMR (300 MHz, CDCl3, δ): 8.28 (s, 1H), 8.12 (d, 2H, J=8.5 Hz), 7.50 (d, 2H, J=8.5 Hz), 4.62 (s, 2H), 4.43 (m, 2H, J=7.4 Hz), 1.41 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].CN(C)C=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1.C(N(CC)CC)C>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:18][C:19]2[CH:24]=[N:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(F)nc1F
Reactant: COc1ccc(N)cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(Nc2ccc(OC)nc2)nc1F
Temperature: -40 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a round bottom flask, 2,6-difluoro-nicotinic acid methyl ester (52, 2.00 g, 11.6 mmol) is combined with 20.0 mL of N,N-dimethylformamide under an atmosphere of nitrogen at −40° C. To this, 5-amino-2-methoxypyridine (53, 1.55 g, 12.5 mmol) and triethylamine (5.0 mL, 36.0 mmol) are added and the reaction stirred at −40° C., then warmed to room temperature and reacted overnight. The reaction is then heated to 50° C. over the weekend, then at 70° C. for 3 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (54, 1.20 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].O=[C:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([O-:27])=[O:26]>C(O)C.C(O)(=O)C.[Pd]>[CH2:8]([C:7]1[C:2]([NH:1][CH:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Reactant: CCCCC(=O)C(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
4-(5-amino-6-benzylpyrazin-2-yl)phenol (200 mg, 0.72 mmol) was mixed with 2-Ketohexanoic acid sodium salt (220 mg, 1.44 mmol) in ethanol (20 mL). Pd/C (10% Palladium in active carbon, 100 mg) was added with a few drops of acetic acid, and the reaction mixture heated to 65° C. Air was bubbled out by N2 gas, and a hydrogen balloon applied to the reaction flask. The reaction was continuously stirred for 4 hrs. After cooling down, it was filtered and the resulting solution was purified by flash chromatography (eluting solvent: 50% EtOAc in heptanes) to give the product as a yellow powder (130 mg, 46%). MS (ESI): m/z 392.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][NH:9][C:10]1[S:11][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[O:16])=[CH:13][N:14]=1.Cl.[S:25]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26]1.CCN(CC)CC>C(Cl)Cl.CO>[S:25]1[CH:29]=[CH:28][C:27]([S:30]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[CH:13][N:14]=2)(=[O:32])=[O:31])=[CH:26]1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCC2CCCCN2)s1
Reactant: O=S(=O)(Cl)c1ccsc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1cnc(NCCC2CCCCN2S(=O)(=O)c2ccsc2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 35.2 mg (0.1 mmol) [2-(2-Piperidin-2-yl-ethylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride, 21.9 mg (0.12 mmol) thiophene-3-sulfonyl chloride (commercially available) and 44.6 ul (0.32 mmol) NEt3 in a mixture of DCM/MeOH 3/1 was stirred at 60° C. for 16 h. After cooling to room temperature the mixture was concentrated and MeOH (1 ml) and formic acid (0.5 ml) was added and the mixture was subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 7 mg (15%) of the title compound was obtained. MS (m/e): 474.0 (MH−, 100%)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[C:12]([C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>CCOCC.Cl[Ni](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:12]([C:16]1[CH:17]=[C:18]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1=Cc2c(Cl)cccc2C1
Reactant: CC(C)(C)c1cc([Mg]Br)cc(C(C)(C)C)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-methylindene (6.1 g, 37 mmol) and NiCl2(PPh3)2(1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Di-t-butylphenylmagnesium bromide (10 g, 37 mmol) as a Et2O solution was added to the solution and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 4.6 g (40%).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:10])[CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1cccc(B(O)O)c1
Reactant: Nc1cc(F)c(Br)c(F)c1
Product: CCCCOc1cccc(-c2c(F)cc(N)cc2F)c1
Yield: 62 %

Procedure:
The title compound (172 mg) was prepared from 4-bromo-3,5-difluoroaniline (200 mg, 1 mmol) and 3-butoxyphenyl boronic acid (242 mg, 1.2 mmol) as a colourless liquid.