Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][C:7]#[N:8].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[Cl:12][C:11]1[C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])=[C:3]([CH3:13])[C:4]([O:5][CH2:6][C:7]#[N:8])=[CH:9][CH:10]=1
Reactant: Cc1c(OCC#N)ccc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-amino-4-chloro-2-methylphenoxy)acetonitrile (4.76 g) was dissolved in pyridine (45 mL) under an atmosphere of nitrogen and cooled in an ice bath. Methanesulfonyl chloride (2.06 mL) was added dropwise, and then the mixture was allowed to stir overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure to afford a residue which was flash chromatographed on silica and eluted with, first ethyl acetate:hexane (1:2), then with ethyl acetate: hexane (1:1) to afford 5.36 g as an 80:20 mixture of mono and bis mesylated product, respectively. This mixture was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:35][CH:34]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(OCCCN3CCOCC3)cc2)OC1(C)C
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(OCCCN3CCOCC3)cc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)morpholine (65 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(4-(3-morpholinopropoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=465).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9](=[O:21])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[CH2:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1)=[O:27].CC(O)=O>CS(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9](=[O:21])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[CH2:25][C:26](=[O:27])[CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:35])[CH2:30][CH2:29]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C(=O)Cc2cccc(C(F)(F)F)c2)n1
Reactant: O=C(CCl)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CSc1nccc(C(=O)C(CC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
Under Ar, a solution of 25 (4.0 g, 12.8 mmol) in DMSO (30 mL) was treated with 95% NaH (0.35 g, 13.8 mmol). After stirring at room temperature for 15 min, a solution of 5 (3.9 g, 13.2 mmol) in DMSO (20 mL) was added in one portion to the deep red solution. After stirring at room temperature for 18 h, 2N AcOH was added and then poured carefully in saturated Na2CO3. The basic aqueous solution was extracted with EtOAc (3×). The organic extracts were backwashed with H2O, brine, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (80 mm) and the product was eluted with 30% EtOAc-hexanes to yield 1.5 g of 26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][NH:60]3)=[N:57][C:53]=2[CH:52]=1>CN(C=O)C>[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][N:60]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])=[N:57][C:53]=2[CH:52]=1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (700 mg, 3.0 mmol), HATU (1.12 g, 3.0 mmol) and N,N-diisopropylethylamine (1.54 ml, 9.0 mmol) in DMF (20 ml) was stirred at room temperature under argon for 2 min. The mixture was then treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 (742 mg, 3.0 mmol) and stirring was continued for 16 h. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-5% methanol-ethyl acetate) afforded the title compound as a pale yellow solid (1.35 g, 97%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([C:9]1[CH:39]=[CH:38][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=O)=[CH:17][CH:16]=2)=[C:11]([CH3:40])[C:10]=1[OH:41])(=[O:8])[CH3:7].[OH-].[K+].Cl>CC(C)=O.O>[OH:41][C:10]1[C:11]([CH3:40])=[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([C:22]3[CH:30]=[CH:29][CH:28]=[C:24]([C:25]4[NH:5][C:3]([SH:4])=[N:2][N:1]=4)[CH:23]=3)[O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[CH:17][CH:16]=2)[CH:38]=[CH:39][C:9]=1[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Reactant: NNC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nnc(S)[nH]4)c3)cc2)c(C)c1O

Procedure:
Heat a solution of 3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoic acid thiosemicarbazide (1.20 g, 2.04 mmol) and potassium hydroxide (0.228 g, 4.08 mmol) in acetone (5.0 mL) and water (5.0 mL) overnight. Acidify with 2N hydrochloric acid and extract with ethyl acetate (5×). Combine organic layers and wash with brine, dry, and concentrate to afford the title compound which was used without further purification (1.12 g, 2.04 mmol, 99%). MS (m/z): 544 (M−H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:25])=[C:19]([CH2:21][C:22]([OH:24])=[O:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH2:27]O.S(=O)(=O)(O)O>O>[CH2:26]([O:23][C:22](=[O:24])[CH2:21][C:19]1[N:20]=[C:16]([C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)[O:17][C:18]=1[CH3:25])[CH3:27]
Reactant: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)oc1C
Yield: 83 %

Procedure:
A mixture of [2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazol-4-yl]-acetic acid (1.5 g, 4.35 mmol), EtOH (50 mL), and concentrated sulfuric acid (0.5 mL) was refluxed for 10 hours. The mixture poured into water, and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from ethyl ether/hexane gave a light brown solid (1.35g, 83% yield), m.p. 103°-105° C.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C:4](=[O:5])[S:3][CH2:2]1.[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>O.C(Cl)Cl>[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25]([NH:7][CH:6]1[C:4](=[O:5])[S:3][CH2:2][CH2:1]1)=[O:26]
Reactant: N[C@H]1CCSC1=O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)NC2CCSC2=O)C(C)(C)CCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
McCully (U.S. Pat. No. 4,618,685; “the '685 patent”, incorporated herein by reference) attempted to synthesize thioretinamide, the precursor to the compound of the invention, from homocysteine thiolactone free base and retinoic acid. McCully's synthesis of thioretinamide involves the conjugation of homocysteine thiolactone to retinoic acid using dicyclohexylcarbodimide as a coupling agent. The process in that patent starts with the preparation of the free base of homocysteine thiolactone. This is done by dissolving sodium hydroxide (NaOH) in water, adding methylene chloride and rapidly mixing. Homocysteine thiolactone hydrochloride is then slowly added to the mixture. After 15 minutes of mixing, the methylene chloride layer is separated, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure at 37° C. The resulting clear liquid (homocysteine thiolactone free base) is immediately added to tetrahydrofuran (or any other non-polar solvent) containing all-trans-retinoic acid. Then, dicyclohexylcarbodiimide is added, and the reaction mixture is stirred 16 hours at 20° C., protected from light. The tetrahydrofuran is removed at 37° C. under reduced pressure, and the yellow-white residue is added to 500 ml of water and 500 ml of ethyl acetate. The mixture is stirred vigorously for one hour, and the ethyl acetate layer is separated and dried over anhydrous sodium sulfate. The ethyl acetate is concentrated to about 20 ml at 50° C. under reduced pressure and cooled. The resulting N-homocysteine thiolactonyl retinamide, (a yellow powder) was produced with a 69% theoretical yield and a melting point of 172° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11](OC2C=CC=CC=2)[N:10]=1.[C:30]1([CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[CH:32]=1)[OH:31].[Cl-].[Al+3].[Cl-].[Cl-].C1S(=O)(=O)CCC1.Cl>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:35]2[CH:36]=[CH:37][C:30]([OH:31])=[CH:32][C:33]=2[OH:34])[N:10]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccc(-c2nc(Oc3ccccc3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 160 °C
Reaction time: 10.5 h
Yield: 68.7 %

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stirrer, a condenser and a nitrogen atmosphere are added 6.00 g (0.0157 mol) of the product of Example 2, 2.08 g (0.0189 mol) of resorcinol, 2.09 g (0.0157 mol) of aluminum chloride and 6 mL of tetramethylene sulfone (sulfolane). The mixture is stirred at 138° C. for six hours, 147° C. for seven hours, 160° C. for 10.5 hours and then allowed to cool to room temperature. A portion of 2N hydrochloric acid is added and the mixture is refluxed for two hours and then allowed to cool to room temperature. The solids formed are collected by vacuum filtration and then washed with portions of water and heptane. The crude solid is taken up in ethyl acetate and passed through a plug of silica gel. The solvent is removed under reduced pressure to give 5.25 g of crude product. The crude product is recrystallized from methanol to afford 4.29 g (69% yield) of the title compound as a yellow solid melting at 199-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][N:39]=1)[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][C:18]([NH:20][C:21]2[N:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[N:24]=[C:23]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:22]=2)=[O:19])=[CH:9][CH:8]=1)=[O:6].CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55](Cl)=[O:56]>C1COCC1>[C:33]([C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[NH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:5]([C:4]3[CH:37]=[CH:38][N:39]=[C:2]([NH:1][C:55](=[O:56])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])[CH:3]=3)=[O:6])=[CH:8][CH:9]=2)[N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[N:24]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: COCCOCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C(=O)c3ccnc(N)c3)c3ccccc23)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCC(=O)Nc1cc(C(=O)c2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a solution of 1-(4-(2-aminoisonicotinoyl)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea (38.0 mg, 0.073 mmol) and DIPEA (64 μL, 0.37 mmol) in dry THF (4.0 mL) under N2 at 0° C. was added 2-(2-methoxyethoxy)acetyl chloride (45.0 mg, 0.29 mmol). The reaction mixture was maintained at 0° C. for 30 min and was then warmed to RT for 1.5 hr. The reaction was quenched by the addition of a solution of NH3 (1% in MeOH, 3.0 mL) and after a further 45 min at RT was evaporated in vacuo. The residue was purified by SCX capture and release followed by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-60%, gradient elution) to afford the title compound, Example 22, as a yellow solid (21 mg, 44%); Rt 2.67 min (Method 2); m/z 635 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.39 (3H, s), 3.29 (3H, s), 3.50 (2H, m), 3.66 (2H, m), 4.14 (2H, s), 6.45 (1H, s), 7.35-7.37 (3H, overlapping m), 7.46 (2H, d), 7.67-7.73 (3H, overlapping m), 8.20 (2H, m), 8.37 (1H, s), 8.49 (1H, m), 8.54 (1H, d), 9.03 (1H, s), 9.47 (1H, s), 10.24 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>C(OCC)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=CCOc1ccc(CCO)cc1
Reaction time: 17 h
Yield: 60.5 %

Procedure:
2-(4-Hydroxyphenyl)ethanol (100 g), anhydrous potassium carbonate (100 g) and allyl bromide (98 g) were refluxed with stirring for 17 hours. The mixture was cooled, filtered (washing through with acetone) and evaporated under reduced pressure to give an oily residue. This residue was dissolved in diethyl ether, washed with aqueous sodium hydroxide, washed with saturated brine, dried (MgSO4) and evaporated in vacuo to afford an oil. This was chromatographed on a silica gel column using dichloromethane to afford 2-(4-allyloxyphenyl)ethanol (78 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:15]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCc2ccccc2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
38.16 g (0.2 mol) of p-toluenesulphonyl chloride are added at room temperature while stirring to a solution of 31 g (0.189 mol) of 2-hydroxymethylchroman in 110 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The oil which separates out is removed by decanting the aqueous phase, dissolved in diethyl ether and washed with ice-cold 2N hydrochloric acid and ice-water. The ethereal phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 58.15 g (96.6%) of 2-(p-toluenesulphonyloxymethyl)chroman are obtained in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:28][C@@H:29]1[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]1>CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:28][C@@H:29]2[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]2)=[N:6][CH:7]=1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: N[C@@H]1CC[C@H](CO)C1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OC[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Yield: 78.7 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (100 mg, 0.301 mmol) was added DMSO (1 ml), ((1S,3R)-3-aminocyclopentyl)methanol (104 mg, 0.903 mmol) and TEA (0.21 ml, 1.51 mmol). The crude mixture was stirred at 100° C. for 20 hours, followed by LCMS. The crude reaction mixture was cooled, was diluted with EtOAc (60 mL), washed H2O (60 mL×2), brine (60 mL), dried over Na2SO4, and reduced. The crude was adsorbed onto silica gel, and purified by silica gel chromatography, 40-80% EtOAc/Heptane, 12 g ISCO silica column, resulting in ((1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentyl)methanol (101 mg, 0.237 mmol). LCMS (m/z): 427.1 (MH+). retention time=0.69 min.
Reaction SMILES: B#B.O1CCCC1.[Cl:8][C:9]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:10]=1[CH2:11][CH2:12][NH:13][C:14](=O)[CH2:15][CH3:16]>CO>[CH2:14]([NH:13][CH2:12][CH2:11][C:10]1[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:9]=1[Cl:8])[CH2:15][CH3:16]
Reactant: CCC(=O)NCCc1ccc(OC)c(OC)c1Cl
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Product: CCCNCCc1ccc(OC)c(OC)c1Cl

Procedure:
To 100 ml. of a solution of diborane in tetrahydrofuran (0.93 molar, 0.093 mole) was added a solution of 9.0 g. (0.033 mole) of the above-prepared propionamide. The mixture was refluxed overnight, cooled and methanol added to destroy unreacted diborane. Ethereal hydrogen chloride and methanol were added and the mixture evaporated to dryness. The residue was dissolved in dilute hydrochloric acid/ether and the acidic aqueous solution was basified, extracted with ether and the dried ether extract evaporated to yield N-(n-propyl)-2-chloro-3,4-dimethoxyphenethylamine. The latter (3.5 g., 0.0137 mole) was dissolved in 100 ml. of propionic anhydride and stirred overnight. The mixture was evaporated nearly to dryness, toluene was added and then further evaporated to leave N-(2-chloro-3,4-dimethoxyphenethyl)-N-(n-propyl)propionamide.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:18][N:19]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (36 mg, 0.13 mmol, CAS RN 1271-19-8) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol) and DIPEA (40 μL, 0.23 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (23 mg, 41%). MS (ESI): m/z=439.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:23][CH2:22][C:9]2[C:10]3[C:11]([C:17]4[S:18][CH:19]=[CH:20][N:21]=4)=[CH:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[H][H]>C(O)C.[Pd]>[F:25][C:2]([F:1])([F:24])[C:3]([N:5]1[CH2:23][CH2:22][C:9]2[C:10]3[CH:11]([C:17]4[S:18][CH:19]=[CH:20][N:21]=4)[CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: O=C(N1CCc2ccc3c(c2CC1)C(c1nccs1)=CC3)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: O=C(N1CCc2ccc3c(c2CC1)C(c1nccs1)CC3)C(F)(F)F
Temperature: 25 °C
Yield: 76.8 %

Procedure:
The product from step (c) (22 mg) was dissolved in ethanol (30 ml) placed in a Parr Hydrogenation bottle. To this solution was added 10% Pd—C (100 mg). The mixture was shaken at 50° C. over 50 psi of hydrogen for 16 hours. The reaction mixture was purged with Nitrogen, cooled to RT, and filtered thru a pad of celite. The solvent was evaporated in vacuo to give the crude product as a light yellow oil. Purification by flash silica-gel chromatography (gradient elution: 0-50% EtOAc in hexanes) gave the sub-title compound (17 mg) as a white film. MS: ESI (positive): 367 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:33]4[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3cnc(N)nc3)cc1-2
Yield: 11.9 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (53.4 mg, 0.130 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (34.4 mg, 0.156 mmol) were reacted to give 281 (6.6 mg, 12% yield, M+1 426.1)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])=[O:20])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: COc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1

Procedure:
Using a procedure similar to Example 1B except starting with 2-nitroaniline and p-anisoyl chloride, the title compound was obtained as a solid (98%); MS(FD): 272.0.