Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:37])([CH3:36])[CH2:9][C@:10]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:11][C:12]#[C:13][C:14]2[C:19]([NH:20]C(=O)C(F)(F)F)=[CH:18][CH:17]=[C:16]([S:27]([CH3:30])(=[O:29])=[O:28])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C(=N)N(C)C>CS(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:37])([CH3:36])[CH2:9][C@:10]([CH2:11][C:12]2[NH:20][C:19]3[C:14](=[N:15][C:16]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][CH:18]=3)[CH:13]=2)([OH:35])[C:31]([F:34])([F:33])[F:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C[C@@](O)(CC#Cc1nc(S(C)(=O)=O)ccc1NC(=O)C(F)(F)F)C(F)(F)F)c1cccc(Br)c1
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C[C@@](O)(Cc1cc2nc(S(C)(=O)=O)ccc2[nH]1)C(F)(F)F)c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 61.1 %

Procedure:
N-{2-[(S)-6-(3-Bromophenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-6-methanesulfonylpyridin-3-yl}-2,2,2-trifluoroacetamide (351 mg, 0.57 mmol) was dissolved in 3.4 mL of DMSO and tetramethylguanidine (0.43 mL, 3.42 mmol) was added. The mixture was stirred at 70° C. for 7 hours. Then it was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and brine, dried over sodium sulfate, and concentrated in vacuo. The mixture was purified by flash chromatography (gradient 0→8% MeOH in DCM). The product was further purified by crystallization (DCM) to give (R)-4-(3-bromophenyl)-1,1,1-trifluoro-2-(5-methanesulfonyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-4-methylpentan-2-ol as a white solid (181 mg, 61%).
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[C:19]([C:23]4([C:29](N)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:5]=1>CO.O1CCCC1>[CH3:3][C:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[C:19]([C:23]4([C:29]([OH:1])=[O:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:5]=1
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(N)=O)CCOCC4)c3)cc2)c(=O)[nH]1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)O)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
Potassium hydroxide (3.0 mmol) is added to a solution of 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxamide (1.0 mmol) (example 10) in methanol and tetrahydrofuran (1:2) and the reaction mixture is refluxed for about 18 hours. The solvent is evaporated under vacuum. A small amount of water and concentrated hydrochloric acid are added to the residue to separate out the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:18][OH:19])[NH:5][C:6]=1[C:7]1[C:8]([CH3:17])=[CH:9][C:10]([CH3:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O.Cl.[F:21][C:22]1([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:25][NH:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:18][OH:19])[NH:5][C:6]=1[C:7]1[C:8]([CH3:17])=[CH:9][C:10]([CH3:16])=[C:11]([CH:15]=1)[C:12]([N:24]1[CH2:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=2)([F:21])[CH2:25]1)=[O:14]
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2Cl)cc1C(=O)O
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2Cl)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 230.6, 180 mg, 0.64 mmol) in N,N-dimethylformamide (15 mL). 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4, 165 mg, 0.78 mmol), EDC.HCl (245 mg, 1.28 mmol) and 4-dimethylaminopyridine (310 mg, 2.54 mmol) were added to the reaction. The reaction mixture was stirred overnight at 25° C. The reaction was then quenched with 5 mL of water. The reaction mixture was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5×10 mL of brine. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and ACN (26.0% ACN up to 39.0% in 10 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 84 mg (30%) of the title compound as a white solid. m/z (ES+) 439 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:17]([NH:25][C:26]([NH:16][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([Br:15])=[CH:13][N:12]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(OCc2ccccc2)c(Br)cn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1cc(OCc2ccccc2)c(Br)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A flask was charged with 4-(benzyloxy)-5-bromopyridin-2-amine (6.90 g, 24.7 mmol), and THF (250 mL). Benzoyl isothiocyanate (4.24 g, 26.0 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction mixture was concentrated, and 9:1 Hexanes:ethyl acetate (400 mL) was added to the residue. The suspension was filtered to give the desired product (10 g, 82.3% yield) as light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH2:15][CH2:14]1)=[O:12].[H-].[Na+].I[CH3:31]>CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH3:31])[CH2:15][CH2:14]1)=[O:12]
Reactant: CI
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cnccc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
A solution of 0.12 g (0.30 mmol) [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 3) in 1 mL N,N-dimethylformamide was treated with 0.014 g (0.32 mmol) sodium hydride (60% suspension in mineral oil) upon which gas evolution set in and a colour change occurred. After stirring for 30 min., 0.022 mL (0.36 mmol) iodomethane were added. After stirring for 7 hours at room temperature, the reaction mixture was poured onto water and was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give the desired compound as an orange solid (32 mg, 26%). MS (ESI): m/z=414.077 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]2[S:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1S
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)cc1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 4-nitrobenzoyl chloride (1.49 g, 8.0 mmol) in benzene (anhydrous, 10 mL) was added dropwise to 2-aminothiophenol (1.0 g, 8.0 mmol in 10 ml of benzene) at room temperature. The reaction mixture was allowed to stir for 16 hr. The reaction was quenched with water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried and evaporated. The crude product was purified with flush column, (hexane:ethyl acetate=85:15) to give 1.5 g (73.2%) of product as light yellow solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:5].[CH3:6][N:7]([CH3:16])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Li]>C1(C)C=CC=CC=1>[CH3:6][N:7]([CH3:16])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Zr:5]([CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[N:7]([CH3:16])[CH3:6])([CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[N:7]([CH3:16])[CH3:6])[CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[N:7]([CH3:16])[CH3:6]
Reactant: [Li]Cc1ccccc1N(C)C
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C)c1ccccc1C[Zr](Cc1ccccc1N(C)C)(Cc1ccccc1N(C)C)Cc1ccccc1N(C)C
Temperature: 50 °C

Procedure:
To a mixture of 0.046 g of zirconium tetrachloride and 0.113 g of 2-dimethylaminobenzyllithium was added 3 ml of toluene, and the mixture was warmed to about 50° C with stirring. Reaction slowly took place to give an orange liquid. When there was no further appreciable change in the color of the liquid, the mixture was cooled and filtered to give an orange solution of tetrakis(2-dimethylaminobenzyl)zirconium.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:15][NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=2[S:36][C:37]=1[C:38](Cl)=[O:39]>>[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=2[S:36][C:37]=1[C:38]([N:16]([CH2:15][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:17]1[CH2:18][CH2:19][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]1)=[O:39]
Reactant: COc1ccc(-c2ccccc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccccc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 46 (423 mg, 1.00 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (507 mg, 2.20 mmol) using Method D to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:25])[CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[CH:5]=1.[Li+].[OH-].Cl>C1COCC1>[CH3:20][O:19][C:18]1[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[C:14]([O:23][CH3:24])[C:13]=1[CH2:12][C:11]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])=[O:25]
Reactant: COC(=O)c1cccc(NC(=O)Cc2c(OC)cc(OC)cc2OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC)c(CC(=O)Nc2cccc(C(=O)O)c2)c(OC)c1
Yield: 99.5 %

Procedure:
Dissolve 3-[2-(2,4,6-Trimethoxy-phenyl)-acetylamino]-benzoic acid methyl ester (16) (140 mg, 0.39 mmol) in THF (25.0 mL) at rt and add 1M aqu LiOH (2.0 mL, 2.0 mmol). Stir reaction mixture 40 h at rt. Quench reaction mixture (cooling bath) with 2M aqu. HCl. Extract the mixture with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4 to obtain 3-[2-(2,4,6-Trimethoxy-phenyl)-acetylamino]-benzoic acid (17) (134 mg, 99%) as a beige solid. 1H NMR (400 MHz, CD3OD): 3.71 (s, 2 H); 3.84 (s, 3 H); 3.85 (s, 6 H); 6.29 (s, 2 H); 7.43 (t, 1 H, J=7.8 Hz); 7.76 (d, 1 H, J=7.8 Hz); 7.83 (d, 1 H, J=8.1 Hz); 8.19 (br.s, 1 H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H]>[Ni]>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: [H][H]
Agent: [Ni]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Yield: 93.8 %

Procedure:
In a 500-mL autoclave were added 100.0 g (0.65 mol) of the 1-isopulegol obtained in Example 44 and 0.4 g of Raney nickel in a nitrogen atmosphere. Hydrogenation was conducted at a hydrogen pressure of 2.5 MPa and 70° C. for 10 hours. The reaction mixture was filtered, followed by distillation to obtain 94.8 g (0.61 mol, 100% e.e.) of 1-menthol.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[CH2:13]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)[CH3:14]>>[CH2:13]([C:15]1[N:19]2[CH2:2][CH2:3][CH:1]=[C:4]([C:6]3[CH:7]=[CH:8][C:9]([N:16]4[CH:17]=[CH:18][N:19]=[C:15]4[CH2:13][CH3:14])=[CH:10][CH:11]=3)[C:18]2=[CH:17][N:16]=1)[CH3:14]
Reactant: CCc1ncc[nH]1
Reactant: O=C(c1ccc(F)cc1)C1CC1
Product: CCc1nccn1-c1ccc(C2=CCCn3c2cnc3CC)cc1

Procedure:
Combine 155 g of (0.94 mol) of cyclopropyl-(4-fluorophenyl)methanone with 300 g (3.1 mol) of 2-ethylimidazole and heat to 175° C. under argon for 18 hr. The title compound is isolated by column chromatography on 1500 g of silica gel using 2% methanol/methylene chloride as solvent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]3[CH:45]=[CH:46][C:36]([F:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(/C=C/c2ccc(F)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), (E)-4-fluorostyrylboronic acid (49.7 mg, 0.299 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 20-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a light yellow solid (32 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=16.17 Hz, 1H), 2.00-2.21 (m, 1H), 3.55-3.71 (m, 2H), 3.79-3.93 (m, 2H), 3.93-4.10 (m, 1H), 4.33-4.46 (m, 2H), 4.54 (d, J=8.84 Hz, 1H), 7.15 (d, J=5.05 Hz, 1 H), 7.28 (t, J=8.84 Hz, 1H), 7.58-7.74 (m, 3H), 7.93 (br s, 3H), 8.15 (d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20F2N4O2, 387. found, 387.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Temperature: 145 °C
Yield: 75.8 %

Procedure:
A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][OH:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27](O)=[CH:28][CH:29]=2)=[CH:21][CH:22]=1.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>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C:20]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CCOc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)—N-Boc-piperidine-2-ethanol (1.00 g, 4.36 mmol), 4-hydroxydiphenylmethane (0.884 g, 4.79 mmol), and triphenylphosphine (1.26 g, 4.80 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added diisopropyl azodicarboxylate (0.92 ml, 4.80 mmol), and the resulting mixture was stirred at ambient temperature for about 20 h. The clear, yellow solution was concentrated in vacuo. The crude liquid was purified by silica gel flash chromatography to obtain the title compound as a clear, yellow oil (1.20 g, 70%): 1H NMR (400 MHz; CDCl3): δ 7.35 (m, 2H), 7.17 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 4.46 (m, 1H), 3.97 (m, 5H), 2.80 (br t, 1H, J=13.2 Hz), 2.12 (m, 1H), 1.85 (m, 1H), 1.60 (m, 5H), 1.40 (m, 10H). MS; m/z 418 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH2:30][C:31]2[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=2)[N:23]=1>>[CH3:36][N:35]1[C:31]([CH2:30][O:29][CH2:28][C:24]2[N:23]=[C:22]([NH:1][C:2]3[S:3][C:4]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=4[F:20])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])[CH:27]=[CH:26][CH:25]=2)=[CH:32][C:33]([CH3:37])=[N:34]1
Reactant: Cc1cc(COCc2cccc(Br)n2)n(C)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1cc(COCc2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)n(C)n1

Procedure:
The title compound was prepared as described Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.68 mmol) and 2-bromo-6-{[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]methyl}pyridine (205 mg, 0.68 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])=[CH:8][N:9]=1)[CH:5]=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])=[CH:8][N:9]=1)[CH:5]=[N:21][OH:22]
Reactant: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=NO
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-5-((5-fluoro-4-methylpyridin-3-yl)ethynyl)isonicotinaldehyde (385 mg, 1.4 mmol), hydroxylamine hydrochloride (107 mg, 1.54 mmol), and sodium acetate (138 mg, 1.68 mmol) in ethanol (5 mL) was stirred at 40° C. for 30 minutes. The reaction mixture was then evaporated in vacuo, re-dissolved in DCM and methanol and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a pale yellow solid that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([OH:10])=[C:2]([N:1]=[CH:14][C:13]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=2[F:11])[CH:7]=1
Reactant: Nc1cc(Br)c(F)cc1O
Reactant: O=Cc1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1cc(F)c(Br)cc1N=Cc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromo-5-fluorophenol (10.1 g, 49 mmol), 2,4-difluorobenzaldehyde (5.36 mL, 49 mmol) and p-toluenesulfonic acid (100 mg, 0.52 mmol) in toluene (250 mL) was heated to reflux in a Dean-Stark apparatus for 0.5 h and then allowed to cool to ambient temperature. After adding triethylamine (1 mL) the reaction mixture was concentrated under reduced pressure to give the crude compound which was used without further purification. (16.1 g, 99%). 1H-NMR (400 MHz, CDCl3) 6.83 (d, J=10.2, 1H), 6.93 (m, 1H), 7.01 (m, 1H), 7.49 (d, J=7.6, 1H), 8.13 (m, 1H), 8.85 (s, 1H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CNc1cc(F)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(F)cc1N(C)C=O
Temperature: 25 °C
Reaction time: 1.83 h

Procedure:
A mixture of acetic anhydride (26.5 ml) and formic acid (98%, 17.4 ml) was stirred at 50°-60° for 110 minutes and then cooled to ambient temperature. 4'-Fluoro-2'-(methylamino)acetophenone (19.9 g) was added and the mixture stirred overnight at ambient temperature. Water (90 ml) was added and the mixture stirred in an ice/ salt bath. Aqueous sodium hydroxide (specific gravity 1.5, 50 ml) was added dropwise over a period of 30 minutes whilst maintaining the temperature below 30°. The mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-5'-fluoro-N-methylformanilide.