Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8]([O:11][C:12](=O)[CH3:13])(=O)[CH3:9].[CH2:15](Cl)Cl>>[CH3:9][C:8]1[O:11][C:12]([CH2:7][CH2:6][NH2:3])=[CH:13][CH:15]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C)=O
Reactant: ClCCl
Product: Cc1ccc(CCN)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the amine C (1 mol) in CH2Cl2 (approx. 10 ml per 1 g of the starting compound) triethylamine (1.1 mol) and acetic anhydride (1.2 mol) were added. The reaction mixture is stirred at room temperature for 1 h and concentrated on rotary evaporator. The residue is triturated with hexane, filtered, washed with hexane to give a crystalline compound in good yields.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(Cl)Cl.CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:15])=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)=[CH:30][CH:29]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cnc(Cl)nc1-c1cccc(Cl)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(Cl)c1
Yield: 77 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chlorophenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 77% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.61 (s, 1H), 7.56 (d, 2H, J=8.2 Hz), 7.48 (m, 1H), 7.40 (m, 2H), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 2.45 (bs, 8H), 2.27 (s, 3H), 2.24 (s, 3H); MS (ESI): 408.4 [M+H]+, 204.7 [M+2H]2+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][CH2:23][CH:24]=[CH2:25]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:22][CH2:23][CH:24]=[CH2:25])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Yield: 162.6 %

Procedure:
A stirred and cooled (32° C.) mixture of 5.52 g (0.022 mole) of crude 3-(4-fluorophenoxy)-1-azetidine carbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 30 ml of tetrahydrofuran was treated with 1.5 g (0.02 mole) of 3-aminopropylene. The reaction mixture was still exothermic and was stirred for 5 hr as it cooled to ambient temperature. The reaction mixture was diluted with 200 ml of water to produce an oil phase separation. The oil portion was dissolved by extracting with 2×50 ml of benzene. The extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield 8.14 g of orange-red oil. The oil partially crystallized from benzene-ligroin with charcoal treatment, yielding first a reddish oil followed by a crystalline product. The total material was concentrated in vacuo to yield 7.45 g of amber-red oil. This oil solidified and was repeatedly triturated with isopropyl ether until only a red oil residue remained. The isopropyl ether portions were repeatedly cooled to the crystallization of residue, decanted from residue and heated to reduce volume until only a straw colored isopropyl ether solution remained. Upon cooling of this solution the title product crystallized and yielded 2.3 g (42.3%) of white crystalline product, m.p. 92°-94° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][CH:19]([CH:28]([CH3:30])[CH3:29])[C:20]([NH:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:21])[CH:15]=[N:16][CH:17]=3)=[CH:10][N:9](COCC[Si](C)(C)C)[C:6]2=[N:7][CH:8]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>ClCCl>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][CH:19]([CH:28]([CH3:30])[CH3:29])[C:20]([NH:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[O:21])[CH:15]=[N:16][CH:17]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(CN)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(CN)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
To 2-(5-(5-(aminomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 10-1b (211 mg, 0.364 mmol) dissolved in dichlormethane (2.0 ml) was added TFA (2.0 ml, 26.0 mmol). The reaction stirred at room temp for 1.5 hrs, concentrated and the residue dissolved in MeOH (2.0 ml). NaOH (0.255 ml, 2.55 mmol) and ethylenediamine (0.049 ml, 0.728 mmol) were added and the reaction stirred for 2 hrs at room temperature. The reaction was then acidified with trifluoroacetic acid, filtered and purified by RP-HPLC (water:acetonitrile w/0.1% TFA, C-18, 15-50%). The pure fractions concentrated to remove acetonitrile and mixture neutralized with saturated sodium bicarbonate. The product was extracted with ethyl acetate (3×10 mL). The combined organics were then washed with brine, dried with sodium sulfate, filtered and concentrated to afford the product 10-1c (140 mg, 89%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=O)[CH3:5].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:15]([CH3:18])([O-:17])=[O:16].C(N)CN>C(#N)C>[CH2:7]([S:14][C:4]([CH3:5])([CH2:18][N+:15]([O-:17])=[O:16])[CH2:3][CH2:2][OH:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: SCc1ccccc1
Reactant: CC(=O)CCO
Solvent: CC#N
Solvent: NCCN
Product: CC(CCO)(C[N+](=O)[O-])SCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 4-hydroxy-2-butanone (5.00 g), benzylmercaptan (6.65 ml), nitromethane (30.7 ml), ethylenediamine (3.80 ml) and acetonitrile (30 ml) was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound (5.70 g, yield 39%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-:39].[K+].O>C1(C)C=CC=CC=1>[C:27]1([P:26]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: [OH-]
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 109 °C
Reaction time: 0.75 h

Procedure:
2.03 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13 g of toluene and, with ice-bath cooling, admixed with 1.69 g (7.60 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. The mixture was heated at 109° C. for 2.5 h. After cooling to room temperature, the mixture was admixed with 1.09 g (8.74 mmol) of a 45 percent strength potassium hydroxide solution and stirred vigorously at 60° C. for 2 h, 45 min. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60° C. and slowly cooled to 4° C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40° C. 2.44 g (76.8 percent; content: 99.1 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:51]([C:53]1[CH:54]=[C:55]([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:56]=[CH:57][CH:58]=1)#[N:52]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([N:62]3[CH2:61][CH2:60][N:59]([C:55]4[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=4)[C:51]#[N:52])[CH2:64][CH2:63]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
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: N#Cc1cccc(N2CCN(C(=O)c3cncc(CCc4ccccc4)c3)CC2)c1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.4 g, 1.8 mmol) in anhydrous dimethylformamide (3 ml) is treated with HATU (0.7 g, 1.8 mmol) and diisopropylethylamine (0.6 ml, 3.3 mmol). The reaction mixture is stirred 10 mins. at ambient temperature before being treated with a solution of 1-(3-cyanophenyl)piperazine (0.3 g, 1.6 mmol) in dimethylformamide (5 ml). The reaction mixture is stirred at ambient temperature for 18 hours, concentrated under vacuum and the residue partitioned between dichloromethane (2×40 ml) and saturated aqueous sodium bicarbonate (40 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (ethyl acetate) to give the title compound as a yellow oil (0.33 g). 1H NMR (CDCl3, 500 MHz) δ8.82 (s, 1H), 8.61 (s, 1H), 7.90 (s, 1H), 7.58 (m, 2H), 7.39 (m, 4H), 7.16 (m, 3H), 3.95 (br m, 2H), 3.63 (br m, 2H), 3.30 (br m, 4H), EI MS M++H: 393.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([O:14][C:10](=[O:13])/[CH:11]=[CH:12]/[C:6]1[C:5]([NH2:9])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH3:16]
Reactant: Nc1ccc(Br)nc1I
Reactant: C=CC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1nc(Br)ccc1N
Temperature: 80 °C

Procedure:
15.5 g 6-Bromo-2-iodo-pyridin-3-ylamine, 5.9 ml ethyl acrylate, 2.72 g triphenylphosphine and 28.75 ml triethylamine were dissolved in 90 ml acetonitrile. An argon stream was bubbled through the reaction mixture for 10 minutes then 2.33 g palladium(II)acetate were added and the reaction mixture stirred at 80° C. The reaction mixture was filtered hot trough a pad of celite then the solvent was removed in vacuo. The residue was purified by chromatography on silica gel to obtain 10.2 g (E)-3-(3-Amino-6-bromo-pyridin-2-yl)-acrylic acid ethyl ester.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:8]([O:10]C)=[O:9])[CH3:3].C1COCC1.[OH-].[Na+]>CO>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=1)[C:8]([OH:10])=[O:9])[CH3:1]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Yield: 95 %

Procedure:
To a solution of methyl 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate (37 g) in a 1:1 mixture of THF:methanol (300 mL) was added 4M sodium hydroxide solution (150 mL). The mixture was refluxed for 45 minutes, following which the organics were removed in vacuo. The aqueous was acidified to pH4 with hydrochloric acid (2M), and extracted with ethyl acetate. The organics were combined, washed with water and brine, dried (MgSO4) and concentrated in vacuo to give the desired compound (33.5 g), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:32]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:30])(=[O:31])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:32])=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2N)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
The product of Example 78C (510 mg, 0.879 mmol), iron powder (302 mg, 5.40 mmol), and ammonium chloride (308 mg, 5.76 mmol) in water (4 mL) and ethanol (8 mL) were heated at 80° for 40 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide the title compound as a white foam (436 mg, 90%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35])#[N:28]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:34]([F:35])=[C:29]([C:27]#[N:28])[CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)c(C#N)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-cyano-4-fluoro-phenylboronic acid, 5-(3-cyano-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=66%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37])#[CH:28].[Cl:40][C:41]1[N:46]=[C:45](Cl)[C:44]([CH3:48])=[CH:43][N:42]=1>CN(C=O)C.CCOC(C)=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.[Cu]I>[Cl:40][C:41]1[N:46]=[C:45]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:44]([CH3:48])=[CH:43][N:42]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1C
Temperature: 120 °C

Procedure:
PPh3 (31 mg, 0.12 mmol), PdCl2(PPh3)2 (84 mg, 0.12 mmol), Et3N (0.67 mL, 4.8 mmol) and methyl 2-(2-ethynylphenyl)acetate (K1) (0.25 g, 1.4 mmol) were added to a solution of 2,4-dichloro-5-methylpyrimidine (0.20 g, 1.2 mmol) in anhydrous DMF (5.0 mL). The solution was degassed with nitrogen for 10 minutes before the addition of CuI (23 mg, 0.12 mmol). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then diluted with EtOAc (30 mL) and filtered through Celite. The filtrate was evaporated under reduced pressure and the resulting residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-35% EtOAc in petroleum benzine 40-60° C.) to give the title compound K7 as a yellow solid (0.28 g, 78%); 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.46-7.40 (m, 1H), 7.39-7.31 (m, 2H), 3.93 (s, 2H), 3.71 (s, 3H), 2.45 (s, 3H). LCMS-A: rt 5.993 min; m/z 301 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10]>O1CCCC1>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:9]1=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncccc1O
Solvent: C1CCOC1
Product: O=c1[nH]c2ncccc2o1

Procedure:
5.5 g (0.05 mol) of 2-amino-3-hydroxypyridine are introduced into a three-necked flask and the system is placed under argon. 100 ml of anhydrous tetrahydrofuran (THF) are added. 12.15 g (0.075 mol) of 1,1'-carbonyl-diimidazole are then introduced. The mixture is heated to reflux for 5 hours (under argon). The THF is then evaporated off. The residue is taken up with dichloromethane. Washings of the organic phase are performed with NaOH (5%) solution (6×150 ml); the cyclized product passes into the aqueous phase and precipitates at a pH in the region of 5 (by adding 2 N hydrochloric acid solution). The product is filtered off and stored in a desiccator.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([CH:19]=[C:20]([F:22])[F:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.O.[F-:28].[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:15][C:16]([CH2:19][C:20]([F:28])([F:21])[F:22])=[CH:17][N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=C(F)F)s2)CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1
Temperature: 120 °C
Yield: 90 %

Procedure:
To a solution of 1.03 mmol 4-[5-(2,2-difluoro-vinyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in 7.5 dimethylsulphoxide and 0.3 ml water was added 7.18 mmol potassium fluoride and the mixture was heated at 120° C. for 2 h. The mixture was then diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow crystalline solid (yield 90%). MS (m/e): 352.3 (M+H+, 100%).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[Br:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Br:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH3:28])[NH:8][C:7]([C:3]2[O:2][CH:6]=[CH:5][N:4]=2)=[N:9]1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1ncco1
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Yield: 38.1 %

Procedure:
Oxazole-2-carboximidamide hydrochloride (1.28 g, 8.69 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (1.76 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1.35 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20].C(O)C>O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Yield: 99.1 %

Procedure:
A mixture of ethyl 3-(4-fluorobenzoyl)pyruvate (11.3 g, 47.4 mmol), hydrazine monohydrate (2.50 g, 50.0 mmol) and ethanol (50 mL) was heated under reflux for 1 hr. The reaction mixture was cooled and poured into water. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (11.0 g, quantitative) as colorless crystals. 1H NMR (CDCl3) δ: 1.41 (3H, t, J=7.2 Hz), 4.41 (2H, q, J=7.2 Hz), 7.05-7.18 (3H, m), 7.76 (2H, dd, J=8.2, 5.4 Hz), 11.21 (1H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.I[CH:18]([CH:20](I)[CH3:21])[CH3:19].O.O.[Sn](Cl)(Cl)(Cl)Cl>CN(C=O)C.CCO>[CH3:3][O:4][C:5]([C:6]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:21][CH2:20][CH2:18][CH2:19]1)=[O:16]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(I)C(C)I
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(N)cc2)CCCC1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
Sodium hydride (2.8 g, 60% dispersion in mineral oil) was added slowly to a solution of (4-nitro-phenyl)-acetic acid methyl ester (6.0 g, 30.7 mmol) in anhydrous DMF (30 mL) under nitrogen at a temperature in the range of 0° C. to 10° C. After stirring at a temperature in the range of 0° C. to 10° C. for 20 min, diiodobutane (7.86 mL, 61 mmol) was added drop-wise under stirring. After complete addition, the reaction mixture was warmed to a temperature in the range of 15° C. to 40° C. and stirring continued for an additional 3 hours. The reaction was quenched by adding water slowly. The mixture was extracted by ethyl acetate (3×40 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant gummy material was purified by column chromatography over silica gel to afford a pale yellow thick liquid which solidified on standing at a temperature in the range of 15° C. to 40° C. (4.1 g, 54% yield). The solid (3.4 g, 13.6 mmol) was dissolved in anhydrous EtOH and tin chloride dihydrate (13.86 g, 61 mmol) was added slowly under nitrogen. Thereafter, the mixture was heated at 90° C. for 3 hours. After evaporation of volatiles under reduced pressure, the resultant mixture was diluted with ice-water and aqueous sodium hydroxide was added to adjust pH ˜11. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a granular light yellow solid (2.67 g, 88% yield).
Reaction SMILES: [N:1]1[C:2]([C:10]([O-:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Na+].[C:14]([C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH:21]1[CH2:24][NH:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH:21]1[CH2:22][N:23]([C:10]([C:2]2[N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]3[CH:3]=2)=[O:12])[CH2:24]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: O=C([O-])c1cn2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)c2cn3ccccc3n2)C1
Yield: 97.2 %

Procedure:
To a stirred solution of sodium imidazo[1,2-a]pyridine-2-carboxylate (0.19 g, 1.0 mmol), 3-(2-tert-butylphenoxy)azetidine (0.21 g, 0.53 mmol) and DIPEA (0.39 g, 3.0 mmol) in DMF (5.0 mL) was added HBTU (0.76 g, 2.0 mmol) at room temperature. After 1 h the reaction mixture was diluted with ethyl acetate (50 mL) and washed with a 10% K2CO3 solution (3×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, ethyl acetate to 95:5 methanol/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(imidazo[1,2-a]pyridin-2-yl)methanone (0.18 g, 51%) as a white solid.