Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2Cc3ccccc3C2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2Cc3ccccc3C2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.9 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 16a) (91 mg, 0.19 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a beige solid (82 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)(=[O:3])[CH3:2]>C(O)C.O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)NCCNc1ccc(N)cn1
Yield: 43.8 %

Procedure:
A suspension of 2-(2-acetamidoethylamino)-5-nitropyridine (4.0 g, 17.86 mmol) in ethanol-water (3:1, 160 ml) was shaken with 10% palladium on charcoal (400 mg) under an atmosphere of hydrogen for 5 h then filtered through Celite™ and the filtrate concentrated. The residue was subjected to column chromatography (silica, 3-10% methanol--CH2Cl2) to afford the title compound (1.52 g) as an air-sensitive deep mauve gum. MS (ES+) 195 (MH+). δH (d6DMSO) 7.89 (1H, br s), 7.45 (1H, d, J 2.5 Hz), 6.82 (1H, dd, J 2.5, 8.7 Hz), 6.28 (1H, d, J 8.7 Hz), 5,60 (1H, br s), 4.34 (2H, br s), 3.16 (4H, m) and 1.79 (3H, s).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]=[O:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[CH:9]=[C:8]2[CH:14]=[O:15]
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Reactant: ClCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(C=O)cn2CCCCCl
Reaction time: 0.5 h

Procedure:
To a stirred mixture of powdered potassium hydroxide in methyl sulfoxide is added dropwise a solution of 5-methoxyindole-3-carboxaldehyde in methyl sulfoxide. The mixture is stirred for 30 min and 1-bromo-4-chlorobutane is added dropwise. The mixture is stirred for 1 h and partitioned between ethyl acetate and water. The combined organic extracts are washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[BH4-].[Na+]>C(O)C.O.C(O)(=O)C>[OH:12][CH2:3][CH:4]1[O:10][CH:8]2[CH2:7][CH:6]([CH2:11][CH:1]([OH:2])[CH2:9]2)[O:5]1
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: OCC1OC2CC(O)CC(C2)O1
Reaction time: 2 h

Procedure:
A solution of 340 mg of 2,5,11-trioxatricyclo[4,3,1,14,8 ] undecan-3-one of the formula Ia in 10 ml of absolute ethanol is treated at room temperature with 150 mg of sodium borohydride and the mixture is stirred for 2 hours. The reaction mixture is diluted with 10 ml of water, the pH adjusted to 8 with a few drops of glacial acetic acid and the resulting solution is concentrated under reduced pressure to about 3 ml. The concentrate is extracted three times with altogether 100 ml of methylene chloride, the combined extracts are dried with sodium sulphate and the solvent is distilled off to give 3-hydroxymethyl-2,4-dioxabicyclo[3,3,1]nonan-7-ol of the formula IIa, which melts at 146°-149°C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:33]([O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]I)=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC>C1COCC1.CCCCCC.C(OCC)(=O)C.O>[CH2:33]([O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:45][C@@H:19]2[CH2:18][C@@H:17]([C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[O:21][C:20]2=[O:22])=[CH:47][CH:48]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Reactant: ICc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
In analogy with Example 5d), 5.2 g (16.7 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-dihydrofuran-2-one [(preparation, see Example 12a)], dissolved in 50 ml of THF, are deprotonated, at -70° C., with 33.4 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated, at -75° C. for 1 h, with 5.2 g (16.07 mmol) of 4-benzyloxybenzyl iodide [preparation, see Example 1d)] in 15 ml of THF. Treating, at -75° C., with 6.2 ml (83.02 mmol) of propionic acid and water, and further working up, affords the title compound after column chromatography (SiO2, hexane/ethyl acetate: 4/1). TLC Rf (hexane/ethyl acetate: 4/1)=0.27; tRet (II)=20.41 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH2:13][CH:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Se](=O)=O.C(O)CCCC>CCOCC>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)CCOc1cccc2c1C(=O)CC(c1nnn[nH]1)O2
Agent: O=[Se]=O
Solvent: CCOCC
Solvent: CCCCCO
Product: CC(C)CCOc1cccc2oc(-c3nnn[nH]3)cc(=O)c12

Procedure:
A solution of 0.3 parts of 5-[2,3-dihydro-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole and 0.44 parts of selenium dioxide in 20 parts of amyl alcohol was heated under gentle reflux for 8 hours. After cooling, ether was added to the reaction mixture, the resulting precipitate was filtered off and the filtrate was evaporated to give a solid which was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60°C) giving 5-[5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole as colourless prisms, m.p. 165°-166°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3C4([C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[NH:35]C4=O)COC3=CC=2ON=1.Br.BrCC1C=CC=CN=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:37][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:35]=1)[C:10]3=[O:18]
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1ccccn1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(pyridin-2-ylmethyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one was obtained (67%) as a colorless solid: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.63 (dd, J=7.8, 7.8 Hz, 1H), 7.32-7.09 (m, 3H), 7.0 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.65 (d, J=7.8 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=7.8, 2.1 Hz, 1H), 5.18 (d, J=15.9 Hz, 1H), 4.98 (d, J=15.9 Hz, 1H), 5.00 (d, J=8.7 Hz, 1H), 4.72 (d, J=8.7 Hz, 1H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 162.1, 161.5, 155.5, 149.4, 142.1, 137.0, 132.3, 128.7, 123.7, 123.6, 123.4, 122.7, 121.5, 120.8, 109.4, 107.5, 96.5, 80.4, 57.6, 55.5, 46.0; MS (ES+) m/z 359.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([S:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Sc2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Sc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenylsulfanyl-pyridine.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:16][N:15]([C:17]2[C:31]([F:32])=[CH:30][C:20]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22])=[C:19]([F:33])[CH:18]=2)[CH2:14]1)#[N:11].O.[OH-].[NH4+]>C(#N)C>[C:10]([CH2:12][C:13]1([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:16][N:15]([C:17]2[C:31]([F:32])=[CH:30][C:20]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:27])([F:28])[F:26])=[O:22])=[C:19]([F:33])[CH:18]=2)[CH2:14]1)#[N:11]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C(F)(F)F
Agent: FB(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron trifluoride etherate (0.051 mL, 0.40 mmol) was added to a solution of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide in acetonitrile (1.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 3 h. (LCMS (M+H)+: m/z=561.3). Then the mixture was cooled to 0° C., water (0.13 mL) was added. After 30 min, 5.0 M ammonium hydroxide in water (0.2 mL, 1 mmol) was added slowly at 0° C. over 5 min. The reaction mixture was stirred at room temperature overnight, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=531.0. 1H NMR (400 MHz, DMSO-d6): δ 12.62 (br, 1H), 9.07 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 8.51 (dd, J=8.8, 1.2 Hz, 1H), 7.78 (br, 1H), 7.35 (dd, J=12.6, 6.5 Hz, 1H), 7.23 (d, J=1.9 Hz, 1H), 6.65 (dd, J=11.9, 7.3 Hz, 1H), 4.76 (m, 1H), 4.70 (d, J=9.3 Hz, 2H), 4.44 (d, J=9.2 Hz, 2H), 3.76 (s, 2H), 1.30 (d, J=7.1 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:21]O>>[CH3:21][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1Oc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (2.0 ml, 28.0 mmol) was added dropwise to a solution of 2-phenoxybenzoic acid (5.0 g, 23.3 mmol) in methanol (70 ml). The reaction mixture was stirred at 70° C. for 3 hours. The solvent was removed in vauco. The crude product was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([N+:12]([O-])=O)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Agent: [Pd]
Solvent: CCO
Product: Cn1nc(N)cc1CN1CCC1

Procedure:
Following Example 156f, 10% palladium on carbon (30% wet, 480 mg dry weight) and a solution of 200a (1.6 g, 8 mmol) in ethanol (50 mL) were reacted. The reaction mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×30 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford 5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-amine 200b (quantitative) as yellow oil. MS (ESI+) m/z 167.1 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:15])=[C:7]([CH:14]=1)[CH2:8][NH:9][C:10](=[O:13])[O:11][CH3:12].[C-:16]#[N:17].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Cl:15][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][C:16]#[N:17])=[CH:14][C:7]=1[CH2:8][NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: [C-]#N
Reactant: COC(=O)NCc1cc(CBr)ccc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(CC#N)ccc1Cl
Reaction time: 1 h
Yield: 69.3 %

Procedure:
2.3 g of the methyl N-(5-bromomethyl-2-chlorobenzyl)carbamate obtained in Reference Example 3 was dissolved in 20 ml of N,N-dimethylformamide, and 0.43 g of sodium cyanide was added thereto at 0° C. Stirring was carried out at 0° C. for 1 hour, and stirring was carried out further for 4 hours at room temperature, then water was added to the reaction mixture, extraction with ethyl acetate was carried out, and the organic solvent was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with hexane to obtain 1.3 g of methyl N-(2-chloro-5-cyanomethylbenzyl)carbamate as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH2:38][CH2:36][OH:37])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:32]([CH3:33])=[C:31]([F:34])[CH:30]=2)[CH2:29][CH2:28]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: NCCO
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNCCO)CC2)c1=O

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 259d, 5 g) and ethanolamine (6.1 mL) were heated at 100° C. in dioxane (20 mL) in a sealed tube for 16 h. Purification of the cooled solution by preparative HPLC (Xterra column, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title product (2.95 g) after solvent removal and trituration with isohexane/diethyl ether (1:1 80 mL)
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]([CH:20]([CH3:22])[CH3:21])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([CH:20]([CH3:21])[CH3:22])[N:3]=1
Reactant: CCOC(=O)C1=C(c2ccc(F)cc2)N=C(N)NC1C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nc(N)nc1C(C)C
Yield: 96 %

Procedure:
Ethyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate (22.6 g) was dissolved in toluene (150 ml) and heated until a solution was obtained. Manganese dioxide (18.8 g) was added as a slurry in toluene (150 ml) and the mixture refluxed under azeotropic conditions for 6 hours until conversion was complete. A small amount of water was collected in the Dean and Stark trap. The slurry was filtered and the solvents removed by evaporation under reduced pressure to give ethyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate as a crystalline solid in 96% yield.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8]C)=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:11](Cl)([CH3:14])([CH3:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].ClCCl>CCOCC.O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:2]=1[CH:1]=[O:10]
Reactant: CC(C)(C)Cl
Reactant: COc1ccccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 40.3 %

Procedure:
To an ice-cold stirred mixture of o-anisaldehyde (50 ml, 326 mmol) and tert-butylchloride (80 ml, 735 mmol) was added aluminum chloride (40 g, 300 mmol). The reaction mixture became thick. Dry dichloromethane (100 ml) and aluminum chloride (60 g, 450 mmol) were added carefully with cooling. Once the reaction became less vigorous the reaction mixture was stirred at room temperature for 2.25 h. Ice (50 g) and subsequently ice-cold water (100 ml) were added carefully and the mixture was left to stir for 20 min. water (250 ml) and ether (550 ml) were added. The aqueous layer was removed and the organic layer was washed with water (3×250 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by distillation under reduced pressure and the fraction (b.p. 80°-86° C., 0.55-0.65 mm Hg) collected to yield (6) as a colourless oil (23.4 g, 40%). Preparation of 2-methoxy-5-tert-butylbenzaldehyde (5) To a solution of (6) (5.01 g, 28.1 mmol) in dry DMF (25 ml) was added a solution of tetra-n-butylammonium hydroxide in methanol (1.0M, 28.5 ml, 28.5 mmol). Methyl iodide (25 ml, 399 mmol) was added and the solution was stirred ac reflux for 1.5 h and then allowed to cool. Ether (250 ml) and water (250 ml) were added. The aqueous layer was removed and the organic layer was washed with water (3×250 ml), brine (250 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/petroleum ether [60/80]; 4:1) to yield a colourless oil of (5) (4.36 g, 81%); δH (CDCl3) 1.29 (9 H, s, tert-butyl), 3.88 (3 H, s, OCH3), 6.95 (1 H, d, J=8.8 Hz, H3), 7.56 (1 H, dd, J=8.8, 2,7 Hz, H4), 7.83 (1 H, d, J=2.7 Hz, H6), and 10.44 (1 H, s, CHO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[O:5][C:6]3[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:8](=[O:10])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1Oc1ccccc1C(=O)O
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc2c(=O)c3ccccc3oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a suspension of 2-(2-methoxy-phenoxy)-benzoic acid (16.8 g, 68.8 mmol) in methylene chloride (100 mL) at 0° C. was added dropwise trifluoroacetic anhydride (12.7 mL, 89.4 mmol), and the reaction was stirred for 30 min at 0° C. At that time, boron trifluoride diethyl etherate (1.29 mL, 10.3 mmol) was added dropwise. The reaction was stirred overnight at rt, poured into H2O, and washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated to give 12.4 g (54.8 mmol) of Compound 2a.
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=[C:7]2[CH:6]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)[O:39][N:38]=2)[CH:33]=[CH:34][C:35]=1[CH3:36]>ClCCl.N1C=CC=CC=1>[CH3:36][C:35]1[CH:34]=[CH:33][C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:43][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:45]3)[O:39][N:38]=2)=[CH:31][C:30]=1[NH:29][C:14]([C:11]1[N:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][C:2](=[O:1])[CH3:17])=[CH:6][C:7]2=[N:13][CH:12]=1)=[O:16]
Reactant: CC(=O)CCc1ccn2c(C(=O)O)cnc2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(CCC(C)=O)ccn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (86) (40 mg, 0.172 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (16 uL, 0.189 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuum. Methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (25 mg, 0.086 mmol) and anhydrous pyridine (1 mL) were added to the acid chloride. The reaction was stirred to room temperature under Argon for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(4-methyl-3-(7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F73). 1H NMR (400 MHz, d6-DMSO) δ 10.24 (s, 1H), 9.44-9.41 (m, 1H), 8.73 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.85 (dd, J=1.6, 8.0 Hz, 1H), 7.73 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.32-7.29 (m, 1H), 4.39-4.35 (m, 2H), 4.31-4.24 (m, 1H), 4.21-4.17 (m, 2H), 3.59 (s, 3H), 2.98-2.91 (m, 4H), 2.37 (s, 3H), 2.13 (s, 3H). MS m/z 503.2 (M+1)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH2:11])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:19](=[O:21])[CH3:20])=[N:8][CH:9]=1
Reactant: NCc1ccc(F)cn1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
In a round-bottomed flask, (5-fluoropyridin-2-yl)methylamine dihydrochloride (800 mg, 4.0 mmol) was suspended in THF (15 ml). The suspension was cooled to 0° C. and triethylamine (1.75 ml, 12.6 mmol) was added followed by dropwise addition of acetyl chloride (0.30 ml, 4.22 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 654 mg (97%) of N-(5-fluoro-pyridin-2-ylmethyl)-acetamide as a light brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[S:13]([Cl:12])(=[O:15])=[O:14])[CH3:2]
Reactant: CCc1cc2ccccc2o1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1oc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-Ethylbenzo[b]furan-3-sulfonyl chloride was prepared by the method of Example 82C with 2-ethylbenzo[b]furan (6.9 mmols, 1.0 g), chlorosulfonic acid (8.9 mmols, 0.6 ml) phosphorous oxychloride (21 mmols, 1.9 ml), phosphorous pentachloride (6.9 mmols, 1.4 g) and CH2Cl2 (10 ml). Flash chromatography (2% ethyl acetate/hexanes) provided 0.71 g (42%) of an orange solid.