Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:29]2[CH:34]=C[CH:32]=[CH:31][N:30]=2)[N:6]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:4]=2[NH:3]1.[N:35]1C=CN=CC=1C(O)=O>>[F:1][C:2]1([C:29]2[CH:34]=[N:35][CH:32]=[CH:31][N:30]=2)[N:6]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:4]=2[NH:3]1
Reactant: O=C(O)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3c(c2)N(Oc2cccnc2)C(F)(c2ccccn2)N3)cn1
Product: CS(=O)(=O)c1ccc(Oc2ccc3c(c2)N(Oc2cccnc2)C(F)(c2cnccn2)N3)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-pyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 211 and pyrazine-2-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][C:7]([C:10]1[CH:11]=[C:12]([CH:21]=[C:22]2[N:26]([CH3:27])[C:25](SC)=[N:24][C:23]2=[O:30])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:9])[CH3:8].CC(C)([O-])C.[K+].O>C(O)C>[CH3:6][C:7]([C:10]1[CH:11]=[C:12]([CH:21]=[C:22]2[N:26]([CH3:27])[C:25]([NH:4][C:3]([NH2:5])=[NH:2])=[N:24][C:23]2=[O:30])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:9])[CH3:8]
Reactant: N=C(N)N
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN1C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N=C1NC(=N)N
Reaction time: 24 h
Yield: 20.2 %

Procedure:
Guanidine hydrochloride (1.7 g, 18 mmoles) is added to a mixture of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene)-1,5-dihydro-1-methyl-2-(methylthio)-4-H-imidazole-4-one (3.0 g, 8 mmoles) and potassium tert-butoxide (1.5 g, 13 mmoles) in ethanol (50 mL), and stirred and heated to reflux under an inert atmosphere. After 24 hours the mixture is allowed to cool, and is poured into water (300 mL) and stirred. After half an hour the product is filtered off, rinsed three times with water and dried. Recrystallization from ethanol/DMF gave pure 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene)-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-guanidine (0.6 g), mp 288°-290° C. (dec).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[C:13]([NH2:22])=[C:14]([NH2:21])[C:15]([F:20])=[C:16]([F:19])[C:17]=1[F:18]>>[F:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]2[C:13]=1[NH:22][C:2](=[O:4])[C:1](=[O:8])[NH:21]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1c(N)c(F)c(F)c(F)c1F
Product: O=c1[nH]c2c(F)c(F)c(F)c(F)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound (Allison, et al., J. Fluorine Chem. 1: 59 (1971)) was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.86 mL, 4.1 mmol) and 3,4,5,6-tetrafluoro-1,2-diaminobenzene (380 mg, 2.11 mmol) was heated to reflux with stirring under N2 for 8 h. The reaction was cooled to room temperature and a small amount of purple precipitate was observed. The excess diethyl oxalate was evaporated and the resulting solid was suspended in 20 ml hexanes, vacuum filtered and the solid rinsed with hexanes (20 mL) and ethyl acetate (10 mL). The solid was air dried to yield 244.8 mg (49.9%). mp 330°-331° C. (lit. ca. 300° C. dec.). 1H NMR (d6-DMSO) δ 12.33 (br s, NH). 19F NMR (C6F6 external standard, δ -162.9), δ -157.7(m), -167.9(m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1C2N(C=CN=2)C=CC=1)C1C=CC=CC=1>>[CH3:1][O:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(COc2cccc3nccn23)cc1
Agent: c1ccc(COc2cccn3ccnc23)cc1
Product: COc1cccc2nccn12

Procedure:
5-benzyloxyimidazo[1,2-a]pyridine and 8-benzyloxyimidazo[1,2-a]pyridine.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[N:7]([N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25]C(C)(C)C)=O)[CH2:19][CH2:18]1.[C:30]1([CH2:36]C(Cl)=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([CH2:36][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][N:3]3[CH2:4][CH2:5][CH2:6][N:7]4[N:8]=[C:9]5[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]5)=[C:15]4[C:2]3=[O:1])[CH2:22][CH2:21]2)=[O:25])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCn3nc4ccccc4c3C2=O)CC1
Product: O=C(Cc1ccccc1)N1CCC(CN2CCCn3nc4ccccc4c3C2=O)CC1

Procedure:
The product was prepared using the method described in example 2e), using tert-butyl 4-[(1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-b]indazol-2(3H)-yl)methyl]piperidine-1-carboxylate (example 16a) and benzeneacetyl chloride as reagents. The product was purified by flash chromatography on silica gel, using the mixture chlorofom:methanol in a ratio of 9:1 as eluent. Thus, 141 mg of 2-{[1-(phenylacetyl)piperidin-4-yl]methyl}-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-b]indazol-1-one were obtained.
Reaction SMILES: NCC[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[Na].C([O-])(=O)C.[Na+].C(NCCC1C=CC(C(O)=O)=CC=1)(=O)C.[OH-].[Na+].ClC1C=C(C=CC=1)CCl.Cl>O.CC(C)=O>[C:8]([OH:10])(=[O:9])[C:7]1[CH:11]=[CH:12][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1ccc(C(=O)O)cc1
Agent: CC(=O)NCCc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1
Reaction time: 1 h

Procedure:
50 ml of a 1-molar solution of 4-(2-aminoethyl)-benzoic acid-sodium, which contained, in addition, 0.05 mole of sodium acetate and which had been prepared by saponification of 4-(2-acetylaminoethyl)-benzoic acid with sodium hydroxide solution, was combined with 50 ml of acetone and then with the solution of 9 g of 3-chlorobenzyl chloride in a small amount of acetone. The whole was stirred for about 1 hour, water and hydrochloric acid were added, filtered off with suction and the product was recrystallized from a mixture of water and isopropanol. The 4-(2-<3-chloro-benzamido>-ethyl)-benzoic acid obtained was found to melt at 200° to 202° C.
Reaction SMILES: [CH2:1]([O:17][CH:18]([CH:20]1[CH2:22][O:21]1)[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>C(O)(=O)C>[CH2:1]([O:17][CH:18]([CH3:19])[CH:20]([OH:30])[CH2:22][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCOC(C)C1CO1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCOC(C)C(O)CO
Reaction time: 0.5 h
Yield: 7520.1 %

Procedure:
A mixture of 30 g of [1-(hexadecyloxy)ethyl]oxirane, 0.2 g of p-toluenesulfonic acid and 200 ml of glacial acetic acid was refluxed for 4.5 hours, then the acetic acid was removed. Toluene was added and removed. The residue was dissolved in 225 ml of methanol and 13.44 g of sodium hydroxide in 14 ml of water was added. This mixture was stirred 1/2 hour, the solvent removed and the residue extracted twice with ether. The ether extracts were combined, washed with brine, dried and the solvent removed. The resulting oil was diluted via a Kugelrohr (200° C., 0.5 mm), giving 28.87 g of the desired compound as a white sticky solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].P([O-])([O-])[O-]>>[CH2:12]([O:11][P:10]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: BrCc1cccc(Br)c1
Reactant: CCOP(OCC)OCC
Agent: [O-]P([O-])[O-]
Product: CCOP(=O)(Cc1cccc(Br)c1)OCC
Temperature: 130 °C
Yield: 98.3 %

Procedure:
To 1-bromo-3-(bromomethyl)benzene (100 g, 400 mmol) in a 500 mL round-bottom flask under nitrogen was added triethyl phosphite (69.6 mL, 400 mmol) and the solution was heated to 130° C. The apparatus was set up ready for distillation. As the heating block reached 130° C. the mixture began to reflux and a large volume of colourless liquid was allowed to distil off. Analysis of the reaction by hplc after 40 min showed some starting material so another 0.5 eq of the phosphite was added and heating with distillation continued. The reaction was then heated under vacuum: the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar, gradually going down to 0.5 mbar). This gave a colorless oil 120.8 g. HPLC 2.20 min (ret time), 97%; LC-MS m/z 307, 309 (M+H)+, 1.01 min (ret time).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([Cl:22])[N:12]=[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:14]=2[N:15]=1)(=O)C.[OH-].[Li+]>C1COCC1.O>[Cl:22][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:14]2[N:15]=[C:6]([CH2:5][OH:4])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: CC(=O)OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl acetate 5 (2.3 g, 7.1 mmol) in THF (50 mL) was added a 1M solution of lithium hydroxide in water (26 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted three times with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanol 6. LCMS (MH)+=281.1. 1H-NMR (400 MHz, CDCl3, ppm): 8.09 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=8.8 Hz), 4.91 (2H, s), 4.56 (4H, br), 3.91 (4H, t), 2.86 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH:17]2[CH2:19][CH2:18]2)=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH:17]2[CH2:19][CH2:18]2)=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:20][N:21]([CH3:23])[CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC1CC1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC1CC1

Procedure:
Ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate (21.8 g, 77 mmol) was dissolved in 150 mL of DMF-DMA. The mixture was heated to reflux for 2 hours. Evaporation gave a yellow solid which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ: 7.69 (s, 1H), 7.39 (s, 1H), 7.29 (dd, J=2.4, 8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 3.92 (q, J=6.8 Hz, 2H), 3.69-3.65 (m, 1H), 3.10 (br, 6H), 0.88 (t, J=6.8 Hz, 3H), 0.77-0.71 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][N:12]1[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:17]2[CH2:16][CH:15]3[CH2:11][N:12]([C:19]4[CH:20]=[CH:21][C:22]5=[N:27][N:26]=[C:25]([C:28]([F:31])([F:29])[F:30])[N:23]5[N:24]=4)[CH2:13][CH:14]3[CH2:18]2)=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Temperature: 70 °C
Yield: 41.7 %

Procedure:
1-Fluoro-4-isocyanatobenzene (0.026 g, 0.19 mmol) was added to a suspension of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.05 g, 0.17 mmol) in toluene (1.5 mL). The reaction mixture was heated at 70° C. for 1 hour and evaporated to give an involatile residue. The residue was purified by hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% trifluoroacetic acid) and acetonitrile as eluents to give N-(4-fluorophenyl)-2-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxamide (0.0309 g, 42%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][OH:27])[C:20]=4[CH:28]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][S:30]([CH3:29])(=[O:32])=[O:31])[C:20]=4[CH:28]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCO)c4c2)CCC3)n1
Solvent: c1ccncc1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCOS(C)(=O)=O)c4c2)CCC3)n1
Yield: 57.8 %

Procedure:
Stir a solution of 3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol (Example 56; 257 mg, 0.67 mmol) and methanesulfonyl chloride (200 μl, 2.06 mmol) in dry pyridine (5 mL) for 2 h. Remove the pyridine in vacuo and dissolve the residue in excess chloroform. Wash the organic layer with saturated sodium bicarbonate and dry over sodium sulfate. Filter and concentrate in vacuo to give the product as a white foam (175 mg, 55%). MS ES+ m/e 452.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[CH2:10]([N:17]1[CH2:25][C:24]2([C:26]([O:28][CH3:29])=[O:27])[CH:19]([C:20](=[O:36])[CH2:21][CH2:22][CH:23]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[CH2:10]([N:17]1[CH2:25][C:24]2([C:26]([O:28][CH3:29])=[O:27])[CH:19]([C:20]([OH:36])([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)[CH2:21][CH2:22][CH:23]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C)cc1)CCC2c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
76.2 g (0.445 mol) of 4-bromotoluene and 10.8 g (0.445 mol) of magnesium turnings in 500 cm3 of diethyl ether are heated at reflux for one hour. After cooling to a temperature in the region of 5° C., a solution of 124.65 g (0.343 mol) of levorotatory enantiomer methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenylperhydroisoindole-3a-carboxylate in 500 cm3 of toluene is added. The reaction mixture is stirred for one hour at a temperature in the region of 20° C. and then hydrolyzed with 450 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase is separated by settling and extracted with two times 500 cm3 of ethyl acetate. The organic phases are combined, washed successively with 100 cm3 of distilled water and 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane/ethyl acetate (95/5 and then 80/20 by volume) mixtures, 135.9 g (87%) of the levorotatory enantiomer of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4-methylphenyl)-4-phenylperhydroisoindole-3a-carboxylate are obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([NH2:17])[CH:10]=1>C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([NH:17][C:5](=[O:7])[CH3:6])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1nc(N)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1nc(Cl)cc(NC(C)=O)n1
Temperature: 135 °C
Yield: 120.4 %

Procedure:
Acetic anhydride (10.4 ml, 0.11 mol) was added to 6-chloro-2-(methylthio)pyrimidin-4-amine (2.5 g, 0.01 mol) and the reaction mixture was refluxed at 135° C. for 5 hr. The reaction mixture was cooled to room temperature and basified to pH 7 with saturated sodium bicarbonate solution (20 ml). The mixture was partitioned between EtOAc and water, the organic layer was washed with water and brine, dried over MgSO4 and concentrated to give the title compound (2.62 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Br[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1.CC(C)([O-])C.[Na+].C1(P(C2C=C(C)C=C(C)C=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=C(C)C=C(C)C=2)C2C=C(C)C=C(C)C=2)C=C(C)C=C(C)C=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccn3nc(N)nc23)c1
Reactant: Cc1cc(Br)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccc3ccccc3c2-c2c(P(c3cc(C)cc(C)c3)c3cc(C)cc(C)c3)ccc3ccccc23)c1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cccn3nc(Nc4ccnc(C)c4)nc23)c1
Temperature: 110 °C
Yield: 38.6 %

Procedure:
A suspension of 8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.150 g, 0.625 mmol, 1 equiv), 4-bromo-2-methylpyridine (0.160 g, 0.935 mmol, 1.5 equiv), tris(dibenzylideneacetone)dipalladium (0) (27.5 mg, 0.03 mmol, 0.05 equiv), sodium tert-butoxide (0.90 g, 0.94 mmol, 1.5 equiv), and 2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl (38.9 mg, 0.625 mmol, 0.1 equiv) in toluene (2 mL) was purged with nitrogen for 15 min. The reaction mixture was heated at 110° C. by microwave for 10 min. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered through celite. The filtrate was then washed with brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded 8-(3-methoxyphenyl)-N-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (80 mg, 39%). LCMS (ESI) m/z: 332.1; 1H NMR (400 MHz, DMSO-d6) δ: 10.45 (br s, 1H), 8.81 (dd, J=6.4, 0.8 Hz, 1H), 8.23 (d, J=6.0 Hz, 1H), 7.88 (dd, J=6.8, 0.8 Hz, 1H), 7.74 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.54 (dd, J=6.0, 2.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.15 (t, J=6.8 Hz, 1H), 7.00 (dd, J=8.0, 2.4 Hz, 1H), 3.83 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:27][CH2:26][CH:25]([C:19]4[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1ccc(C2CCNCC2)cc1OC
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1OC

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3,4-dimethoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 82% overall yield. FDMS m/e=410 (M+ of free base). α[D]589 =-11.84 (c=0.46, methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7](=O)[C:6](=O)[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.[CH2:32]([NH2:35])[CH2:33][NH2:34].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>COCCOCCOC>[CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7]3[N:35]=[CH:32][CH:33]=[N:34][C:6]=3[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15]
Reactant: NCCN
Reactant: CC1C(C)(C)C2=C(C(=O)C(=O)CC2)C1(C)C
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: COCCOCCOC
Product: CC1C(C)(C)C2=C(c3nccnc3CC2)C1(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione is first prepared with 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF) via oxidation with (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione (10 g, 0.04 mol), ethylene diamine (NH2CH2CH2NH2) (2.5 g, 0.04 mol), and diglyme (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The reaction mixture is then cooled to 25° C. and further oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 g, 0.045 mol) for another 8 hours. The crude mass is washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Diglyme is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 7,7,8,9,9-pentamethyl-5,7,8,9-tetrahydro-6H-cyclopenta[f]quinoxaline (˜10 g) is obtained.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH3:10].C([O:24][C:25](=O)[C@H:26]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.O>[C:13]([O:12][C:9](=[O:11])[CH2:10][C:25](=[O:24])[C@@H:26]([N:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -53 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution (2.0M) (24 ml, 48 mmol) of LDA in heptane, THF and ethyl benzene was dissolved in 64 ml of anhydrous THF, and the mixed solution was cooled to −53° C. in an argon atmosphere. To this solution was added dropwise a solution of 5.8 g (50 mmols) of tert-butyl acetate in 12 ml of THF for approximately 15 minutes, while maintaining the temperature of from −45° C. to −50° C. After the completion of the dropwise addition, the mixture was stirred at −53° C. for 1 hour. Subsequently, a solution of 7.2 g (15 mmols, purity 90%) of N,N-dibenzyl-L-phenylalanine benzyl ester (Ia) in 8 ml of THF was added dropwise thereto for approximately 15 minutes while maintaining the temperature at from −48° C. to −52° C. After the completion of the dropwise addition, the reaction temperature was raised to −5° C. After three hours, a solution of 16.5 g of citric acid in 50 ml of water was added to the reaction solution to stop the reaction. The resulting mixture was extracted twice with ethyl acetate (100 ml and 50 ml), and the organic layer was washed with 20 ml of 10% citric acid, with 10 ml of a saturated aqueous solution of sodium chloride, with 5% sodium hydrogencarbonate aqueous solution (20 ml×4) and with 10 ml of a saturated aqueous solution of sodium chloride in this order. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The concentrate was purified through silica-gel column chromatography (eluent-mixture of n-hexane and ethyl acetate at a ratio of 4:1) to give 6.09 g (13.7 mmol) of the above-mentioned compound (IIa).