Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Cl:18])[CH:12]=2)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH2:19][CH2:20][CH2:21][SH:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Cl:18])[CH:12]=2)[S:22][CH2:21][CH2:20][NH2:19])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCCS
Reactant: Cc1ccc(B(O)c2ccc(C)c(Cl)c2)cc1Cl
Solvent: CCO
Product: Cc1ccc(B(SCCN)c2ccc(C)c(Cl)c2)cc1Cl
Yield: 97.5 %

Procedure:
di(3-Chloro-4-methylphenyl)borinic acid (44 mg) and 2-aminoethanethiol (35 mg) were reacted in ethanol (1 mL) to give the title compound (52 mg).
Reaction SMILES: [CH3:1][C:2]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3]1.Cl.[CH3:11][NH:12][NH2:13]>CCO.O1CCOCC1>[CH3:11][N:12]1[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[CH:6][C:7]([NH2:8])=[N:13]1
Reactant: CNN
Reactant: CC1(C(=O)CC#N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cn1nc(N)cc1C1(C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (1.0 g, 8.1 mmol) in EtOH (10 mL) is added 4N HCl in Dioxane (10 mL). The mixture is stirred at room temperature for 16 hour. Concentrated under reduced pressure, the residue is dissolved in MeOH (40 mL) and treated with methylhydrazine (0.56 g, 12.2 mmol). The mixture is heated at 80° C. for 16 h. The solution is then concentrated in vacuo and the residue is purified by HPLC give product. MS (ESI) m/z 152.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:34])[CH2:9][C:10]2[N:11](C(OC(C)(C)C)=O)[C@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:21]1([C@H:12]2[C@@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:14][C:10]([CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:34])=[N:11]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C(CC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To a cold (0° C.) solution of 257 (458 mg, 1.0 mmol) in dichloromethane (25 mL) is added TFA (1.5 mL). The reaction mixture is stirred for 20 min. at 0° C., and at RT for 30 min. The solution is poured into cold sat. sodium bicarbonate solution, and the mixture extracted with EtOAc. The organic layer is separated, dried (MgSO4), and filtered. The filtrate is rotary evaporated, and the residue is recrystallized from Et2O to give 170 mg of the product 258. 1H NMR (CDCl3) δ 10.60-8.80 (bs, 1 H), 8.00-7.80 (m, 2 H), 7.20-7.00 (m, 9 H), 7.00-6.85 (m, 4 H), 5.50 (bs, 1 H), 5.30 (s, 2 H); MS: m/z 359 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23](Br)[CH:22]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([F:20])[CH:10]=2)[N:3]=1.[CH3:29][N:30]([CH3:33])C=O>C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:9]3[CH:29]=[N:30][CH:33]=[C:11]([F:20])[CH:10]=3)[CH:22]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([F:20])[CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)(F)F)c(F)c2)(c2ccc(F)c(Br)c2)N=C1N
Reactant: CN(C)C=O
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CN1C(=O)C(c2ccc(OC(F)(F)F)c(F)c2)(c2ccc(F)c(-c3cncc(F)c3)c2)N=C1N
Temperature: 150 °C
Yield: 74 %

Procedure:
A mixture of 2-amino-5-(3-bromo-4-fluorophenyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-methyl-3,5-dihydroimidazol-4-one (0.17 g, 0.366 mmol), 5-fluorpyridin-3-yl-tri(n-butyl)stannate (0.212 g, 0.55 mmol) and bis(triphenylphosphino)palladium(II) chloride (0.013 g, 0.018 mmol) in dimethyl formamide is degassed, heated at 150° C. for 1 h, cooled to room temperature and diluted with ethyl acetate and 2% aqueous lithium chloride. The organic phase is separated, washed with 2% aqueous lithium chloride, dried over sodium sulfate and concentrated in vacuo. Purification of the resultant residue by flash chromatography (silica, 97:3:0.25 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) affords the title compound as a white solid, 0.130 g (74% yield), mp 91-97° C.; identified by HNMR and mass spectral analyses. 1H NMR (300 MHz, CD3OD) 8.55 (m, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.60-7.21 (m, 6H), 3.13 (s, 3H); IR (ATR) 3352, 3070, 1732, 1669, 1598, 2502, 1479, 1421, 1252, 1217, 1171, 883, 817, 794, 703 cm−1; ESI MS m/z 481
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][NH2:4].[CH2:5]1[O:7][CH:6]1[CH2:8][Cl:9].Cl.[C:11](=[O:14])([OH:13])[O-:12].[Na+]>O>[CH2:1]=[CH:2][CH2:3][NH3+:4].[CH2:5]1[O:7][CH:6]1[CH2:8][Cl:9].[C:11]([O-:14])([OH:13])=[O:12]
Reactant: C=CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCC1CO1
Solvent: O
Product: C=CC[NH3+]
Temperature: 62.5 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
Sevelamer hydrochloride (1.1 Kg) was added into 15.5 L solution of sodium bicarbonate (1.1 Kg NaHCO3 in 14.3 L water). The obtained mixture was stirred at 60-65° C. for 4 hrs. The obtained material was filtered by centrifuge filter. The obtained wet cake was added into 15.5 L solution of sodium bicarbonate (1.1 Kg NaHCO3 in 14.3 L water) and stirring was maintained at 60-65° C. for 4 hrs. The material was filtered by centrifuge filter assembly and obtained wet cake was stirred in 11 L water for 1 hr at 60-65° C. The material was filtered by centrifuge filter. The washings of the wet cake with water were repeated thrice at 60-65° C. The obtained wet cake was dried in air tray dryer (ATD) at about 90-100° C. for 30-36 hrs and LOD was checked after every five hours till LOD was in the range of 5 to 10% to get Sevelamer carbonate (0.995 Kg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=1.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.CS(C)=[O:39]>>[CH:18]([OH:22])=[O:39].[CH:31]1([NH:36][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@H:11]3[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]4[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=4)[O:12]3)=[C:4]([NH:25][CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[N:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NC1CCCC1
Reactant: CS(C)=O
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NC5CCCC5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 80 °C

Procedure:
Intermediate 9 (0.070 g, 0.161 mmol) and cyclopentylamine (0.08 ml, 0.807 mmol) were dissolved in DMSO (0.03 ml) and heated at 80° C. in a sealed vial (eg Reacti vial™), for 20 h. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a cream solid (0.008 g). LC/MS system B Rt=3.01 min, m/z=486 MH+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(OC)c(F)c2)nc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(O)c(F)c2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(3-fluoro-4-methoxyphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethyl benzyl bromide.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](=[O:18])([O-])[O-:16].[Cs+].[Cs+].[NH:21]1[CH:25]=[CH:24][N:23]=[N:22]1.CN[C@@H]1CCCC[C@H]1NC>CCOCC.O.[Cu](I)I.CN(C=O)C>[CH3:15][O:18][C:7]1[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:2]([N:22]2[N:23]=[CH:24][CH:25]=[N:21]2)[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:11][C:9]1[C:8]([O:13][CH3:14])=[CH:7][CH:3]=[C:2]([N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[C:10]=1[C:15]([OH:16])=[O:18]
Reactant: COc1cc(Br)c(C(=O)O)cc1OC
Reactant: O=C([O-])[O-]
Reactant: c1c[nH]nn1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2ccnn2)c(C(=O)O)c1OC
Product: COc1ccc(-n2nccn2)c(C(=O)O)c1OC
Temperature: 120 °C
Yield: 60 %
Yield: 20 %

Procedure:
To a 20 ml microwave vial containing 2-bromo-4,5-dimethoxybenzoic acid (3 g, 11.5 mmol), copper iodide (0.04 g, 0.5 mol %), cesium carbonate (7.5 g, 23 mmol), triazole (1.33 mL, 23 mmol) and finally (R,R)-(−)-N,N′-dimethyl-1,2-cyclohexanediamine ligand (0.36 mL, 2.3 mmol) was added DMF (12 mL). The resulting clumpy yellow slurry was stirred until evenly dispersed then heated to 120° C. for 10-20 min using a microwave. At this point the reaction mixture appeared as a blue slurry which was then diluted with 20 mL ether and 20 mL H2O. The resulting solution was thoroughly stirred and transferred to a seperatory funnel then the RBF was subsequently rinsed with 20 mL ether and H2O each. The aqueous layer was separated from the organic layer and acidified to pH 1 with 6 mL conc. HCl. The now brown/lime green aqueous layer was extracted twice with EtOAc. The bright yellow organic layers were combined and dried with Na2SO4 and then conc. into a yellow powder under reduced pressure which was purified by FCC (0-5% MeOH in DCM w/0.5% AcOH) to afford 2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid (60%) and 2,3-dimethoxy-6-[1,2,3]triazol-1-yl-benzoic acid (20%). Data for 2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid, MS (ESI): mass calculated for C11H11N3O4, 249.23; m/z found 250.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.87 (s, 2H), 7.47 (s, 1H), 7.18 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: COc1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 4-methoxybenzyl chloride, in 48% overall yield after flash chromatography eluting with EtOAc/hexane, mp 80°-82° C.; IR (KBr) 3496, 1660, 1515, 1501, 1412, 1250, 1057, 754 cm-1 ; 1H NMR (CDCl3) δ 2.00 (v br s, 1H), 2.16-2.37 (m, 2H), 3.77 (s, 3H), 3.91 (t, J=6.1 Hz, 2H), 4.82 (dd, J=7.5, 5.6 Hz, 1H), 5.09 (s, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.91-7.00 (m, 4H), 7.18 (d, J=8.7 Hz, 2H); MH+ at m/z=314; Anal. Calc'd for C18H19 NO4 : C, 68.99; H, 6.11; N, 4.47. Found: C, 69.22; H, 6.10; N, 4.35.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([CH3:18])[NH:15][C:16]=1[CH3:17])=[O:10].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([CH3:18])[NH:15][C:16]=1[CH3:17])=[O:10])([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCO)C1c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOS(=O)(=O)c2ccc(C)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 62.4 %

Procedure:
43.3 g (0.10 mole) of the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(6-hydroxyhexyl) ester produced in Step i described above was dissolved along with 29.5 g (0.16 mole) of tosyl chloride in 200 ml of chloroform, to which was added dropwise 25.0 g (0.32 mole) of pyridine with stirring under ice cooling. This reaction mixture was allowed to stand at room temperature for 2 hours, then, after adding 100 ml of water, was stirred for 3 hours. The chloroform layer of the obtained liquid was separated, washed with 200 ml of 0.02 N sulfuric acid, 200 ml of water and 200 ml of saturated aqueous sodium bicarbonate successively, and dried over anhydrous sodium sulfate. This chloroform solution was chromatographed on a silica gel column using a mixed solution of benzene-ethyl acetate (the ratio by volume of 8:1) as an eluent to obtain 36.6 g (yield 62.5%) of the 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(6-tosyloxyhexyl) ester as a pale yellow oil.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([CH:7]=[CH:8][C:9]2[N:19]=[C:12]3[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[C:5]([CH:7]=[CH:8][C:9]3[N:19]=[C:12]4[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]4[N:10]=3)=[N:6][C:2]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:3]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2nc(Br)nc2C=Cc2nc3c(C)ncc(C)n3n2)cc1
Reactant: C1CCNC1
Product: COc1ccc(Cn2nc(N3CCCC3)nc2C=Cc2nc3c(C)ncc(C)n3n2)cc1
Yield: 42.7 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 9 using 2-(2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (55 mg, 125 μmol, Eq: 1.00) and pyrrolidine (17.8 mg, 20.7 μl, 250 μmol, Eq: 2) as starting materials. Chromatography afforded 2-{2-[2-(4-Methoxy-benzyl)-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl]-vinyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (23 mg, 42.8%) as a light yellow solid. MS: m/z=431.5 (M+H+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1.[C:13]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)(=[O:15])[CH3:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[C:13]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[NH:12][C:10]4[N:9]([N:8]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[N:11]=4)[C:27](=[O:28])[CH:26]=3)=[CH:22][CH:23]=2)[CH:18]=[N:17]1)(=[O:15])[CH3:14]
Reactant: Nc1nc(-c2ccccn2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(-c5ccccn5)nc4[nH]3)ccc21
Temperature: 170 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(pyridin-2-yl)-1H-1,2,4-triazol-5-amine (150 mg, 0.93 mmol) in diphenyl ether (3 mL) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (510 mg, 1.86 mmol) and TsOH (8 mg, 0.05 mmol), and the mixture was stirred for 1 h at 170° C. The resulting solution was diluted with n-hexane (8 ml), and the product was collected by filtration and washed with methanol (2 ml) to afford 5-(1-acetyl-1H-indazol-5-yl)-2-(pyridin-2-yl)-4H,7H-[1,2,4]triazolo[1,5-α]pyrimidin-7-one as a brown crude solid (120 mg, crude).
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([C:10]2[N:14]=[C:13]([C:15](Cl)(Cl)Cl)[O:12][N:11]=2)[N:4]=1.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:36][NH:35][CH2:34]2)=[CH:29][CH:28]=1.[O:37]1CCOCC1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:9][C:7]1[N:8]=[C:3]([N:2]([CH3:1])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=[C:5]([C:10]2[N:14]=[C:13]([C:15]([N:35]3[CH2:34][CH:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[CH2:36]3)=[O:37])[O:12][N:11]=2)[N:6]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Reactant: Fc1ccc(C2CNC2)cc1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(=O)N3CC(c4ccc(F)cc4)C3)n2)n1
Yield: 65 %

Procedure:
To N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-[1,3,5]triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 63 mg, 0.16 mmol) was added 3-(4-fluoro-phenyl)-azetidine hydrochloride (Intermediate 122, 39 mg, 0.19 mmol). Disiopropylethylamine (42 μL) and dioxane (1 mL) were added and the mixture heated at 70 C for 4 h. The mixture was diluted with 1 M citric acid to give a precipitate which was filtered. The pad was washed with a 1 M aq. solution of sodium bicarbonate (2 mL), water (2 mL) and then the solid was slurried in MeOH (2 mL) to give the title compound (48 mg, 65%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=O.[NH2:9][C:10]1[C:11](=[O:24])[N:12]([CH2:21][CH2:22][CH3:23])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][CH3:19])[C:15]=1[NH2:16].Cl.[OH-].[Na+]>O>[CH2:21]([N:12]1[C:11](=[O:24])[C:10]2[NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:16][C:15]=2[N:14]([CH2:17][CH2:18][CH3:19])[C:13]1=[O:20])[CH2:22][CH3:23]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccco3)nc2n(CCC)c1=O
Reaction time: 2 h

Procedure:
The starting 1,3-dipropyl-8-(2-furanyl)xanthine is prepared as follows: 1.8 g (17 mmol) 2-furoic acid is added to a solution of 3.7 g, 5,6-diamino-1,3-dipropyluracil (17 mmol) (J. Am. Chem. Soc. (1954) 76 2798) in 50 ml water. The pH is adjusted to 5, then 3.2 g (17 mmol) ethyl-3-(3-dimethylamino) propylcarbodiimide is added. The pH is maintained between 5 and 6 using 1 N HCl. After 2 hours the pH stabilizes, and the solution is taken to pH 13 using 50% aqueous NaOH. The resulting mixture is refluxed for 30 minutes, activated carbon added, and filtered hot through celite. The filtrate is then extracted (3×100 ml CH2Cl2), dried (MgSO4), and concentrated to yield 1.7 g yellow solid. This is recrystallized from methanol to give the 1,3-dipropyl-8-(2-tetrahydrofuranyl)xanthine as white needles, mp 246°- 248° C. Analysis as C15H18N4O3 (302.3); Calculated: C, 59.59; H, 6.00; N, 18.53. Found: C, 58,86; H, 6.53; N, 19.45.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC.O>COCCOC>[CH3:9][N:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc[nH]c(=O)c1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CI
Product: Cc1ccn(C)c(=O)c1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a suspension of 4-methy-2(1H)-pyridone (5 g, 45.82 mmol) and potassium carbonate (12.64 g, 91.64 mmol) in DME (100 mL) was added iodomethane (50.5 g, 366 mmol) at room temperature and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, poured into water (200 mL) and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine solution (200 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography on a Biotage (40 m) column to afford 2.5 g (44% yield) of 1,4-dimethyl-2(1H)-pyridone as an amorphous white solid. FAB-HRMS m/e calcd for C7H9NO (M+H) 123.0241. found 123.0246. b) Preparation of 1,4-dimethyl-3-iodo-2(1H)-pyridone and 1,4-dimethyl-5-iodo-2(1H)-pyridone
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[N:25]=[C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[S:27][CH:28]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:35]=O>C(O)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[N:25]=[C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[S:27][CH:28]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(C2CCNCC2)n1
Reactant: C=O
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(C2CCN(C)CC2)n1
Product: Cl
Temperature: 95 °C
Yield: 75.3 %

Procedure:
N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine (0.078 g, 0.15 mmol) was combined with 37% aqueous formaldehyde (0.025 mL, 0.34 mmol) in formic acid (2 mL) and the solution was heated to 95° C. for 1 h. The solvent was removed in vacuo and the residue was taken up in 10% MeOH/ethyl acetate (100 mL) and washed with saturated NaHCO3 (aq) (100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Trituration from MeOH and treatment of the resultant yellow solid with 4.0 M HCl/dioxane (0.050 mL) in MeOH, followed by lyophilization, provided 0.032 g (37%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine hydrochloride as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.55 (s, 1H), 8.25 (d, 1H), 7.89 (dd, 2H), 7.76 (s, 1H), 7.63 (d, 1H), 7.41 (s, 1H), 5.30 (s, 2H), 3.96 (s, 3H), 3.52 (d, 2H), 3.29 (m, 2H), 3.08 (m, 1H), 2.79 (s, 3H), 2.29 (d, 2H), 1.95 (m, 2H); MS (EI) for C26H25N5O2SCl2: 530 (M+).
Reaction SMILES: [CH:1]1([C:5]([NH:7][CH2:8][C:9](OCC)=[O:10])=O)[CH2:4][CH2:3][CH2:2]1.Cl.ClCCl>O1CCCC1.CO>[NH3:7].[CH:1]1([CH2:5][NH:7][CH2:8][CH2:9][OH:10])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)C1CCC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: N
Product: OCCNCC1CCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 157.1 %

Procedure:
Ethyl N-(cyclobutylcarbonyl)glycinate (7.6 g, 41 mmol) in tetrahydrofuran (40 ml) was added to borane-tetrahydrofuran complex (100 ml of a 1.0 N solution in tetrahydrofuran, 100 mol) and heated at 60° C. for 24 hours. Additional borane-tetrahydrofuran complex (20 ml) was added to the mixture and heating continued for a further 8 hours. The reaction mixture was then diluted slowly with methanol (20 ml) and stirred at ambient temperature for 0.5 hour. A concentrated solution of hydrochloric acid (6 ml) was slowly added following dilution with dichloromethane. The solid which precipitated was removed by filtration and washed with dichloromethane. The organic phase was dried (magnesium sulphate), concentrated and purified by chromatography on silica gel. Elution with dichloromethane:methanol (96:4) then dichloromethane:methanolic ammonia (94:6) yielded 2-((cyclobutylmethyl)amino)ethanol (4.16 g, 78% yield):
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1ccc2cc(O)ccc2n1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-Methyl-quinolin-6-ol (4.13 g, 0.0259 mol), cis 4-tert-Butyl-cyclohexanol (4.86 g, 0.0311 mol) and triphenylphosphine (9.53 g, 0.0363 mol) in tetrahydrofuran (100 mL, 1 mol), cooled in an ice bath, was added diisopropyl azodicarboxylate (7.61 mL, 0.0363 mol) in Tetrahydrofuran (10 mL, 0.1 mol). The reaction mixture was stirred for 72 h at room temperature. The solvent was removed under reduced pressure and the residue was taken up in methylene chloride, adsorbed onto silica gel and purified by flash chromatography (0-30% ethyl acetate in hexanes) to give the title compound in 56% yield. ESI-MS (M+H+): 298.3.