Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.Cl>CC(O)C>[ClH:18].[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][N:15]2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)NCC3)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(OCc5ccccc5)cc43)c2cc1OC
Yield: 80 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 80% yield from 6-benzyloxy-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to the procedure given in Example 2. (M.P. 249°-250° C.(dec); LC-MS: 414 (MH+); anal. RP18-HPLC RT: 5.01 min.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[N:7]=1.CN(C(ON1N=N[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]([C:11]([N:39]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[O:13])[CH:14]=[CH:15][CH:16]=2)[N:7]=1
Reactant: Nc1nc(-c2cccc(C(=O)O)c2)cn2nc(-c3ccco3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccc(C(=O)N3CCCCC3)c2)cn2nc(-c3ccco3)nc12
Yield: 61.3 %

Procedure:
A solution of 3-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-benzoic acid (20.mg, 0.063 mmol; see Example 5 above), HATU (30 mg, 0.095 mmol), piperdine (0.125 mmol), and diisopropylethylamine (11 μL, 0.063 mmol) in DMF (200 μL) was stirred at room temperature for 30 minutes. The solvent was removed, and the residue was purified by HPLC (C18, H2O:MeCN gradient) to afford the product as a white solid (15 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ 1.56 (br. s, 6H),3.35 (br. s,2H), 3.65 (br. s, 2H), 6.76 (dd, J=3.4, 1.7 Hz, 1H), 7.18 (dd, J=3.4, 0.8 Hz, 1H), 7.4 (br. dt, J=7.6, 1.4 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.63 (br. s, 2H), 7.96 (dd, J=1.7, 0.8 Hz, 1H), 8.11 (br. s, 1H), 8.14 (dt, J=7.5, 1.5 Hz, 1H),8.9 (s, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([C:16]([F:19])([F:18])[F:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([O-])([OH:22])=[O:21].OS(O)(=O)=O>C(O)(=O)C>[N+:20]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([C:16]([F:18])([F:19])[F:17])=[N:8]2)=[CH:6][CH:5]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
Intermediate 8 (2 g, 7.4 mmol) was dissolved in acetic acid (15 ml), cooled to 0° C. and added nitration mixture (6 ml HNO3 and 6 ml H2SO4) drop-wise. Reaction mixture was heated to 60° C. for overnight. Work up (AcOEt:H2O) and purification on silicagel (60-120 mesh silicagel) using EA and pet ether (3:97) as eluent afforded the title compound (850 mg) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.37 (d, J 9, 2H), 7.68 (d, J 9, 2H), 7.31 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.CC1C=C(C=CC=1)CC1(CO)CCNCC1.Cl.[CH3:36][C:37]1[CH:51]=[CH:50][CH:49]=[CH:48][C:38]=1[CH2:39][C:40]1([CH2:46][OH:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[OH:47][CH2:46][C:40]1([CH2:39][C:38]2[CH:48]=[CH:49][CH:50]=[CH:51][C:37]=2[CH3:36])[CH2:45][CH2:44][N:43]([C:13]([C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:17][CH:16]=3)[CH:9]=[N:10][CH:11]=2)=[O:15])[CH2:42][CH2:41]1
Reactant: Cc1ccccc1CC1(CO)CCNCC1
Reactant: N#Cc1ccc(Cn2cncc2C(=O)O)cc1
Agent: Cc1cccc(CC2(CO)CCNCC2)c1
Agent: Cl
Product: Cc1ccccc1CC1(CO)CCN(C(=O)c2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared as white solid according to the procedure described in Example 38, Step A-B substituting 1-(4-cyanobenzyl)imidazole-5-acetic acid-lithium chloride with 1-(4-cyanobenzyl)imidazole-5-carboxylic acid and 4-(3-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4-(2-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt (Example 35) in Step B. The crude product was purified with column chromatography on silica gel eluting with 2-5% methanol in chloroform.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8]>>[Cl:1][CH:2]([Cl:6])[C:3](=[O:4])[CH:8]=[CH:7][O:9][CH2:10][CH3:11]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C=COCC
Product: CCOC=CC(=O)C(Cl)Cl
Reaction time: 5 h
Yield: 68 %

Procedure:
At about 0° C., dichloroacetyl chloride (95% pure, 16.5 g, 0.11 mol) and ethyl vinyl ether (99% pure, 48.7 g, 0.67 mol) were added and stirred for 5 h. The mixture was then stirred at 22° C. for about 11 h. Most of the excess ethyl vinyl ether was then removed by distillation under reduced pressure (40° C./300-400 mbar). The product was separated off from the residue (18.7 g) by flash distillation (oil bath 100° C./0.7 mbar; transition 72° C.). The distillate obtained was a product mixture (15.6 g). This consisted to 80% (GC area %) of the desired product. Furthermore, the product mixture consisted to about 5% (GC area %) of 1,1-dichloro-4,4-diethoxy-2-butanone. Including the corresponding diethyl acetal, the yield was about 68%.
Reaction SMILES: [NH2:1][C@:2]([CH3:9])([CH2:6][C:7]#[CH:8])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][C@:2]([CH3:9])([CH2:6][C:7]#[CH:8])[C:3]([O:5][CH3:14])=[O:4]
Reactant: CO
Reactant: C#CC[C@@](C)(N)C(=O)O
Solvent: O=S(Cl)Cl
Product: C#CC[C@@](C)(N)C(=O)OC
Temperature: 2 °C

Procedure:
(2R)-2-amino-2-methylpent-4-ynoic acid (1.3 kg) was suspended in methanol (6.5 L) and cooled to 2±3° C. The mixture was treated with thionyl chloride (1.48 L) at 2±3° C. over at least 30 mins. The mixture was heated at 40±3° C. for at least 17 hours then sampled for completion of reaction (COR) by 1H NMR. Once complete, the mixture was stripped to low volume (ca. 1 vol) then azeotroped with toluene (ca. 2×2.5 L) and evaporated to dryness to afford crude methyl (2R)-2-amino-2-methylpent-4-ynoate which was then diluted with dioxane (9.1 L). The suspension was treated with aqueous potassium carbonate (2.82 Kg dissolved in 5.46 L of water) at ambient temperature and stirred for at least 30 minutes. Di-tert butyl dicarbonate (BOC2O) (2.43 Kg) was then added and the mixture heated at 40±3° C. with stirring under inert atmosphere for at least 17 hours. The mixture was sampled for completion of reaction (COR) by 1H NMR Once complete the mixture was filtered to remove solids then diluted with ethyl acetate (5 L), stirred and separated. The organic layer was washed with water (5 L) then the organic layer separated and dried over anhydrous sodium sulphate. The solution was then concentrated to a clear oil which crystallized upon standing. The crude product was recrystallised from cyclohexane (2.6 L) and washed with further cyclohexane (2.6 L). The product was dried in vacuo at 35° C. to furnish the title compound (1.5 Kg.). 1H NMR (400 MHz, MeOD-d4) δppm: 1.42 (9H, s), 1.46 (3H, s), 2.32-2.34 (1H, m), 2.65-2.71 (1H, dd), 2.92-2.99 (1H, d), 3.70 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]1[N:18]=[CH:17][N:16]([C:19](N2C=NC=C2)=O)[CH:15]=1>C1COCC1.CN(C)CCN>[CH3:17][N:16]([CH2:15][CH2:14][NH:18][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:19]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73610.6 %

Procedure:
A solution of 10 g (0.050 mmol) of 2-chloro-5-nitrobenzoic acid in 60 ml of THF was cooled over an ice bath, followed by the addition of 10 g (0.064 mmol) of CDI. The thus-obtained mixture was stirred at room temperature for 1 hour. To the solution, 12 ml (0.11 mmol) of N,N-dimethylethylenediamine were added dropwise, followed by stirring at room temperature for 3 hours. After the solvent was distilled out, the residue was dissolved in ethyl acetate. After the solution so obtained was washed with a 10% aqueous solution of sodium hydrogencarbonate, magnesium sulfate was added to the solution to dry the same. The ethyl acetate was distilled out under reduced pressure and the residue was purified by chromatography on a silica gel column (ethyl acetate), whereby 10 g of the title compound were obtained as a colorless oil (yield: 74%).
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:9][CH:8]=1.[Cl-].[NH4+]>O1CCCC1.C(O)C.O.[Fe]>[Cl:35][C:2]([Cl:1])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of the product of Example 361D (6.0 g, 10.0 mmol), iron powder (2.8 g, 50 mmol, 5 equiv, from Acros, electrolytically reduced, reagent, powder), and ammonium chloride (0.81 g, 15.0 mmol, 1.5 equiv) in tetrahydrofuran/ethanol/water (60/60/20 mL) was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature and filtered through Celite, rinsing the Celite pad with 50 mL of ethanol. The resulting filtrate was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give the title compound (4.71 g, 83%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:17][C:16]=1[NH2:26]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:26][C:16]1[CH:17]=[CH:18][C:19]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:20][C:15]=1[Cl:14])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Reactant: Nc1ccc(-c2nnn[nH]2)cc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1ccc(F)cc1Cl)Nc1ccc(-c2nnn[nH]2)cc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the solution of 100 mg of 2-chloro-4-(1H-tetrazol-5-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at 40° C. for 60 minutes. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: C([N:3](C=O)[CH2:4][C:5]([C:7]1[CH:11]=[C:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:9]([CH3:21])[CH:8]=1)=[O:6])=O>Cl.CCO>[ClH:19].[NH2:3][CH2:4][C:5]([C:7]1[CH:11]=[C:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:9]([CH3:21])[CH:8]=1)=[O:6]
Reactant: Cn1cc(C(=O)CN(C=O)C=O)cc1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Cn1cc(C(=O)CN)cc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
6.18 g (0.0186 mole) 2-[(Bis-formyl)amino]-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanone was stirred 3 days in 5% HCl/EtOH. A 0.5 mL portion of conc. HCL was added and the reaction stirred for two more days. The solid was collected by filtration. The solid was stirred in refluxing methanol and the undissolved solid collected by filtration and discarded. The filtrate was cooled to room temperature and diethyl ether was added. The solid was collected. It was twice treated with boiling methanol to give pure product: mp 290° C. (decomp.); mass spectrum (CH4—Cl) m/z=277 (M+1); NMR (Me2SO-d6) d 8.2 (br s, 4 H); 7.85 (d, 2 H); 7.6 (d, 2 H); 7.2 (s, 1H); 4.3 (s, 2 H); 4.0 (s 3 H). Anal Calcd for C14H13ClN2O2—HCl: C, 53.69; H, 4.51; N, 8.94. Found: C, 53.91; H, 4.4.1; N, 8.76.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].[Cl-].[Mg+2].[Cl-].CON(C)[C:16]([C:18]1[CH:26]=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[CH:19]=1)=[O:17].[Cl-].[NH4+]>O1CCCC1.O>[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([C:16](=[O:17])[CH2:2][CH2:3][CH:4]3[O:8][CH:7]=[CH:6][O:5]3)=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCO2
Reactant: BrCCC1OCCO1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCC1OC=CO1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (4.5 ml) was added dropwise within 15 minutes under argon and while stirring at a maximum 30° C. to a suspension of Rieke magnesium, prepared from 5.1 g of magnesium chloride, in 150 ml of absolute tetrahydrofuran. The suspension was stirred at room temperature for 30 minutes, cooled to -70° C. and treated within 10 minutes with 6.1 g of N-methoxy-N-methyl-1,3-benzodioxol-5-carboxamide. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature for 2 hours and subsequently hydrolyzed with 100 ml of saturated ammonium chloride solution while cooling at a maximum 20° C. After the addition of 50 ml of water the mixture was extracted once with 150 ml of ethyl acetate and twice with 100 ml of ethyl acetate each time. The combined organic extracts were dried over MgSO4 and freed from solvent. The residue, 8.0 g of yellow oil, was chromatographed on 490 g of silica gel with ethyl acetate/hexane (1:5) as the eluent. 5.3 g (72%) of 1-(1,3-benzodioxol-5-yl)-3-(1,3-dioxol-2-yl)-1-propanone were isolated as a colourless solid. A sample crystallized colourless from a 20-fold amount of diethyl ether and melted at 94°-96° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCl>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[C:17]([CH3:23])[CH:16]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A 250 mL round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (2.80 g, 15.0 mmol, 1.00 equiv), 4-bromo-2-methylbenzaldehyde (3.28 g, 16.5 mmol, 1.10 equiv), dichloromethane (80 mL). Triethylamine (4.56 g, 45.1 mmol, 3.00 equiv) was added. The resulting solution was stirred for 30 mins at room temperature. Sodium triacetoxyborohydride (9.60 g, 45.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (100 mL). The resulting solution was extracted with dichloromethane (3×60 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 5.70 g (98% yield) of tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 369 [M+H]+.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.[CH2:9]([C:16]1([OH:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:9]([C:16]1([OH:22])[CH2:21][CH2:20][N:19]([CH2:8][CH2:7][C:6]#[CH:5])[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C#CCCS(C)(=O)=O
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(O)(Cc2ccccc2)CC1
Yield: 86.3 %

Procedure:
A mixture of 1-mesylbut-3-yne (1.63 g, 11.0 mmol), 4-benzyl-4-hydroxypiperidine (1.91 g, 10.0 mmol) and K2CO3 (4.14 g, 30.0 mmol) in 50 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×30 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a colorless solid (2.1 g, 86%): mp 51-53° C.; 1H NMR (CDCl3) 1.50 (m, 2 H), 1.65 (m, 3 H), 1.97 (s, 1 H), 2.35 (m, 4 H), 2.62 (m, 4 H), 2.75 (s, 1 H), 7.21-7.31 (m, 5 H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1.Cl[CH2:34][S:35](Cl)(=[O:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:22]([O:21][C:20](=[O:26])[NH:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:5]3[C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][C:2]4[NH:1][S:35](=[O:37])(=[O:36])[CH2:34][O:8][C:7]=4[N:6]=3)=[CH:14][CH:13]=2)[CH2:18][CH2:17][CH2:16]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3[nH]c(=O)c(N)cc3-c3ccccc3)cc2)CCC1
Reactant: O=S(=O)(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
In a 40 mL reaction tube was added tert-butyl 1-(4-(5-amino-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl)phenyl)cyclobutylcarbamate (500 mg, 1.159 mmol) in anhydrous pyridine (5 mL) to give a yellow solution. After stirring at room temperature for 15 minutes, chloromethanesulfonyl chloride (126 μl, 1.390 mmol) was added and the resulting solution stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and redissolved in anhydrous methanol (5 mL), followed by the addition of potassium carbonate (641 mg, 4.63 mmol) and heating to 60° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was redissolved in ethyl acetate (5 mL) and washed with 50:50 water:brine (2×5 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate:dichloromethane:methanol, gradient elution from 80:10:10:0 to 0:90:10:0 then to 0:90:10) to give the desired product as an off-white solid (330 mg, 56% yield). 1H-NMR (500 MHz, d6-Acetone) δ 7.35 (1H, s), 7.23-7.32 (7H, m), 7.16-7.32 (2H, m), 5.39 (2H, s), 2.30-2.60 (4H, m), 2.00-2.12 (1H, m), 1.75-1.88 (1H, m), 1.05-1.40 (9H, br m). LCMS (Method A) RT=6.68 min, M+H+=508.01.
Reaction SMILES: C1(C(C2C=CC=CC=2)CCO[C:11](=[S:15])[CH:12]([F:14])[F:13])C=CC=CC=1.[NH2:22][CH2:23][CH:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH:41]=[CH:40][C:39](=[O:42])[CH2:38][CH2:37]3)=[C:32]([F:43])[CH:31]=2)[CH2:25]1>CC#N.CN(C=O)C>[F:13][CH:12]([F:14])[C:11]([NH:22][CH2:23][CH:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH:37]=[CH:38][C:39](=[O:42])[CH2:40][CH2:41]3)=[C:32]([F:43])[CH:31]=2)[CH2:25]1)=[S:15]
Reactant: FC(F)C(=S)OCCC(c1ccccc1)c1ccccc1
Reactant: NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1C=CN(c2ccc(N3CC(CNC(=S)C(F)F)OC3=O)cc2F)CC1
Reaction time: 36 h

Procedure:
Difluoro-thioacetic acid-O-(3,3-diphenyl-propyl)ester (84 mg, 0.25 mmol) is added to a solution of 1-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-2,3-dihydro-1H-pyridin-4-one in MeCN (1.2 mL) and DMF (0.2 mL). This solution is stirred for 36 h at which time the reaction is concentrated under reduced pressure and the title compound is purified by silica gel column chromatography (eluent: 1% MeOH in EtOAc). Yield 45 mg (41%). MS (m/z) 400 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.83–7.51 (m, 4H), 6.69 (t, J=55.2 Hz, 1H), 5.25–5.17 (m, 2H), 4.39 (t, J=9.1 Hz,1H), 4.22–4.03 (m, 6H), 3.55–3.49 (m, 2H).
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:9])[C:5]([OH:8])([CH3:7])[CH3:6].Br[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Br:20])[N:12]=1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:9])[C:5]([O:8][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Br:20])[N:12]=1)([CH3:7])[CH3:6]
Reactant: COC(=O)C(C)(C)O
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Agent: [Na]
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)Oc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
330 mg sodium were suspended in 10 ml 1,4-dioxan. Then 1.7 g 2-Hydroxy-2-methyl-propionic acid methyl ester were added dropwise. The mixture was stirred at 50° C. for thirty minutes and then at 70° C. for thirty minutes until all sodium was dissolved. This solution was then added dropwise to a solution of 2.7 g 2,6-dibromo-3-nitro pyridine in 5 ml 1,4 dioxan at 0° C. The cooling bathe was removed and the mixture stirred at room temperature overnight and then at 70° C. for four hours. The cooled reaction mixture was reduced in vacuo and the residue purified by chromatography on silica gel to obtain 640 mg 2-(6-Bromo-3-nitro-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester as a white solid.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][OH:42])[CH:36]=2)[C:31]([F:43])=[CH:30][N:29]=1.C1COC2C=CC(N)=CC=2O1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:28]3[N:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][OH:42])[CH:36]=4)[C:31]([F:43])=[CH:30][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: OCc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: OCc1cccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (d, 1H, J=3.0 Hz), 7.78 (bs, 1H), 7.41-7.31 (m, 3H), 7.12 (d, 1H, J=7.2 Hz), 6.94 (bs, 1H), 6.81-6.75 (m, 3H), 4.68 (s, 2H), 4.25 (s, 4H); 19F NMR (CDCl3): −47438; LCMS: ret. time: 17.73 min.; purity: 100%; MS (m/e): 369 (MH+)