Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:5]=1>O1CCOCC1>[NH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:6]2[N:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[N:9]=[C:4]([CH2:3][OH:2])[CH:5]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(CO)nc(C(F)(F)F)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OCc1cc(NC2CCNCC2)nc(C(F)(F)F)n1
Yield: 103.8 %

Procedure:
4.0 M Hydrogen chloride in dioxane (8.0 mL, 32 mmol) was added to a solution of tert-butyl 4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidine-1-carboxylate (0.58 g, 1.5 mmol, from Step 4) in 1,4-dioxane (3.9 mL) and the mixture was stirred until deprotection was complete as determined by LCMS. The mixture was then quenched by the addition of 1N NaOH to pH 12-13 (pH needs to be high enough for better extraction), and was saturated with solid NaCl. The product was extracted with 6 portions of chloroform, and the combined extracts were dried over sodium sulfate, filtered and concentrated to afford product as a white solid (0.43 g, 91%). 1H NMR (400 MHz, CDCl3) δ 6.48 (s, 1H), 4.65 (s, 2H), 3.13 (dt, J=11.9, 2.9 Hz, 2H), 2.81-2.66 (m, 2H), 2.04 (d, J=10.3 Hz, 2H), 1.51-1.31 (m, 2H). 19F NMR (376 MHz, CDCl3) δ −71.75 (s). LCMS (M+H): 277.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)CN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 25.4 %

Procedure:
Compound A2 (0.12 mmol, 50 mg), and 1-bromo-3,3-dimethyl-butan-2-one (0.12 mmol, 16 μL) were dissolved in DMF (1 mL) and triethylamine (0.36 mmol, 50 μL). The reaction was heated in a microwave at 80° C. for 4 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by HPLC provided Compound A11 as a yellow solid (15 mg, 25%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.11 (s, 1H), 8.32 (s, 1H), 7.89 (d, 2H), 7.78 (d, 2H), 5.49 (s broad, 1H), 3.53 (s broad, 2H), 3.01 (s, 3H), 2.78 (m, 4H), 2.18 (m, 2H), 1.96 (m, 2H), 1.20 (s, 9H). LCMS (ESI), m/z 492.3 (M+H+, 100%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].O=C1CCCCC1C(OCC)=O.[Cl:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:22]([Cl:29])[C:21]=1I.[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34]>CS(C)=O.CC(=O)OCC>[Cl:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:22]([Cl:29])[C:21]=1[O:34][CH2:33][C:32]([F:36])([F:35])[F:31]
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
A Mixture of Cs2CO3 (17.22 g, 52.84 mmol), CuBr (361 mg, 2.52 mmol) and ethyl 2-oxocyclohexanecarboxylate (856 mg, 5.03 mmol) in DMSO (30 mL) under N2 was stirred for 0.5 h at rt. Then a solution of 1,3-dichloro-2-iodo-5-nitrobenzene (8.0 g, 25.16 mmol) and 2,2,2-trifluoroethanol (3.02 g, 30.19 mmol) in DMSO (20 mL) was added to it. The reaction mixture was stirred at 80° C. for 18 h and cooled to room temperature, and then directly passed through celite. After rinsed with 250 ml of EA, the combined filter was washed by brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (100:1) to provide 1,3-dichloro-5-nitro-2-(2,2,2-trifluoroethoxy)benzene (1.93 g, yield 12.6%) as pale yellow solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.O[NH:9][C:10](=[NH:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1>CN(C=O)C>[CH3:20][S:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:9]=[C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[O:7][N:21]=2)=[CH:16][CH:15]=1)(=[O:18])=[O:19]
Reactant: O=C1CCC(=O)O1
Reactant: CS(=O)(=O)c1ccc(C(=N)NO)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2noc(CCC(=O)O)n2)cc1
Temperature: 120 °C

Procedure:
Succinic anhydride (85 mg, 0.85 mmol) and N-hydroxy-4-methanesulfonyl-benzamidine (180 mg, 0.85 mmol) were dissolved in 2.0 mL of DMF and heated at 120° C. overnight. The cooled solution was evaporated and dried to yield 3-[3-(4-methanesulfonyl-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid which was used without further purification.
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.[Cl-].[CH2:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO>[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([CH2:16][OH:17])=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: C=[N+]1CCOCC1
Reactant: Nc1ncnn2cc(CO)cc12
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CN3CCOCC3)c(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of DMF (50 mL) was added (4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol (550 mg, 3.35 mmol) and 4-methylenemorpholin-4-ium chloride (Eur. J. Med. Chem. 1989, 24, 379-384) (636 mg, 4.69 mmol). The solution was stirred at rt for 1 h and then the solvent was evaporated. The oil was triturated with CH2Cl2 and a white solid was collected. The free based was obtained by stirring over a Dowex 66 solid support resin in MeOH. The material was filtered and evaporated yielding 794 mg (90%) of the desired product as a white solid. MS [M+H]+=264; LCMS RT=1.07.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11][CH2:10]2.Cl.C(OCC)(=O)C>O1CCOCC1>[O:17]=[C:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH:2]=[O:1])=[CH:16][CH:15]=2)[CH2:10][CH2:11][O:12]1
Reactant: O=C1OCCc2cc(CC3OCCO3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=CCc1ccc2c(c1)CCOC2=O
Temperature: 25 °C

Procedure:
6-(1,3-Dioxolan-2-ylmethyl)-3,4-dihydro-1H-isochromen-1-one (4.42 g, 18.9 mmol) was dissolved in dioxane (25 mL) and treated with 3 M HCl (40 mL). The reaction mixture was stirred at RT over night, and then was warmed to 50° C. for 2 hrs to drive the reaction to completion. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed with brine and dried over MgSO4 to afford the title compound. LCMS: m/z 191 (M+1)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[NH4+:14].BrBr>C(O)(=O)C.O>[NH2:13][C:12]1[S:11][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N:14]=1
Reactant: [NH4+]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc2sc(N)nc2c1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
13.5 g of p-aminoacetophenone and 31.70 g of ammonium thiocyanate were dispersed in a mixture of 800 ml of glacial acetic acid and 40 ml of water, and a solution of 20 g of bromine dissolved in 100 ml of glacial acetic acid was dropwise added thereto at 7° to 10° C. over about 1 hour while stirring. After stirring at 10° C. for 2 hours, the solution was heated and stirred at 70° C. for 5 hours. The reacted mixture was filtered at 50° C. or more, and the obtained filtrate was added to 1000 ml of a hot water of about 70° C. To this mixture, crystals of anhydrous sodium carbonate were added while leaving it to cool and stirring until the pH became 5. Fresh pale yellow crystals were filtered and dried to obtain 15.83 g of 2-amino-5-acetylbenzothiazole of the following structural formula: ##STR158## Then, 2.00 g of (0.0105 mol) of 2-amino-5-acetylbenzothiazole obtained above, 0.69 g (0.0105 mol) of malononitrile and 0.4 g of ammonium acetate were added to a mixture of 10 ml of glacial acetic acid and 5 ml of toluene, heated while stirring, and refluxed for 2 hours while evaporating toluene and water. The resulting product was left to cool, and then added to 100 ml of water. The obtained fresh yellow crystals were filtered and dried to obtain 2.47 g of 5-(2',2-dicyano-1'-methyleteno)-2-aminobenzotiazole of the following structural formula. The molecular weight of this compound was confirmed with a mass spectrum. ##STR159##
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C@@H:3](/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:4][O:5][Si](C)(C)C.[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:1][CH:2]([CH3:18])[C@@H:3]([NH:10][C@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:4][OH:5]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)[C@H](CO[Si](C)(C)C)/N=C/c1ccccn1
Solvent: C1CCOC1
Product: CC(C)[C@H](CO)N[C@H](c1ccccc1)c1ccccn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The silylated imine from the previous step, e.g. (2R)-3-methyl-N—[(E)-2-pyridinylmethylidene]-1-[(trimethylsilyl)oxy]-2-butanamine was dissolved in dry THF (500 ml) and the solution was cooled down to −78° C. A 1 M solution of phenylmagnesiumbromide in THF (200 ml, 200 mmol, 2 eq) was added dropwise while the mixture was stirred by a magnetic bar. The mixture was further stirred 2 hours at −78° C. The temperature was then slowly increased up to room temperature overnight. A sample of the reaction mixture was quenched with aqueous NaHCO3 and analysed by LC-MS to detect the O-silylated products. After one night, the mixture was quenched with HCl 1M (250 ml) and the mixture was stirred at room temperature until the desilylation was complete (after 1 h, LC/MS analysis). The aqueous phase was further acidified with the addition of 5M HCl solution (20 ml). The aqueous phase was washed with 300 ml cyclohexane/Et2O (2:1), then made basic with 60 ml NaOH 5M at 0° C., and the organic products were extracted with Et2O, dried (MgSO4) and concentrated to give the desired product (XX*), e.g. (2R)-3-methyl-2-{[(R)-phenyl(2-pyridinyl)methyl]amino}-1-butanol as a yellowish oil (22.9 g, 85% yield, d.e.=99%, determined by 1H NMR).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@H:60]([OH:59])[CH3:65])[C@@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@@H](C)O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
5-{9-Isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (150 mg, 0.33 mmol), dicyclohexylcarbodiimide (103 mg, 0.5 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (R)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (50 mg, 28%) as a white solid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][C@H:10]1[C:24]([O:26][CH3:27])=[O:25])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][S:14][C@@H:12]2[CH2:13][NH:9][C@H:10]([C:24]([O:26][CH3:27])=[O:25])[CH2:11]2)=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
27.3 ml of a 4N ethyl acetate solution of hydrogen chloride were added, whilst ice-cooling, to a solution of 5.22 g of (2S, 4S)-1-(t-butoxycarbonyl)-4-(4-methoxybenzylthio)-2-methoxycarbonylpyrrolidine [prepared as described in step (8) above] dissolved in 14 ml of ethyl acetate, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 3.3 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH:22](OCC)=[O:23].C(O)C>C(OCC)C.O>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7](=[CH:22][OH:23])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CCOC=O
Reactant: O=C1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cl
Product: O=C1C(=CO)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the solution of 2.6 g of 8-chloro-1-phenyl-3,4-dihydro-2-benzazepin-5-one in 4- ml of diethyl ether, 0.5 g of sodium hydride in 10 ml of diethyl ether are added and the mixture stirred for 1/2 hour. Thereupon 1.2 ml of ethyl formate and 0.1 ml of ethanol are added and the mixture refluxed for 24 hours. It is cooled in an ice bath, 30 ml of water are added, the aqueous layer separated, acidified with 2N hydrochloric acid and the precipitate formed filtered off, to yield the 8-chloro-4-hydroxymethlidene-1-phenyl-3,4-dihydro-2-benzazepin-5-one hydrochloride melting at 185° with decomposition.
Reaction SMILES: [C:1]([O:6][C@H:7]1[C:24]([CH3:26])([CH3:25])[O:23][C:22]2[C:9](=[C:10]3[C:19](=[C:20]([O:27][CH3:28])[CH:21]=2)[C:18](=[O:29])[C:17]2[CH:16]=[C:15]4[CH:30]=[CH:31][CH:32]=[CH:33][C:14]4=[CH:13][C:12]=2[N:11]3[CH3:34])[C@H:8]1O)(=[O:5])[CH2:2][CH2:3][CH3:4]>ClCCl.Cl>[C:1]([O:6][C:7]1[C:24]([CH3:25])([CH3:26])[O:23][C:22]2[C:9](=[C:10]3[C:19](=[C:20]([O:27][CH3:28])[CH:21]=2)[C:18](=[O:29])[C:17]2[CH:16]=[C:15]4[CH:30]=[CH:31][CH:32]=[CH:33][C:14]4=[CH:13][C:12]=2[N:11]3[CH3:34])[CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@@H]1[C@H](O)c2c(cc(OC)c3c(=O)c4cc5ccccc5cc4n(C)c23)OC1(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCC(=O)OC1=Cc2c(cc(OC)c3c(=O)c4cc5ccccc5cc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.29 mmol of the compound obtained in Step 1 in 6 ml of dichloromethane there are added 4 drops of 10% HCl solution. The reaction mixture is stirred at ambient temperature for 3 days and is then dried and evaporated under reduced pressure. Chromatography of the residue over silica gel (dichloromethane/methanol: gradient from 0.2 to 5%) allows the expected product to be isolated.
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CS(C)=O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH2:19][C:1]#[CH:2])[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)CCC2C)cc1
Reactant: [C-]#[C-]
Agent: [Li+]
Solvent: CS(C)=O
Product: C#CCC1CN(C(=O)OC(C)(C)C)CCC1C
Temperature: 8 °C
Reaction time: 4.5 h

Procedure:
A flask containing lithium acetylide, ethylene diamine complex (3.82 g, 37.4 mmol) was taken up in dry DMSO (50 mL) and cooled to approximately 8° C. (dilute ice bath) under argon atmosphere. To the cooled mixture was added a solution of (+/−)-4-methyl-3-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (6.91 g, 17.79 mmol) in dry DMSO (40 mL), via slow drop-wise addition. The dark brown-black mixture was stirred vigorously to ambient temperature for 4.5 hours. The reaction was carefully quenched via the addition of a saturated solution of aqueous ammonium chloride (60 mL), followed by the addition of diethyl ether (120 mL) and water (50 mL). The mixture was transferred to a separatory funnel and shaken. The ether phase was collected and shaken with an equal volume of brine. The aqueous phases were back extracted with diethyl ether (2×100 mL). The crude was taken up in methylene chloride (40 mL) and adsorbed onto 25 g of silica gel. The solvent was stripped and the crude material was purified by silica gel chromatography, eluting with 4% to 20% ethyl acetate in hexanes, providing 2.21 g of (+/−)-4-methyl-3-prop-2-ynyl-piperidine-1-carboxylic acid tert-butyl ester as a clear mobile oil. MS (M+Na)+=260.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[CH3:11][N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17].[CH3:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[C:28]([O:30][C:31]3[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=3)[CH:27]=[CH:26][N:25]=2)[CH:21]=[N:20]1>C(Cl)Cl>[CH3:11][N:12]1[CH2:16][CH2:15][N:14]([C:13]([NH:37][C:34]2[CH:33]=[CH:32][C:31]([O:30][C:28]3[CH:27]=[CH:26][N:25]=[C:24]([C:22]4[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=4)[CH:29]=3)=[CH:36][N:35]=2)=[O:17])[C:1]1=[O:2]
Reactant: CN1CCNC1=O
Reactant: O=C(Cl)Cl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5 mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236 mmol) and 1-methylimidazolidin-2-one (0.056 g, 0.561 mmol) in DCM (5 mL), stirred at RT for 2 h, then concentrated to dryness. The residue was dissolved in DCM (5 mL), cooled to 0° C., treated with a solution of Example A2 (0.10 g, 0.374 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT and stirred for 4 h. The solids were removed via filtration, washed with DCM and the filtrate concentrated to dryness. The residue was treated with EtOAc/DCM/MeCN, allowed to stand overnight and the resulting solid collected via filtration to afford 3-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (80 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 11.04 (s, 1 H), 8.66 (s, 1 H), 8.52 (d, J=6.7 Hz, 1 H), 8.35 (s, 1 H), 8.32 (m, 1 H), 8.12 (d, J=9.1 Hz, 1 H), 7.83 (dd, J=9.1, 2.9 Hz, 1 H), 7.64 (s, 1 H), 7.13 (m, 1 H), 3.90 (s, 3 H), 3.80 (m, 2 H), 3.45 (m, 2 H), 2.80 (s, 3H); MS (ESI) m/z: 394.2 (M+H+).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10]([O:12]CC)=O>CCOCC>[C:1]1([NH:8][C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cccc(N)c1
Solvent: CCOCC
Product: CCOC(=O)C(=O)Nc1cccc(NC(=O)C(=O)OCC)c1

Procedure:
A mixture of m-phenylenediamine (10.8 grams) (0.10 ml.) and diethyl oxalate (50 ml.) is refluxed for 2.5 hours. The cooled reaction mixture is diluted with ether (200 ml.) and the crude product collected (19.2 grams, M.P. 150° C.). Two recrystallizations from methanol give off white crystals (6.65 grams, 155°-160°).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1c2ccccc2C(=O)N1OCc1ccccc1
Yield: 64 %

Procedure:
The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and (bromomethyl)benzene in 64% yield using the same procedure as described in the synthesis of intermediate G. LCMS (method A): [MH]+=254, tR=5.19 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][CH:47]=2)=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:64][CH:65]4[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]4)=[O:52])=[CH:48][CH:47]=2)=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]benzoic acid, (Intermediate 129; 123 mg, 0.3 mmol) DIPEA (261 uL, 1.5 mmol) and 4-amino N-methylpiperidine (43 mg, 0.375) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave a pale yellow amorphous solid. (100 mg, 66%)