Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][C:34](O)=O.C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:33][CH3:34])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.06 mmol) in THF and AcOH (4.8 mg, 0.08 mmol) was added acetaldehyde (2.0 mL, 0.2 mmol) and sodium triacetoxy borohydride (85.0 mg, 0.4 mmol). The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-ethylpiperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=481)
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[OH:14][CH2:15][C:16]1([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[CH:24]2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>O1CCCC1.CN(C)C=O>[OH:14][CH2:15][C:16]1([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[CH:24]2)[CH2:21][CH2:20][C:19](=[CH:3][C:1]#[N:2])[CH2:18][CH2:17]1
Reactant: O=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (38.6 mg, 0.218 mmol) in tetrahydrofuran (0.5 mL) stirring at about 0° C. was added sodium hydride (10.5 mg, 0.262 mmol). To this was added a solution of 4-(hydroxymethyl)-4-(1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexanone (56 mg, 0.18 mmol) in N,N-dimethylformamide (0.45 mL). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, causing formation of solids. The solids were filtered to give 18 mg of pure desired product. The filtrate was diluted with EtOAc, washed with water, and concentrated to give an additional 39 mg of the crude product. LCMS calculated for C17H17N4OS (M+H)+: m/z=325.1. Found: 325.0. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 8.15 (s, 1H), 7.47 (d, J=5.6 Hz, 1H), 7.18 (d, J=5.6 Hz, 1H), 5.20 (s, 1H), 4.34 (s, 2H), 2.80 (d, J=4.0 Hz, 3H), 2.59-2.29 (m, 4H), 1.26 (d, J=15.3 Hz, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1(CO)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([Cl:12])[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:15]([C@:23]([C:38]([OH:40])=[O:39])(O)[C@:24](C(=O)C1C=CC=CC=1)(O)[C:25]([OH:27])=[O:26])(=[O:22])C1C=CC=CC=1.C(O)(=O)/C=C/C(O)=O>C(O)C>[C:38]([OH:40])(=[O:39])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[CH:7][CH2:6][C:5]([CH2:15][OH:22])([Cl:12])[C:4]=2[CH2:3]1
Reactant: NC1(CO)CCc2cccc(Cl)c2C1
Reactant: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: NC1CCC2=C(C1)C(Cl)(CO)CC=C2

Procedure:
The expected product is obtained by resolving the compound obtained in stage D of Example 9 using (+)-dibenzoyl-D-tartaric acid by successive recrystallizations in ethanol. The enantiomeric purity is checked by chiral chromatography on a DIACEL-AD column, using an isopropanol/n-heptane/diethylamine mixture (40/1000/0.8) as eluent. The salt is then partitioned between 9N sodium hydroxide and dichloromethane. The aqueous phase is extracted with dichloromethane. After drying and evaporating the organic phases, the residue is dissolved in ethanol with one equivalent of fumaric acid and the mixture is brought to reflux. The expected product is then obtained after cooling, in the form of a white solid which is filtered off.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:13](=[O:29])[N:12](COCC[Si](C)(C)C)[C:11]=2[N:10]=[C:9]1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>C(O)C>[Cl:38][C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:39])=[CH:4][CH:3]=2)[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:29])[NH:12][C:11]=2[N:10]=1
Reactant: Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(COCC[Si](C)(C)C)c1=O
Solvent: CCO
Product: O=c1[nH]c2nc(Cl)n(Cc3ccc(Cl)cc3)c2c(=O)n1CCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 7-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (340 mg, 0.56 mmol) in ethyl alcohol (20 mL) was added concentrated HCl (2 mL). The mixture was stirred at 80° C. overnight. The reaction was concentrated, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 8-chloro-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (180 mg, 87.5% yield) as colorless oil. LCMS retention time 1.990 min; LCMS MH+ 369.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH2:17][C:18]#[N:19].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:38](=[O:53])[C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:40]=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[C:18]([CH2:17][N:16]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:1])([F:20])[F:21])[C:38](=[O:53])[C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:42]=[C:41]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:40]=1)#[N:19]
Reactant: N#CCNc1cnccc1-c1ccccc1OC(F)(F)F
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C(=O)N(CC#N)c2cnccc2-c2ccccc2OC(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-(2-(trifluoromethoxy)phenyl)pyridin-3-ylamino)acetonitrile (0.07 g, 239 μmol) in CH2Cl2 (2 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (137 mg, 477 μmol, example 223, intermediate d) and DIPEA (123 mg, 167 μL, 955 μmol) and the clear, yellow solution was stirred at room temperature for 18 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.085 g; 65%). MS (ESI): m/z=544.08 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[OH:17]O.[OH-].[Na+]>C(O)C>[NH2:2][C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:17]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4-cyanophenoxy phenyl methane (10.45g.; 0.05 mole), 30% hydrogen peroxide (20ml) and 6N NaOH (20ml) and ethanol (30ml) was maintained at 40°-50° for 3 hrs., cooled and neutralised. The product was filtered off and recrystallised from ethanol M.p. 186°-7°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:18]([CH3:19])[C:17]3[C:16](=[O:20])[N:15]([CH2:21][C:22]#[CH:23])[C:14](=[O:24])[N:13]([CH3:25])[C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C([O-])(O)=O.[Na+]>[C:26]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:18]([CH3:19])[C:17]3[C:16](=[O:20])[N:15]([CH2:21][C:22]#[CH:23])[C:14](=[O:24])[N:13]([CH3:25])[C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCn1c(=O)c2c(nc(C#Cc3cccc(O)c3)n2C)n(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: C#CCn1c(=O)c2c(nc(C#Cc3cccc(OC(C)=O)c3)n2C)n(C)c1=O

Procedure:
A mixture of 0.1 mmol of 8-(3-hydroxyphenylethynyl)-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione and 0.5 mL acetic anhydride was heated under reflux for 15 min. Subsequently the mixture was hydrolyzed with concentrated NaHCO3-solution (50 mL) and the product was extracted with dichloromethane. The organic extracts were dried over MgSO4 and filtered and concentrated under vacuum. The crystalline residue was treated with ether and filtered under reduced pressure yielding 8-(3-acetoxyphenylethynyl)-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione: colorless crystals (yield >95%), m.p. 238° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:34](OCC)[O:35]CC)=[C:5]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:34]=[O:35])=[C:5]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCOc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Yield: 102.4 %

Procedure:
Starting from a mixture of 2-phenoxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (1.24 g) in acetone (12 ml) and 6 N hydrochloric acid (1.2 ml) was obtained an oil (1.1 g) of 2-phenoxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate, in a substantially similar manner to that of Example 2-6).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:6][CH2:5]1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]2)[CH2:5][CH2:6]1)=[O:26]
Reactant: O=C(Nc1cc(Cl)ccc1N1CCC(CCBr)CC1)c1cccc(Cl)c1
Reactant: OC1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)ccc1N1CCC(CCN2CCC(O)CC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 54.9 %

Procedure:
A mixture of 0.040 g (0.088 mmol) of N-{2-[4-(2-bromo-ethyl)-piperidin-1-yl]-5-chloro-phenyl}-3-chloro-benzamide, 0.044 g (0.44 mmol) of 4-hydoxypiperidine, and 0.50 mL (2.9 mmol) of N,N-diisopropylethylamine in acetonitrile (1 mL) is heated to 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and purified by preparative reverse phase HPLC to provide 0.023 g (55%) of the title compound (100) as a colorless solid. [M+H]+=476.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CN(C)C=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH2:8])[N:7]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Nc1cncc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2cncc(N)n2)CC1
Temperature: 100 °C

Procedure:
4-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine was prepared from 6-chloro-pyrazin-2-ylamine (1.00 g, 7.72 mmol) and 1-methylpiperazine (942 L, 8.49 mmol) combined in N,N-dimethylformamide (35 mL) and heated at 100° C. overnight. The reaction was poured into water and extracted with 3 portions of dichloromethane. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield an off-white solid. This solid was purified via chromatography (silica gel 40 g methanol in dichloromethane). Product isolated as a tan oil that solidified upon standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm):7.33 (s, 1H), 7.16 (s, 1H), 5.93 (s, 2H), 3.40 (s, 4H), 2.36 (s, 4H), 2.20 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[C:12](O)(=[O:17])[CH2:13][C:14](O)=[O:15].C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:17][C:12]1[C:3]2[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=2[S:1][C:14](=[O:15])[CH:13]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1c(S)cc(=O)n(C)c1=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(O)cc(=O)sc2n(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of Step 2 intermediate (12.75 g, 74.127 mmol), malonic acid (9.30 g, 88.953 mmol), acetic acid (7.41 ml) and acetic anhydride (16.8 ml) was heated to 80° C. under nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and quenched with water (50 ml). Precipitated solid was filtered, washed with water (2×50 ml) and dried well to obtain 14.4 g of the product as brown solid; 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 3.48 (s, 3H), 5.73 (s, 1H), 13.76 (br s, 1H).
Reaction SMILES: S1CCS[C:2]21[C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH:8]([NH:14][CH:15]=[O:16])[CH2:7][CH2:6]2.O.C(=O)([O-])[O-:19].[Ca+2]>C(#N)C>[O:19]=[C:2]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]([NH:14][CH:15]=[O:16])[CH2:7][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: O=CNC1CCC2(SCCS2)c2sccc21
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Product: O=CNC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a stirred mixture of N-(5,6-dihydrospiro[benzo-[b]thiophen-7(4H), 2'-[1,3]dithiolan]-4-yl)formamide (1.5 g), acetonitrile (20 ml) and water is added calcium carbonate (1.65 g) and mercuric chloride (3.0 g). The mixture is stirred at room temperature for 35 minutes and acetonitrile is added. The solid is filtered and washed with acetonitrile. The filtrate (100 ml) is evaporated to dryness to afford the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[N:10]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([C:27]([OH:29])=[O:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.CCO.O=[Pt]=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[N:10]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([C:27]([OH:29])=[O:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(Cc2cccnc2)c2ccc([N+](=O)[O-])c(C(=O)O)c2)cc1OC1CCCC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N(Cc2cccnc2)c2ccc(N)c(C(=O)O)c2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 27.9 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxy-N-(3-carboxy-4-nitrophenyl)-N-(3-pyridylmethyl)aniline (200 mg, 0.43 mmol) in 20 mL of EtOAc and 5 mL of EtOH was hydrogenated at atmospheric pressure over 20 mg of PtO2 with stirring for 16 hours. The catalyst was removed by filtration and the solution concentrated. The residue was chromatographed over SiO2 using MeOH/DCM (1/10) as eluant. The oily residue was further purified by trituration with 1 mL of CH3CN to give 52 mg (28% yield) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[N:3]1.C([Li])CCC.C(O[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(C)C>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[C:6]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)=[C:5]([CH3:7])[CH:4]=[N:3]1
Reactant: Cc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1,4-Dimethyl-1H-pyrazole (50 mg, 0.5 mmol) was stirred in THF (2 mL) and cooled to 0° C. A solution of 1.6 M n-butyllithium in hexanes (390 mL) was added dropwise by syringe and the mixture was allowed to warm to room temperature for 2 h. The mixture was cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110 mL, 0.52 mmol) was added dropwise by syringe. The mixture was stirred at −78° C. for 15 min. and at 0° C. for 3 h. The mixture was diluted with EtOAc and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel using EtOAc in hexanes gave the sub-title compound. LCMS calc. for C11H20BN2O2 (M+H)+: m/z=223.2. found: 223.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:19])[C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:22](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.N>C1COCC1>[NH2:22][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:19]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(=O)O
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of (R)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylbutanoic acid (9.0 g, 33.9 mmol) in THF (100 mL) under N2 atmosphere DIPEA (17.77 mL, 102 mmol) was added followed by addition of HOBT (5.19 g, 33.9 mmol) and EDC (6.50 g, 33.9 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. Then freshly prepared saturated ammonia in THF 50 mL (50 mL of THF, ammonia gas was purged at −40° C. for 20 min) was poured into the above reaction mixture at −20° C. and slowly allowed reaction mass temperature to 25° C. and stirred for further 12 h. Upon completion of the reaction, it was quenched with water (250 mL) and extracted into ethyl acetate (2×200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain pale brown oil. This crude product was purified by column chromatography using 60-120 silica gel, by eluted with ethyl acetate:hexane (40:60) to yield (R)-benzyl (4-amino-3,3-dimethyl-4-oxobutan-2-yl)carbamate (4.8 g, 46.5%) as pale yellow oil. 1HNMR (400 MHz, CDCl3) δ ppm: 7.36-7.35 (d, J=4.4 Hz, 5H), 5.104 (s, 2H), 3.75-3.67 (t, J=16, 18.4 Hz, 1H), 1.25-1.24 (d, J=5.2 Hz, 6H), 1.18-1.17 (d, J=6.8 Hz, 3H). HPLC purity: Column: Sunfire C18 (4.6×150 mm, 3.5 μm), Buffer: 0.05% TFA in H2O (pH 2.5, adjusted with ammonia), Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 12-100, 15-100 min, Flow: 1.0 mL/min Retention Time: 7.408: Purity: 93.74%. Chiral HPLC purity: Column: CHIRALPAK AD-H (250×4.6 mm) 5 micron, Mobile Phase: 0.2% DEA in hexane:ethanol (50:50). Flow: 1.0 mL/min: Retention Time: 6.036. Purity: 100%. LCMS Purity: Column: Ascentis C18 (5×2.1 mm-2.7 μm). Mobile Phase A: 2% ACN −98% H2O-10 mM NH4COOH. Mobile Phase B: 98% ACN −2% H2O-10 mM NH4COOH. Flow: 1.0 mL/min. Retention Time: 1.785 Min. Purity: 99.9% (m/z=265.2 M+).
Reaction SMILES: [BrH:1].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11](O)[C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1>C1(C)C=CC=CC=1>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([Br:1])[C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)C(O)c1ccc2c(c1)OCO2
Reactant: Br
Solvent: Cc1ccccc1
Product: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reaction time: 3 h

Procedure:
Hydrobromic acid (20 ml of 62% w/v solution in water) was added to methyl 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetate (from step (b), 11 g, 52 mmol) in toluene (200 ml). After stirring for 3 hours the aqueous layer was removed and the organic layer was evaporated in vacuo. The residue was flash chromatographed, eluting with dichloromethane, and then crystallised with diisopropylether and hexane.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[C:15]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.10 g, 0.50 mmol) was combined with acetic anhydride (0.052 mL, 0.55 mmol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give tert-butyl 4-(acetylamino)piperidine-1-carboxylate, LCMS [M+Na]+: m/z=265.1. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give crude HCl salt product (0.057 g), which was used directly in the next step. LCMS calculated for C7H15N2O (M+H)+: m/z=143.1; Found: 143.1.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:4]1[N:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:3]([CH3:2])[C:4]2[N:5]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:16][CH:15]=3)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=2)[CH2:29]1)=[O:40].[ClH:1]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CN(c1cnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1)[C@@H]1CCCNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C/C=C/C(=O)N1CCC[C@@H](N(C)c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (42 mg, 0.25 mmol), DIEA (150 μL, 0.84 mmol) and then PyBOP (88 mg, 0.17 mmol). The mixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (94) as an HCl salt (29 mg). MS found for C28H38N8O4 as (M+H)+ 551.3, (M−H)− 549.3. UV: λ=274, 281, 313, 344, 369 nm.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CO>[CH:27]1([NH:30][CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CNC4CC4)CC3)c(F)c2)C(=O)O1
Yield: 73 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with cyclopropylamine (2.06 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 73% yield.