Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[N:20][CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a solution of N-tert-butyl-2-(2-methylpyrimidin-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 171 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (390 mg, 264 μL, 3.42 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (2.5 mL), methanol (1.2 mL) and ammonium hydroxide (0.35 mL) and the mixture stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo then triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(2-methylpyrimidin-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (43 mg, 132 μmol, 77%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.31 (s, 1H), 9.57 (s, 1H), 8.90 (s, 2H), 7.96 (d, J=3.3, 1H), 7.92 (s, 1H), 7.53 (s, 1H), 2.46 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 326.1 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CCOC(C)=O>[C:27]([O:26][C:24](=[O:25])[C:23]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([NH:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5][C:4]=2[CH:3]=1)([CH3:32])[CH3:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CC(=O)NC1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NC1CCc2cc(OC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a suspension of N-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (0.439 g; 2.1 mmol) in DMF (6 mL) is added Cs2CO3 (1.7 g; 5.2 mmol) and tert-butyl 2-bromoisobutyrate (2.1 mL; 9.4 mmol) and the reaction mixture was stirred at 100° C. for 18 h. The reaction was cooled to RT, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to provide a crude oil, which was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 0.51 g (69%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy)-2-methylpropionic acid tert-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]([NH:36][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])([CH3:35])[CH3:34]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with isopropylamine (16 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 96 mg of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[N:24]=1>C(O)(=O)C.C1COCC1>[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:3]=[C:4]([NH:20][CH3:21])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[C:13]([F:19])[C:14]([F:18])=[C:15]([F:17])[CH:16]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[N:24]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)n1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)n3)c(OC)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (80 mg, 0.255 mmol) was added to a solution of 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (86 mg, 0.383 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 120° C. for 4 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (15.5 mg, 0.025 mmol, 9.77% yield). LC-MS (M+H)+=502.0. 1H NMR (500 MHz, CDCl3) δ ppm 11.88-12.12 (1H, m), 8.63 (1H, s), 7.68-7.81 (1H, m), 7.60 (1H, s), 7.47 (1H, s), 6.92 (1H, t, J=7.2 Hz), 3.94-3.99 (1H, m), 3.52 (8H, s), 3.22-3.29 (1H, m), 2.87-3.01 (1H, m), 2.74-2.85 (1H, m), 2.22-2.38 (1H, m).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])=[C:7]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH:6]=1)(=[O:3])[CH3:2].[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[O:10])=[C:7]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[CH2:27][CH2:26]2)=[O:24])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccncc1
Reactant: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)C2CCN(Cc3ccncc3)CC2)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred suspension of 4-acetylamino-N-(4-methoxyphenyl)-2-[(4-piperidinylcarbonyl)amino]benzamide (0.4 g, 0.97 mmol), 4-pyridinecarboxaldehyde (0.11 mL, 1.17 mmol) and acetic acid (0.085 mL, 1.46 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (0.31 g, 1.46 mmol). After stirring overnight, the white solid was filtered off and the filtrate was concentrated in vacuo. The residue was suspended in diethyl ether, sonicated, and filtered. The combined solids were then washed with water, filtered and dried in vacuo to give 0.37 g (76%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[C:21]3[C:16](=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[C:21]3[C:16](=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([CH2:26][NH2:27])=[N:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Nc2cnc(CNC(=O)OC(C)(C)C)c3c(OC)cc(OC)cc23)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1csc(Nc2cnc(CN)c3c(OC)cc(OC)cc23)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
2-[1-(tert-Butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinolin-4-ylamino]thiazole-4-carboxylic acid ethyl ester (22 mg, 0.045 mmol) in CH2Cl2 (1.0 mL) was added a 4.0 M HCl solution in dioxane (0.67 mL) at room temp. After the reaction mixture was stirred at room temperature for 4.5 h, the suspension was filtered. The yellow solid was dried in vacuo to give 2-(1-aminomethyl-6,8-dimethoxy-isoquinolin-4-ylamino)thiazole-4-carboxylic acid ethyl ester hydrochloride salt (14.0 mg; 73% yield). 1H-NMR (D2O): δ, 8.84 (d, 1H, J=6.3 Hz), 7.70 (s, 1H), 6.92 (s, 1H), 6.77 (s, 1H), 4.66 (s, 2H), 4.20 (q, 2H, J=7.1 Hz), 3.92 (s, 3H), 3.84 (s, 3H), 1.20 (t, 3H, J=7.3 Hz); MS: calculated for C18H21N4O4S (M−Cl) 389.0; found: 389.0.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:19]=[CH:18][C:14](C(O)=O)=[C:13]([F:20])[C:12]=3[Cl:21])=[CH:6][C:5]=12.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O>CN(C=O)C>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:19]=[CH:18][C:14]([NH2:24])=[C:13]([F:20])[C:12]=3[Cl:21])=[CH:6][C:5]=12
Reactant: O=C(O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vial was charged with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoic acid (0.090 g, 0.2925 mmol), triethylamine (0.1223 ml, 0.8776 mmol) and DMF (1.5 ml). Diphenylphosphoryl azide (0.1630 ml, 0.7313 mmol) was added. The reaction was stirred at ambient temperature for 3 hours, then water (0.2199 ml, 0.2925 mmol) was added. The vial was sealed and heated to 100° C. for 1 hour, then cooled to ambient temperature and poured into 1 N NaOH/ice. The reaction was extracted with EtOAc, and the organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography, eluting with a gradient from 100% EtOAc to 10% (with 6% NH4OH) MeOH/EtOAc.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])O1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:19]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH2:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[N:19]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3N)n2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A 20 mL reaction vial was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.31 g, 1.42 mmol, Oakwood Products, West Columbia, S.C.), tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.06 mmol, Newburyport, Mass.), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.42 g, 1.10 mmol), sodium carbonate (0.29 g, 2.73 mmol), DME (5 mL), and water (1.5 mL). The vial was sealed and purged with argon for several minutes. The reaction mixture was stirred at 90° C. for 2 h and allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic extract was washed with water and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was adsorbed ontodsilica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 0% to 1% MeOH in CH2Cl2 to give the title compound as a light yellow oil. m/z (ESI, +ve ion) 441.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21]C(=O)C)[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11](=[O:14])[CH2:10][CH2:9]1.O.NN.CS(C)=O>[Cl-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH2:21])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[O:14])[CH2:12][CH2:13]1
Reactant: CC(=O)NCC1CC(c2ccc(N3CCS(=O)CC3)c(F)c2)=NO1
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCC1CC(c2ccc(N3CCS(=O)CC3)c(F)c2)=NO1
Temperature: 130 °C
Yield: 104.4 %

Procedure:
423 mg (1.0 mmole) of N-({3-[3-fluoro-4-(1-oxo-1lambda4,4-thiazinan-4-yl)phenyl}-4,5-dihydro-5-isoxazolyl}methyl)acetamide is combined with 1.5 ml hydrazine hydrate and 1.5 ml dimethylsulfoxide in a 15 ml screw cap pressure tube. The reaction is heated to 130° C. for 24 hours. The mixture is cooled to room temperature, is diluted with 25 ml 50% saturated sodium chloride, and is extracted with 5×20 ml 5% methanol/chloroform. The organics are dried over potassium carbonate and are concentrated in vacuo to give 325 mg (87%) of N-({3-[3-fluoro-4-(1-oxo-1lambda4,4-thiazinan-4-yl)phenyl}-4,5-dihydro-5-isoxazolyl}methyl)amine. The crude solid, 315 mg (1.01 mmole) is dissolved in 10 ml 1:1 dichloromethane/tetrahydrofuran in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution is treated with triethylamine (0.28 ml, 2.02 mmole) followed by ethyl dithioacetate (0.23 ml, 2.02 mmole) and the reaction is stirred 1 hour at room temperature. The suspension is brought to homogeneity with chloroform, is treated with 4 g silica gel (230-400 mesh), and is concentrated to dryness. The plug is chromatographed over 30 g silica gel (230-400 mesh) eluting with 2% methanol/dichloromethane for a 350 ml forerun followed by 3% methanol/dichloromethane while collecting 50 ml fractions. Fractions 2-5 are combined and concentrated to provide 277 mg (75%) of the title compouns as solid. mP=199° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([O:17][CH3:18])[CH:9]=1.O.NN>CO>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:17][CH3:18])[CH:9]=1
Reactant: COc1cc(N2CCOC[C@@H]2C)ccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(N2CCOC[C@@H]2C)ccc1N
Yield: 81.3 %

Procedure:
A solution of (3S)-3-methyl-4-[3-(methyloxy)-4-nitrophenyl]morpholine (2.46 g, 9.76 mmol), FeCl3 (0.400 g, 2.44 mmol), activated carbon (2.0 g), and hydrazine hydrate (2.5 mL, 78 mmol) was heated in methanol (150 mL) for 3 hours. Once the starting material was judged consumed by thin layer chromatography (10% MeOH/CH2CL2) the mixture was filtered over celite and concentrated to give 4-[(3S)-3-methyl-4-morpholinyl]-2-(methyloxy)aniline as a dark purple solid (1.76 g, 7.93 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.90 (d, J=6.60 Hz, 3 H), 2.95 (dd, J=6.97, 3.30 Hz, 1 H), 2.98-3.06 (m, 1 H), 3.28 (td, J=6.42, 3.30 Hz, 1 H), 3.50 (dd, J=11.00, 6.60 Hz, 1 H), 3.64 (d, J=13.20 Hz, 2 H), 3.76-3.82 (m, 1 H), 3.83 (s, 3 H), 3.84-3.90 (m, 2 H), 6.50 (dd, J=8.43, 2.20 Hz, 1 H), 6.56 (s, 1 H), 6.66 (d, J=8.43 Hz, 1 H).
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.C(O)C.O.[NH2:18][NH2:19]>O>[CH3:2][O:3][C:4]([C:5]1[CH:10]=[N:18][NH:19][CH:6]=1)=[O:12]
Reactant: NN
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cn[nH]c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
44.45 g of methyl 3,3-dimethoxypropionate and 45 ml of methyl formate was dissolved to 180 ml of dimethoxyethane. Under nitrogen atmosphere, 12.8 g of 60% sodium hydride was added to the solution keeping the temperature of the solution at 40 to 50° C. during addition. Then the mixture was stirred at room temperature for 18 hours. 180 ml of diethylether was added to the reaction mixture, as a result, a solid was formed. The solid was collected by filteration, followed by washing with 60 ml of diethylether. The obtained solid was dried under reduced pressure for overnight to obtain 49.41 g of methyl 2-(dimethoxymethyl)-3-hydroxy-acrylate sodium salt. 9.91 g of methyl 2-(dimethoxymethyl)-3-hydroxy-acrylate sodium salt was suspended to 100 ml of ethanol. 2.50 g of hydrazine hydrate was added to the suspension, followed by stirring at room temperature for 3 hours and at 80° C. for 1 hour. 100 ml of water was added to the reaction mixture which was cooled to room temperature. The mixture was concentrated under reduced pressure to about 100 ml. The concentrated solution was extracted by ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved to ethyl acetate, activated carbon was added to it, and stirred for overnight. The suspension was filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 1.40 g of 4-methoxycarbonyl-1H-pyrazole.
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][C@:5]1([NH2:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1.[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[CH3:19][N:20]1[C:3](=[O:18])[CH2:4][C@@:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[CH2:7][CH2:6]2)[N:17]=[C:21]1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)C[C@@]1(N)CCc2ccc([N+](=O)[O-])cc21
Product: CN1C(=O)C[C@]2(CCc3ccc([N+](=O)[O-])cc32)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from ((S)-1-amino-6-nitro-indan-1-yl)-acetic acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product tert-butyl [(1S)-1′-methyl-6-nitro-6′-oxo-2,3,5′,6′-tetrahydro-1′H-spiro[indene-1,4′-pyrimidin]-2′-yl]carbamate was obtained as pale brown solid. MS (ESI): m/z=373.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=O)=[CH:5][N:6]=1.O.[CH3:17][NH2:18]>C(O)(C)(C)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:4]([OH:3])=[CH:5][N:6]=[C:2]([NH:18][CH3:17])[N:1]=2)=[CH:10][CH:11]=1
Reactant: Nc1ncc(C(=O)c2ccc(F)cc2)o1
Reactant: CN
Solvent: O
Solvent: CC(C)(C)O
Product: CNc1ncc(O)c(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
(2-Amino-1,3-oxazol-5-yl)(4-fluorophenyl)methanone (US2005032859, 1 g, 4.85 mmol) and 40% methyl amine water in excess (50 mL) were combined in tert-butanol (50 mL). The mixture was stirred at 50° C. under nitrogen for 2 hours. The mixture was concentrated in vacuo. The residue was filtered through a pad of silica gel using neat ethyl acetate as eluant. The solution was concentrated in vacuo to afford 0.73 g (66%) of 4-(4-fluorophenyl)-2-(methylamino)pyrimidin-5-ol as a crystalline brown solid. MS m/z 220 [M]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[CH:11]12[O:16][CH:12]1[CH2:13][CH2:14][CH2:15]2>O1CCCC1.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[OH:16])[CH:6]=[CH:7][CH:8]=1
Reactant: C1CC2OC2C1
Reactant: COc1cccc([Mg]Br)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1cccc([C@@H]2CCC[C@H]2O)c1
Yield: 56.3 %

Procedure:
To a solution of 3-methoxyphenyl magnesium bromide 1.0M (59.4 ml, 59.4 mmoles) and copper(I) iodide (0.762 g, 4.0 mmoles), add (dropwise) a solution of cyclopentene oxide (5.2 ml, 59.4 mmoles) in tetrahydrofuran (5 ml) over 40 minutes. The reaction is exothermic and the temperature rises to 45° C. Cool the reaction to ambient temperature and quench with a 25% solution of ammonium chloride (40 ml), extract with ether and shake with brine. Dry the organic layer over sodium sulfate and concentrate in vacuo to yield an oil which is flash chromatographed on silica with 14-25% ethyl acetate/hexanes to yield 6.43 g of the titled compound. 1H NMR (CDCl3): 7.23 (d, J=8.4, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.81 (s, 1H), 6.77 (m, 1H), 4.15 (m, 1H), 3.81 (s, 3H), 2.86 (m, 1H), 2.18-2.04 (m, 2H), 1.9-1.6 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([C:7]([Br:17])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccnc(N)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 2-amino-isonicotinonitrile (10.0 g, 83.9 mmol) in DMF (20 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (16.5 g, 92.3 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (500 mL) and washed with water (200 mL). The aqueous phase was separated and extracted with AcOEt (2×500 ml). The combined organic fractions were dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 98:2→6:4) to yield the title compound (13.0 g, 65.6 mmol, 78%) as a pale yellow solid. MS: 199 [M+1]+; HPLC: AtRet=1.13; TLC: RF 0.39 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:10]([CH3:29])=[N:11][C:12]3[C:17]([N:18]=2)=[C:16]([C:19]2[NH:23][C:22]4[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=4[CH:20]=2)[CH:15]=[CH:14][CH:13]=3)[CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:29][C:10]1[C:9]([NH:8][C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:30](=[O:32])[CH3:31])[CH2:3]2)=[N:18][C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]1[NH:23][C:22]2[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=2[CH:20]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCC[C@H](Nc2nc3c(-c4cc5c([nH]4)[C@@H](C)NC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A mixture of (R)-2-(3-(((1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483) (29 mg, 0.074 mmol), acetic anhydride (35.0 μL, 0.37 mmol), and N-ethyl-N-isopropylpropan-2-amine (91 μL, 0.52 mmol) in DCM (743 μL) was stirred at RT for 30 min when mostly product was observed via LCMS. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aqueous sodium bicarbonate (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product in DCM was loaded onto the column and was purified via automated flash chromatography (silica gel) with 100% DCM to 8% 2 M ammonia in MeOH/DCM to give N-((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)acetamide (486, 19 mg, 0.044 mmol, 59% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 1H) 1.20-1.32 (m, 1H) 1.42 (d, J=6.65 Hz, 3H) 1.44-1.52 (m, 2H) 1.78 (s, 3H) 1.80-1.90 (m, 2H) 2.11 (br. s., 2H) 2.53 (s, 3H) 3.58-3.71 (m, 1H) 4.04-4.17 (m, 1H) 4.54 (q, J=6.59 Hz, 1H) 6.87 (d, J=7.63 Hz, 1H) 6.95 (d, J=1.57 Hz, 1H) 7.33 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.02, 1.37 Hz, 1H) 7.62 (s, 1H) 7.81-7.88 (m, 2H) 11.99 (s, 1H). MS (ESI, pos. ion) m/z: 433.1 (M+1).