Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:5].[C:15]([O:20][CH3:21])(=[O:19])/[CH:16]=[CH:17]/[CH3:18]>C(O)(=O)C>[CH3:18][CH:17]([CH:12]([C:13]#[N:14])[C:11]1[C:6]([C:4]#[N:5])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][C:15]([O:20][CH3:21])=[O:19]
Reactant: N#CCc1cccnc1C#N
Reactant: C/C=C/C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(C)C(C#N)c1cccnc1C#N

Procedure:
A catalytic amount of a 5% strength methanolic sodium methylate solution is added to a mixture of 4.9 g (0.03 mol) of 2-cyano-3-pyridylacetonitrile and 3.4 g (0.03 mol) of methyl crotonate with stirring at a rate such that the reaction temperature remains below 40° C. When the evolution of heat has subsided, the mixture is neutralized using dilute acetic acid. The mixture is extracted with chloroform and the organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified over a silica gel column using chloroform as eluent.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>CO.C(O)C.[C].[Pd]>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:15]1[N:16]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:18][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: CC(=O)Nc1nc(-c2ccco2)c(N2CCN(Cc3ccccc3)CC2)s1
Agent: [Pd]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1nc(-c2ccco2)c(N2CCNCC2)s1
Yield: 19.3 %

Procedure:
Compound 79 (274 mg, 0.72 mmol) was dissolved in methanol (7 mL), and 10% palladium-carbon (274 mg) was added thereto, followed by stirring in an atmosphere of hydrogen at 50° C. for 24 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to afford a free form of the entitled Compound. The resulting free form was dissolved in ethanol (5 mL), fumaric acid (83.0 mg, 0.51 mmol) was added thereto, and the precipitated solid was collected by filtration to afford the entitled Compound 80 (40.1 mg, 14%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Temperature: 55 °C
Yield: 83.3 %

Procedure:
To a solution of 4-bromo-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (0.50 g, 1.47 mmol) in ethanol (5.0 mL), was added SnCl2.2H2O (1.3 g, 5.88 mmol) and the mixture was heated at 55° C. overnight. The ethanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO4 and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.38 g, 85%). LCMS m/z (%)=311 M+H+, (79Br, 100), (81Br, 96.5), 1H NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.72 (dd, J1=8.01 Hz, J2=2.78 Hz, 1H), 6.54 (d, J=2.78 Hz, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J=6.57 Hz, 3H), 1.23 (d, J=6.57 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:16]O>>[CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:16])=[O:5]
Reactant: CCCC[C@@H](C)CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCC[C@@H](C)CC(=O)OC
Yield: 76.8 %

Procedure:
In a 500 ml flask were charged 300 ml of methanol, 35.5 g of (R)-3-methylheptanoic acid obtained in Step 3, and 0.5 g of concentrated sulfuric acid, and the mixture was heated at a methanol refluxing temperature for 18 hours. Methanol was distilled off under reduced pressure, and the residue was extracted with diethyl ether. The extract was washed with water, neutralized with a sodium carbonate aqueous solution, and then washed with a sodium chloride aqueous solution. Diethyl ether was removed by distillation, and the residue was distilled under reduced pressure to obtain 29 g (76.8%) of the titled compound (b.p.: 80° C./20 mmHg).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[NH:8][C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4].Cl[CH2:33][O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH2:33][O:34][CH3:35])[C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4]
Reactant: COCCl
Reactant: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)n(COC)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (0.88 g), chloro(methoxy)methane (0.19 mL), potassium carbonate (0.58 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].O=[C:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:24][CH:25]=2)[N:17]=[C:16]2[N:26]([CH:29]([CH3:31])[CH3:30])[N:27]=[CH:28][C:15]=12)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 g, 2.38 mmol) in methanol (15 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (1.18 g, 5.95 mmol) and acetic acid (0.17 g, 2.85 mmol) stirred it at room temperature for 2 days. Then NaBH3CN (0.224 g, 3.57 mmol) was added to it resulting reaction mixture was stirred at room temperature for 8 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.5 g, 34.5%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26](=[O:29])[NH:27][NH2:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26](=[O:29])[NH:27][N:28]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: COc1ccc(NC(=O)NN)cc1OC
Agent: Cl
Product: COc1ccc(NC(=O)NN=c2c(=O)c3ccccc3c2=O)cc1OC

Procedure:
ninhydrin, 4-(3,4-dimethoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]([CH:37]([CH3:39])[CH3:38])=[C:35]=[O:36]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:35]([NH:34][CH:37]([CH3:39])[CH3:38])=[O:36])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)Nc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 60 °C
Yield: 20.4 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol) obtained in Example B19, and 2-isocyanato-propane (3 equiv, 0.00063 mol) in THF (1 ml) was heated at 60° C. for 5 hours. A few drops of water were added. The mixture was evaporated till dryness and purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.024 g (20.3%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-N′-(1-methylethyl)-urea, MS (ESI) m/z: 561 563 565.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CCCCCC.C(OCC)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]([NH2:6])=[NH:17])=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
380 mL 1N LiHMDS-solution in n-hexane was added to 20 g 4-fluoro-benzonitrile in 1 L diethylether. The reaction was stirred 2 h at RT and 4N HCL solution was added at 0° C. until pH=12. The water layer was extracted with chloroform. The organic layer was dried and evaporated to give 6.64 g of the desired product. Rt: 2.28 min (method K), (M+H)+: 139
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:35][CH:36]1[CH2:39][C:38]([F:41])([F:40])[CH2:37]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][C:38]1([F:41])[CH2:39][CH:36]([CH2:35][O:17][C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:7]4[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:3][C:2]=4[F:1])[O:9][C:10]=3[CH:16]=2)[CH2:37]1
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (770 mg), (3,3-difluorocyclobutyl)methyl methanesulfonate (459 mg), potassium carbonate (317 mg), and DMF (10 mL) was stirred at 60° C. for 2 hr. Then additional (3,3-difluorocyclobutyl)methyl methanesulfonate (459 mg) and potassium carbonate (317 mg) were added, and the mixture was stirred at 60° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (780 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[C:6]([F:13])[C:5]=1[F:14])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)=[C:6]([F:13])[C:5]=1[F:14])[CH3:2]
Reactant: Brc1ccc(I)cc1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Temperature: 25 °C
Yield: 94 %

Procedure:
4-Ethoxy-2,3-difluorophenylboronic acid (7) (14.4 g), 4-bromoiodobenzene (8) (20.0 g), potassium carbonate (29.3 g), Pd(Ph3P)2Cl2 (1.49 g), toluene (100 ml), Solmix A-11 (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. Then, the solution was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization (Solmix A-11), giving 20.8 g of 4-ethoxy-4′-bromo-2,3-difluoro-1,1′-biphenyl (9). The yield based on the compound (8) was 94.0%.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28]([C:30]1([C:33]([O:35]C)=O)[CH2:32][CH2:31]1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:38].[Na+]>N.CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28]([C:30]1([C:33]([NH2:38])=[O:35])[CH2:31][CH2:32]1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: COC(=O)C1(C(=O)N2CCN(c3ccc(OC)c(OC4CCCC4)c3)C[C@@H]2Cc2ccccc2)CC1
Agent: N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)C3(C(N)=O)CC3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 22 %

Procedure:
A solution of (S)-methyl 1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazine-1-carbonyl)cyclopropanecarboxylate (123 mg, 0.25 mmol) was dissolved in a 7 N ammonia solution in MeOH (10 mL), treated with catalytic amount of sodium cyanide, then heated in a sealed tube at 80° C. for 5 days. The reaction mixture was then evaporated, washed with water and air dried to afford a residue then purified by silica gel flash chromatography with 50% then 100% EtOAc/hexanes as eluant to afford the title compound as colorless foam (26 mg, 22%). LC/MS (Method B) 3.49 min, [M+1]+ 478.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CN1C(=O)CCC1>[C:17]([C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1)#[N:18]
Reactant: [C-]#N
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(CCNC(=O)C(F)(F)F)cc1
Temperature: 200 °C

Procedure:
A mixture of N-(4-bromophenethyl)-2,2,2-trifluoroacetamide (2.96 g, 10 mmol), NiBr2 (2.19 g, 10 mmol) and NaCN (0.98 g, 20 mmol) in 2.0 mL of NMP was heated at 200° C. in microwave twice. After cooling down to RT, the mixture was filtered with the help excess of DCM. The filtrate was evaporated to dryness and was submitted to flash chomatography (SiO2, DCM to DCM/EtOAc=3:1) to give (N-(4-cyanophenethyl)-2,2,2-trifluoroacetamide was a white solid, together with 1.1 g for recovered starting material.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:20][N:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=[C:7]2[N:6]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:22]=2)[CH2:5]1.[CH3:36][C:37]([CH3:39])=O.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:37]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:20][N:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=[C:7]2[N:6]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:22]=2)[CH2:5]1)([CH3:39])[CH3:36]
Reactant: NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(2-Amino-ethyl)-9-(2-phenethylamino-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (70 mg, 0.15 mmol), acetone (0.02 mL), dichloromethane (0.5 mL) and methanol (0.5 mL) was added sodium triacetoxyborohydride (38 mg, 0.18 mmol) Reaction stirred for 2 h at room temperature. Solvents removed under vacuum. Residue partitioned between dichloromethane and 5% sodium bicarbonate. Organics purified on silica to afford a white solid. M+1=510. 1NMR (CDCl3) d (6H, 1.17 ppm), m (2H, 1.68 ppm), m (1H, 2.32 ppm), m (3H, 2.78 ppm), t (2H, 2.94 ppm), m (1H, 3.55 ppm), dd (2H, 3.70 ppm), d (1H, 4.40 ppm), dd (1H, 4.53 ppm), m (1H, 5.10 ppm), s (1H, 6.60 ppm), m (3H, 7.24 ppm), m (2H, 7.32 ppm), m (3H, 7.44 ppm), m (2H, 7.90 ppm) d (1H, 8.18 ppm).
Reaction SMILES: C(O)(=O)C.[NH2:5][NH2:6].[CH3:7][O:8][C:9](=[O:21])[C:10](=O)[CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)(=O)C>[CH3:7][O:8][C:9]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:6][N:5]=1)=[O:21]
Reactant: COC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccccc2)[nH]n1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
983 mg hydrazine acetate was added to 2 g 2,4-Dioxo-4-phenyl-butyric acid methyl ester in 10 mL concentrated acetic acid. The mixture was stirred over night at RT. Then water was added. The precipitate was filtered, stirred with diisopropylether and again filtered to give 1.3 g desired product. Rt: 1.39 min (method O), (M+H)+: 203
Reaction SMILES: C[O:2][C:3](=[O:38])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[NH:32]1[C:33]2[C:29](=[C:28]([CH2:27][NH:26][C:25]([C:19]3[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:38])=[O:2])=[O:16])=[C:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=3)=[O:37])[CH:36]=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (S)-2-({5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-isopropyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (109.6 mg, 0.020 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (84 mg, 2.0 mmol) in water (6 mL). The mixture was then stirred at room temperature 2 d. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 85.8 mg (79%). MS m/e 540.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([NH2:29])[C:24]([CH3:30])=[CH:23]2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([NH:29][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[C:24]([CH3:30])=[CH:23]2
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: COc1ccc2c(c1)cc(C)n2N
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C)n2NC(=O)c1cnc(-c2cccc(F)c2)nc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (719 mg, 3.1 mmol) and 5-methoxy-2-methyl-indol-1-ylamine (550 mg, 3.1 mmol) in DMF (4 mL) is stirred at 50° C. for 15 min. The mixture is treated with DMTMM (856 mg, 3.1 mmol) and stirred at 50° C. for 1 h. The mixture is concentrated in vacuo, diluted with EtOAc (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methoxy-2-methyl-indol-1-yl)-amide (180 mg, 15%, 2 steps). MS: 391 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.34 (d, 1H), 8.18 (d, 1H), 7.63 (m, 1H), 7.46 (m, 1H), 7.31 (d, 1H), 7.02 (d, 1H), 6.77 (m, 1H), 6.25 (s, 1H), 3.76 (s, 3H), 2.77 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24](OC)[O:25]C)=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH3:1][C:2]1[NH:3][C:4]([CH:24]=[O:25])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Yield: 98.2 %

Procedure:
To a solution of dimethyl 2-methyl-4-(2-cyanophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (6.0 g) in acetone (60 mg) was added 6 N hydrochloric acid (6 ml), and the resultant mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with water (30 ml), and adjusted to pH 7.5 with an aqueous sodium bicarbonate solution, and acetone was distilled off under reduced pressure. The resultant crystalline mass was crushed as finely as possible with a glass rod, washed with an additional water (100 ml), collected by filtration, further washed thoroughly with water, and air-dried to give crystalline powder of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (5.19 g).