Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([C:9]#[N:10])=[N:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.Cl.[NH2:19][OH:20]>CO>[OH:20][N:19]=[C:9]([C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[CH:6][N:7]=1)[NH2:10]
Reactant: CNc1nccnc1C#N
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1nccnc1C(N)=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methylamino-3-cyanopyrazine (J. Heterocycl. Chem. 1992, 29, 1689-92) (0.37 g, 2.8 mmol) in methanol (10 mL) was added triethylamine (0.4 mL, 2.8 mmol) followed by hydroxylamine hydrochloride (0.19 g, 2.8 mmol) and the reaction was stirred at room temperature for 4 hours. The mixture was filtered, the filtrate was then evaporated to dryness. The residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give the title compound was a white solid (0.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH3:26].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:17]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH3:26])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[N:3]=1
Reactant: Cc1cnccc1N
Reactant: Cc1cccc(-c2nc3nccnc3c(=O)[nH]2)n1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Cc1cccc(-c2nc(Nc3ccncc3C)c3nccnc3n2)n1

Procedure:
The title product was synthesized by reaction of the 2-(2-methyl-6-pyridyl)pteridin-4-one with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)-(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: Cl.N1CCCCC1=N.BrC(=COC(C)C)C=O.[CH:18]1([N:21]2[C:25]([CH:26]=[O:27])=[CH:24][N:23]=[C:22]2[CH3:28])[CH2:20][CH2:19]1>>[N:23]1[CH:24]=[C:25]([CH:26]=[O:27])[N:21]2[CH2:18][CH2:20][CH2:19][CH2:28][C:22]=12
Reactant: Cc1ncc(C=O)n1C1CC1
Agent: CC(C)OC=C(Br)C=O
Agent: Cl
Agent: N=C1CCCCN1
Product: O=Cc1cnc2n1CCCC2

Procedure:
5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-3-carbaldehyde (2:1 with 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-2-carbaldehyde) was prepared from piperidin-2-ylideneamine hydrochloride (Aldrich) and 2-bromo-3-isopropoxy-propenal in the same manner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)[CH3:2].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:18][CH2:2][CH2:1][O:3][CH2:4][CH2:5][O:6][CH2:7][CH3:8])=[O:17]
Reactant: CCOCCOCCO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CCOCCOCCOC(=O)CCC(=O)CN
Reaction time: 4 h

Procedure:
From diethylene glycol monoethyl ether (5.0 g; 37 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 4 h. The yield was 0.90 g (53%) of light tan solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=2[F:19])[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[ClH:27]>C(Cl)Cl.CCOCC>[ClH:27].[CH:1]1([C:4]2[CH:5]=[C:6]([CH2:7][NH2:8])[CH:16]=[CH:17][C:18]=2[F:19])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(C2CC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 3-cyclopropyl-4-fluorobenzylcarbamate (0.220 g, 0.829 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL, 64.9 mmol). The solution was stirred at room temperature for 1 h. To the solution was added 2M HCl in Et2O (5 mL). The solids were collected via filtration to give the title compound as a white solid (0.154 g, 92% yield). 1H NMR (400 MHz, MeOD) δ: 7.21-7.33 (1 H, m), 7.03-7.16 (2 H, m), 4.06 (2 H, s), 2.06-2.18 (1 H, m), 0.99-1.09 (2 H, m), 0.74-0.86 (2 H, m). 13C NMR (500 MHz, MeOD) δ: 162.09 (1C, d, J=245.84 Hz), 131.64 (1C, d, J=14.64 Hz), 128.98 (1C, d, J=3.08 Hz), 127.33 (1C, d, J=8.48 Hz), 126.78 (1C, d, J=4.62 Hz), 115.15 (1C, d, J=23.12 Hz), 42.43 (1C, s), 8.03 (1C, d, J=5.39 Hz), 7.04 (1C, s).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[CH2:48][CH2:49][N:50]1[CH2:54][CH2:53][C@H:52]([NH:55]C(=O)OC(C)(C)C)[CH2:51]1>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:48][CH2:49][N:50]3[CH2:54][CH2:53][C@H:52]([NH2:55])[CH2:51]3)=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCO)C1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: N[C@H]1CCN(CCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)C1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-tert-butyl 1-(2-hydroxyethyl)pyrrolidin-3-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.91 (s, 2 H), 8.37 (s, 1H), 8.08 (d, J=1.6 Hz, 2 H), 7.40-7.29 (m, 4 H), 4.43-4.33 (m, 2 H), 3.88-3.78 (m, 1 H), 3.09-2.96 (m, 2H), 2.95-2.74 (3 H), 2.61 (dd, J=9.6, 5.0 Hz, 1 H), 2.43-2.31 (m, 1 H), 1.79-1.68 (m, 1 H); MS (ESI) m/z 451.1 (M−H)−; MS (ESI) m/z 453.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][N:31](C(OCC)=O)[CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)=[CH:4][CH:3]=1.[Si](I)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.C(O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(c2nc(-c3ccc(F)cc3)c(-c3ccnc(N[C@@H](C)c4ccccc4)c3)s2)CC1
Agent: C[Si](C)(C)I
Agent: Cl
Agent: [Na+]
Solvent: CCCO
Solvent: ClC(Cl)Cl
Product: C[C@H](Nc1cc(-c2sc(C3CCNCC3)nc2-c2ccc(F)cc2)ccn1)c1ccccc1
Reaction time: 3 h
Yield: 70.7 %

Procedure:
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole (2 g 3.7 mmol) is dissolved in CHCl3 (37 ml) and treated with Me3SiI (1.5 ml 11.1 mmol) at 60° C. for 5 h. A second portion of Me3SiI (0.75 ml 5.55 mmol ) was added and stirring continued for another 3 h at 60° C. The reaction mixture was combined with 6M HCl in propanol (15 ml), homogenized by vigorous stirring, poured on 2N NaOH and extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 80/18/2) to yield the title compound (1.2 g 71%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1([C:21](O)=[O:22])[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[CH3:54][O:55][C:56]1[CH:68]=[CH:67][C:59]([CH2:60][C:61]2[NH:65][N:64]=[C:63]([NH2:66])[N:62]=2)=[CH:58][CH:57]=1>C(#N)C>[CH3:54][O:55][C:56]1[CH:57]=[CH:58][C:59]([CH2:60][C:61]2[N:62]=[C:63]([NH2:66])[N:64]([C:21]([C:2]3([CH3:1])[CH2:17][C:10]4([N+:18]([O-:20])=[O:19])[C:11]5[C:16]([CH:3]3[C:4]3[C:9]4=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:15][CH:14]=[CH:13][CH:12]=5)=[O:22])[N:65]=2)=[CH:67][CH:68]=1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: COc1ccc(Cc2nc(N)n[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(Cc2nc(N)n(C(=O)C3(C)CC4([N+](=O)[O-])c5ccccc5C3c3ccccc34)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (25 mg, 0.08 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), and N-ethyl-N,N-diisopropylamine (0.1 mL) in anhydrous acetonitrile (1 mL) was added EDCI (38 mg, 0.2 mmol) at RT under argon. After the mixture was stirred at RT for 5 min, 5-(4-methoxybenzyl)-1H-1,2,4-triazol-3-amine (21 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT overnight and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 35 mg (87% yield) of the title compound as a white solid. (M+H)+=496.20
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Si:39]([O:38][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:40])[CH3:41]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 92.3 %

Procedure:
A solution of 5 g (7.6 mmol) 5′-O-(4,4′-dimethoxytrityl)-3′-O-(tert-butyldimethylsilyl)thymidine 17 in 100 ml 80% aq. acetic acid was stirred until the removal of dimethoxytrityl group was completed. Saturated Na2CO3 was then added to adjust the pH of the solution to 6-7. The solution was then extracted with ethyl acetate. The extract was dried and the mixture was chromatographed on a silica gel column (CH2Cl2:MeOH=20:1) to give 2.5 g of 3′-O-(tert-butyldimethylsilyl)thymidine 18 (92.6%).: m.p.93-95° C. (lit. 83-84° C.); H NMR (200 MHz, CDCl3) δ9.18 (s, 1H, NH), 7.36 (b, 1H, H-6), 6.12 (t, J=6.8 Hz, 1H, H-1′), 4.44-4.48 (m, 1H, H-3′), 3.69-3.91 (m, 3H, H-4′, H-5′), 2.87 (m, 1H, OH), 2.15-2.35 (m, 2H, H-2′), 1.87 (S, 3H, C═CMe), 0.86 (s, 9H, CMe3), 0.05 (s, 6H, SiMe2); 13C NMR (125 MHz, CDCl3) δ163.9 (C-4), 150.4 (C-2), 137.1 (C-6), 110.9 (C-5), 87.6 (C-4′), 86.8 (C-1′), 71.5 (C-3′), 61.9 (C-5′), 40.4 (C-2′), 25.7 (SiCMe3), 17.9 (SiCMe), 12.5 (C═CMe), −4.7 (SiMe2), −4.9 (SiMe2).
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[C:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[C:5]([C:6]3[CH:7]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=3)[CH2:4][OH:3])[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(=C1c2ccccc2CCc2ccccc21)c1cccc(NS(C)(=O)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CS(=O)(=O)Nc1cccc(C(CO)=C2c3ccccc3CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
Treat (10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-(3-methansulfonylamino-phenyl)-acetic acid ethyl ester (1 equivalent) with lithium aluminum hydride (2 equivalents) in a suitable dry solvent and stir at room temperature for four hours. Quench by the dropwise addition of water and partition between dichloromethane and water. Dry the organic layer over anhydrous sodium sulfate and evaporate. Purify the crude residue by silica gel chromatography to obtain a 33% yield on the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:21])([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH3:21][C:11]1([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC1(C(=O)N2CCCC2)CCNCC1
Yield: 99.9 %

Procedure:
A solution of 4-methyl-4-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (296 mg, 1.0 mmol) in TFA (5 mL), DCM (5 mL) and water (0.1 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed to give the desired product as a white solid (196 mg, 66%). LCMS (Method A): RT 0.31 min; [M+H]+ 197
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][NH2:28])=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCOC(C)=O>C(#N)C.O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:27][NH:28][C:16]([C:9]2[S:8][C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:22][CH:21]=1
Reactant: O=C(O)c1sc(-c2ncccn2)nc1C(F)(F)F
Reactant: NCC(c1ccc(Cl)cc1)N1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCCCC1)c1sc(-c2ncccn2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-pyrimidin-2-yl-4-trifluoromethyl-thiazole-5-carboxylic acid (60 mg), 2-(4-chloro-phenyl)-2-piperidin-1-yl-ethylamine (60 mg), BOP (100 mg) and TEA (40 mg) in ACN (1 mL) is stirred at RT overnight. EtOAc and water added to the mixture and the organic layer is separated, washed twice with water and concentrated in vacuo. The residue is purified by PTLC (10% MeOH in methylene chloride) to give the title compound. MS (M+1)=496.09; RT=1.14 min. *IC50.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:21])[CH:9]=[CH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.[C:22](=O)(O)[O-:23].[Na+]>CN(C=O)C.O>[CH3:6][O:7][C:8](=[O:21])[CH:9]=[CH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH:22]=[O:23])=[CH:15][NH:16]2
Reactant: COC(=O)C=CCc1cccc2[nH]ccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)C=CCc1cccc2[nH]cc(C=O)c12
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychoride (0.65 g, 4.16 mmol) was added dropwise to DMF (3 mL) at 0° C. After 0.5 hour, Example 7b (0.81 g, 3.70 mmol) in DMF (3 mL) was added at 0° C., then the mixture warmed to 35° C. for 0.75 hour. The solution was cooled to ambient temperature and crushed ice (10 g) was added. Solid sodium bicarbonate was added and to pH 8, the mixture diluted with water (100 mL), and the aqueous extracted with ethyl acetate (3×). The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent removed in vacuo. The residue was chromatographed (eluting ethyl acetate/hexanes) to yield 0.39 g of the title compound as a purple solid; MS(CI/NH3) m/e 244 (M+H)+. 1H NMR(CDCl3, 300 MHz) δ3.68 (s, 3H), 4.26 (m, 2H), 5.14 (m, 1H), 7.06 (d, 1H), 7.18 (m, 3H), 7.84 (d, 1H), 9.09 (br s, 1H), 9.88 (s, 1H).
Reaction SMILES: [C:1]([C:3]1([CH3:15])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[N:2].[ClH:16]>CO>[ClH:16].[CH3:15][C:3]1([C:1]#[N:2])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC1(C#N)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CC1(C#N)CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of tert-butyl 3-cyano-3-methylpyrrolidine-1-carboxylate (0.50 g, 2.38 mmol) was dissolved in 1.0 M HCl in MeOH (12 mL). The reaction mixture was stirred at room temperature overnight then concentrated to afford 0.38 g of 3-methylpyrrolidine-3-carbonitrile hydrochloride as a hydroscopic white foamy solid which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[S:21][CH:20]=[N:19][CH:18]=3)[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.CO.[Pd]>[S:21]1[C:17]([C:13]2[CH:12]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)=[CH:18][N:19]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Yield: 92.6 %

Procedure:
A solution of 5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.18 g, 0.599 mmol) in EtOAc (10 mL) and MeOH (3 mL) was treated with 10% Pd/C (50% wet, 0.064 g, 0.060 mmol) and hydrogenated (1 atm) for 16 h. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate was concentrated to dryness to afford 5-((2-(thiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (150 mg, 74%). MS (ESI) m/z: 271.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH3:27].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH3:27])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: Cc1cnccc1N
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Cc1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]3[NH:11][C:10](=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:13]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2cc(=O)[nH]c3cc(C)nn23)c1
Solvent: c1ccncc1
Product: Cc1cccc(-c2cc(Cl)nc3cc(C)nn23)c1
Temperature: 25 °C

Procedure:
7-(3-Methylphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (673 mg) is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (381 mg). 1H NMR (CDCl3, 300 MHz): δ 7.79 (m, 2H), 7.45 (m, 3H), 6.77 (m, 1H), 6.46 (s, 1H), 2.50 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: I[C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].C(N(CCCC)CCCC)CCC.CC(C)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:18][C:3]1[C:2](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N

Procedure:
3-Iodo-4-(4-nitrophenoxy)-2-pyridinamine (500 mg), ethyl acrylate (0.3 ml), palladium (II) acetate (30 mg), tributylamine (0.66 ml) and dimethylformaldehyde (5 ml) were stirred at 130° C. for 20 minutes. After returning the reaction solution to room temperature, water was added and extraction was performed with ethyl acetate. NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=3:1). The solvent was distilled off under reduced pressure to obtain 330 mg of the target substance as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:12])[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1.Cl[CH2:14][C:15](=[O:17])[CH3:16].[NH4+].[Cl-]>CN(C=O)C>[CH3:3][C:4]1([CH3:12])[CH2:9][C:8](=[O:10])[CH:7]([CH2:14][C:15](=[O:17])[CH3:16])[C:6](=[O:11])[CH2:5]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)CC1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An oven dried flask was charged with sodium hydride (3.61 g, 142.7 mmol) to which 200 mL of anhydrous DMF was added. The flask was cooled in an ice bath before adding 5,5-dimethyl-1,3-cyclohexanedione (20.0 g, 142.7 mmol) and chloroacetone (11.36 mL, 142.7 mmol) in 100 mL DMF in a controlled manner. The reaction was allowed to warm to RT and stirred for 3 h. Saturated NH4Cl was added and the mixture was washed several times with EtOAc. The combined organic layer was dried over MgSO4, filtered, the solvent removed in vacuo (below 40° C.). LCMS m/z M+H=197.1.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:35]([CH2:36][CH2:37][C@:20]12[CH3:21])[C@:33]1([CH3:34])[C:28](=[CH:29][CH2:30][CH2:31][CH2:32]1)[CH2:27][CH2:26]3>C(OCC)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:35]([CH2:36][CH2:37][C@:20]12[CH3:21])[C@:33]1([CH3:34])[C:28](=[CH:29][CH2:30][CH2:31][CH2:32]1)[CH2:27][CH2:26]3
Reactant: C1=COCCC1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 ml of dihydropyran containing 450 mg of p-toluenesulfonyl chloride is added 6.0 g of the product of Step B and the solution is stirred at room temperature for 1 hour. The solution is the diluted with ethyl ether and washed with a 20% pyridine water mixture twice, and then water, then brine, and dried and evaporated to yield a pale yellow oil which crystallizes (8.5 g), and has a m.p. of 92°-96° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][CH2:12][C:13](O)=[O:14].FC(F)(F)S(O)(=O)=O.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:9])[O:8][CH2:11][CH2:12][C:13]2=[O:14]
Reactant: O=C(O)CCCl
Reactant: Oc1ccc(F)c(O)c1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: O=C1CCOc2cc(O)c(F)cc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a 15 mL vial was added 4-fluorobenzene-1,3-diol (500 mg, 3.9 mmol) and 3-chloropropanoic acid (424 mg, 3.9 mmol) and trifluoromethanesulfonic acid (2 mL). The mixture was heated to 80° C. and stirred at that temperature for 4 hour. The reaction was cooled and poured into water (10 mL). The product was extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated. To the dark red solid obtained was added sodium hydroxide (2 N, 5 mL) and the solution was let stirred at RT for 18 hours. The mixture was neutralized with 2 N HCl, extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated. The crude was used to next step without purification. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.61 (1H, d, J=10.3 Hz), 6.56 (1H, d, J=3.1 Hz), 4.48 (2H, t), 2.78 (2H, t).