Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([OH:4])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (105 mg, 0.23 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 105 mg of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid as a light orange solid, which was immediately used in the next step without purification.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([OH:23])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:24][CH2:25][C:26](O)=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([O:23][C:26](=[O:27])[CH2:25][Cl:24])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CC[C@@H](CCCc2ccccc2)[C@H](O)C1
Reactant: O=C(O)CCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCOC(=O)N1CC[C@H](CCCc2ccccc2)[C@H](OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.242 g (0.75 mmol) of 1-butyloxycarbonyl (trans)-3-hydroxy4-(3-phenylpropyl)piperidine, 0.189 g (1.5 mmol) of chloroacetic acid, and 0.524 g (1.5 mmol) of triphenylphosphine in 5 mL of THF at 0° C. was slowly added 0.348 g (1.5 mmol) of diethylazodicarboxylate (DEAD). The reaction mixture was allowed to warm to rt and was stirred for 16 h. To the reaction mixture was added 20 mL of ether and it was filtered through a thin pad of celite. The filtrate was washed with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:31]1([C:34]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Yield: 68.3 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[3-(trifluoromethyl)phenyl]benzamide (429 mg, 1.00 mmol), cyclopropanecarbonyl chloride (525 mg, 5.0 mmol) and N,N-dimethylpyridine-4-amine (610 mg, 5.00 mmol) in pyridine (5 mL) was stirred at room temperature for 2 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (340 mg, 68%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(OCC)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)cc1
Solvent: CCOCC
Product: O=C(CBr)c1ccc(F)cc1
Yield: 79 %

Procedure:
In 25 ml of diethyl ether was dissolved 5.00 g (36.2 mmol) of p-fluoroacetophenone and while stirring the solution on an ice bath, 5.8 g (36.2 mmol) of bromine was dropped. After dropping, the mixture was stirred for 5 minutes and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform 100%). The results of NMR measurement revealed that it contained the target compound, and in addition, the raw materials and a dibromo form as a side product. Yield after adjustment was 6.21 g and % yield was 79.0%.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(O)C>[CH3:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.266 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for ½ h. acidified with 5% aqueous citric acid and extracted with ethyl acetate, dried and evaporated to dryness. Yield: 100 mg (75%). HPLC-MS: m/z: 535.7 (M)+; Rt: 2.78 min.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([CH:36]=[C:37]([CH3:39])[CH:38]=2)[NH2:35])[CH2:27][CH2:26]1)(=[O:24])[CH3:23]>CO.C(Cl)Cl>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([NH:35][C:5]3[N:10]=[C:9]([N:11]4[CH:15]=[CH:14][N:13]=[C:12]4[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:8]=[CH:7][N:6]=3)[CH:36]=[C:37]([CH3:39])[CH:38]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: CS(=O)(=O)c1nccc(-n2ccnc2-c2ccccc2)n1
Reactant: CC(=O)N1CCN(Cc2cc(C)cc(N)c2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(Cc2cc(C)cc(Nc3nccc(-n4ccnc4-c4ccccc4)n3)c2)CC1
Temperature: 130 °C

Procedure:
2-(Methylsulfonyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (1-3, 100 mg, 0.33 mmol) and 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylaniline (240 mg) were combined neat and heated to 130° C. After 2 hours the mixture was cooled to room temperature. Flash column chromatography (gradient, 2-5% MeOH/CH2Cl2) gave the title compound as an off-white foam. 1H-NMR (300 MHz, CDCl3) δ 8.26 (d, J=5.5 Hz, 1H), 7.68 (d, J=1.53 Hz, 1H), 7.50 (m, 2H), 7.40 (m, 4H), 7.30 (s, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 6.25 (d, J=5.49 Hz, 1H), 3.64 (t, J=5.19 Hz, 2H), 4H), 3.46 (m, 4H), 2.44 (m, 4H), 2.35 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=[O:11])=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14]([NH:16][C:17]1[S:21][C:20]2[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=2[C:18]=1[C:26]([NH:28][CH3:29])=[O:27])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH:28][CH3:29])=[O:27])=[O:15])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: CC(C)(C)c1n[nH]cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(C)(C)C)n2)sc2c1CCCC2
Temperature: 60 °C
Yield: 90.7 %

Procedure:
3-Tert-butyl-1H-pyrazole-4-carbaldehyde (150 mg, 0.986 mmol), 2-(2-bromoacetamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (490 mg, 1.478 mmol) and potassium carbonate (545 mg, 3.94 mmol) were mixed with DMF (5 mL) and heated for 3 h at 60° C. The reaction was partitioned between water and EtOAc. Organics were combined and purified by chromatography (0-60%, EtOAc/heptane) to give the title product as a white solid (360 mg, 0.894 mmol, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=2)[N:3]=1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:25][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:4]2[C:5]([CH3:13])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3]2)=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethanol (step 1 of Example 2, 100 mg, 0.34 mmol) in toluene (3 mL) and chloroform (1 mL) was added thionyl chloride (50 μL, 0.68 mmol), and the resulting mixture was stirred at 80° C. for 3h. The reaction mixture was quenched by 2 M NaOH aq. and extracted with dichloromethane. Organic layer was dried (Na2SO4) and the solvent was evaporated to give the title compound as brown solids (quant.): MS (ESI) m/z 311 [M+H]+, 1H-NMR (CDCl3) δ 7.46-7.31 (9H, m), 3.74 (2H, t, J=7.3 Hz), 3.12 (2H, t, J=7.3 Hz), 2.34 (3H, s), 2.30 (3H, s).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:16])[O:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH3:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[N-:17]=[N+:18]=[N-:19].[NH4+]>CCO>[CH2:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[C:3]=1[C:1]1[NH:19][N:18]=[N:17][N:2]=1)[CH2:14][CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(C#N)c(=O)oc2ccccc12
Agent: [NH4+]
Solvent: CCO
Product: CCCc1c(-c2nnn[nH]2)c(=O)oc2ccccc12

Procedure:
The reaction of 3-cyano-4-n-propyl coumarin (41.67 g; 0.196 mole) with ammonium azide as described in Example 1 afforded the title product, m.p. (EtOH) 178°-181° C (Found; C, 61.03; H, 4.95; N, 22.48; C13H12N4O2 requires; C, 60.93; H, 4.72; N, 21.86%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[CH2:38]([N:46]=[C:47]=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:47]([NH:46][CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C=NCCc1ccccc1
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCN(C(=O)NCCc3ccccc3)CC2)cc1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in NMP (2 mL) at room temperature was treated with phenethylisocyanate (0.2 mmol), stirred for 18 hours, diluted with water, and centrifuged. The solid was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 687 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.75 (t, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.75 (d, 2H), 7.39-7.34 (m, 2H), 7.31-7.14 (m, 9H), 6.94 (d, 2H), 6.71 (t, 1H), 3.66 (q, 2H), 3.42-3.39 (m, 4H), 3.30-3.21 (m, 8H), 2.72 (dd, 2H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=O)[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([Cl:28])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Product: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Yield: 98.5 %

Procedure:
2-(biphenyl-4-ylmethyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (25 mg, 0.075 mmol) is refluxed in POCl3 (10 mL) for 60 hours, and the mixture is evaporated to dryness. The residue is purified by silica gel flash chromatography to give 26 mg product as white solids (Yield: 98.5%). 1H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 5.45 (s, 2H), 7.39 (m, 3H), 7.43 (m, 2H), 7.59 (m, 4H), 8.01 (s, 1H). MS (FAB) m/z 351.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([Cl:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:3]=1.Br[CH2:23]CBr>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:23][O:10][C:6]=2[C:5]([Cl:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:20][CH2:21]3)=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Clc1c(Cc2ccc(C3CC3)cc2)cc(Br)c2c1OCO2
Reactant: BrCCBr
Product: Clc1c(Cc2ccc(C3CC3)cc2)cc(Br)c2c1OCCO2

Procedure:
Similar procedure with preparation of 193 proceeded except for using 1,2-dibromoethane to obtain the compound 200.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:14][CH2:15][CH2:16][N:17]1[CH:21]=[C:20]([CH:22]=O)[CH:19]=[N:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:22][C:20]3[CH:19]=[N:18][N:17]([CH2:16][CH2:15][OH:14])[CH:21]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=Cc1cnn(CCO)c1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OCCn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.789 g, 4.01 mmol) and 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.562 g, 4.01 mmol) in DCE (35 mL) add sodium triacetoxyborohydride (1.28 g, 6.02 mmol) and acetic acid (0.382 mL) and stir at room temperature for 20 hr. Add saturated aqueous sodium bicarbonate, separate the layers, extract the aqueous layer twice with DCM, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 6:94 methanol (with 2N ammonia):DCM to give the title preparation as a yellow oil (1.16 g, 90%). MS (ES): m/z=323 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]
Reactant: COCCOCCl
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCOc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid methyl ester 9.9 g (50 mmol) in dimethylformamide 100 mL were added K2CO3 7.6 g (55 mmol) and chloromethoxyethoxymethane 6.3 mL (55 mmol), followed by stirring at room temperature for 2 hrs. The resulting reaction mixture was concentrated in a vacuum, diluted with ethylacetate and washed with distilled water and a saturated NaCl solution. The residue was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound 14.0 g (yield 98%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[N:33][CH:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[N:33][CH:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M114) (1.47 g, 2.29 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (1.0 g, 99%).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([NH2:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[H-].[Na+].C(OCC)(=O)C>CS(C)=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:5](=[O:6])[C:7]([CH3:9])=[N:8][NH:1][C:2]2=[O:3])=[CH:13][CH:12]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1n[nH]c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
According to Scheme 4 Step 1: To a solution of Azathymine (300 mg, 2.36 mmol) and 4-chlorobenzyl bromide (485 mg, 2.36 mmol) in DMSO (10 mL) was added portionwise NaH (55%) (103 mg, 2.36 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for 15 min at room temperature. Ethyl Acetate was then added (150 mL) and the organic layer was extracted thrice with water (100 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow solid. The crude solid was purified by flash chromatography with silica gel using CH2Cl2/MeOH 98/2 as eluant to afford 4-(4-chlorobenzyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione 8(A) (500 mg, 84%) as a white solid.
Reaction SMILES: [C:1]([Sn](CCCC)(CCCC)CCCC)#[CH:2].Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:28])=[N:26][N:27]=2)=[C:19]([O:29][CH3:30])[CH:18]=1>C1COCC1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:28])=[N:26][N:27]=2)=[C:19]([O:29][CH3:30])[CH:18]=1)#[CH:2]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)ccc1-c1nnc(C)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2nnc(C)o2)c(OC)c1
Temperature: 120 °C
Yield: 50 %

Procedure:
Pd(Ph3P)4 (100 mg, 0.087 mmol) and ethynyltributylstannane (600 mg, 1.904 mmol) was treated with a solution of 2-(4-bromo-2-methoxyphenyl)-5-methyl-1,3,4-oxadiazole (457.7 mg, 1.701 mmol) in 10 ml of THF and heated to 120° C. for 15 minutes in a microwave. The reaction was dissolved in brine and extracted three times with EtOAc. Organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (100% hexanes followed by 0-25% EtOAc/DCM) gave a cream-colored solid (180 mg, 0.850 mmol, 49%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23](=[O:25])(=[O:24])[N:22](C(C)(C)C)[C:21](=[O:30])[CH:20]=2)=[CH:15][CH:14]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5].[N:31]([C@@H:34]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:35]([O:37]C)=[O:36])=[C:32]=[O:33].C(N(CC)CC)C>CN(C)C=O>[CH2:7]([NH:6][C:4]([C@@H:3]([NH:2][C:32](=[O:33])[NH:31][C@@H:34]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:35]([OH:37])=[O:36])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23](=[O:25])(=[O:24])[NH:22][C:21](=[O:30])[CH:20]=2)=[CH:15][CH:14]=1)=[O:5])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCNC(=O)[C@@H](N)Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCNC(=O)[C@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)NC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A solution of 9-E (150 mg, 0.33 mmol), methyl (S)-(−)-2-isocyanato-3-phenylpropionate (120 μL, 0.66 mmol), and triethylamine (140 μL, 0.99 mmol) in dimethylformamide (2 mL) was stirred at 25° C. for 16 h. The reaction mixture was treated with Triamine-3 functionalized silica gel (1.2 mmol) and stirred for 1 h. The reaction mixture was filtered through a short plug of silica gel and washed with ethyl acetate (10 mL). The filtrate was concentrated and used without further purification. The crude product was dissolved in trifluoroacetic acid (10 mL) and heated at 70° C. for 16 h. The reaction mixture was concentrated and purified using preparative LCMS to yield the product (29 mg, 15%) as a white solid. 1H NMR (500 MHz, CD3OD): δ 7.83 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 2H), 7.31–7.28 (m, 2H), 7.25–7.22 (m, 1H), 7.18 (dd, J=8.3, 1.5 Hz, 2H), 7.02 (s, 1H), 4.53 (dd, J=7.8, 5.9 Hz, 1H), 4.44 (dd, J=7.3, 6.8 Hz, 1H), 3.69 (s, 3H), 3.19–3.04 (m, 4H), 3.00–2.94 (m, 2H), 1.42–1.35 (m, 2H), 1.34–1.28 (m, 2H), 1.24–1.19 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); LCMS found for C28H35N4O7S (M+H)+: m/z=571.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])[CH:12]=[CH:11][C:10]=1[CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35]>CN(C=O)C.C(N(CC)CC)C>[CH2:2]([N:39]1[CH2:38][CH2:37][N:36]([C:34](=[O:35])[CH2:33][CH2:32][C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:26][C:25]4[CH:24]=[N:23][N:22]([CH3:27])[C:21]=4[NH:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)=[O:16])=[CH:14][C:9]=2[CH3:8])[CH2:41][CH2:40]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCNCC1
Reactant: CCCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCN1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-piperazin-1-yl-propan-1-one from Example E47 (2.29 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=543.4