Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:23])[C:10]([C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:15])[CH3:14])=[N:11][N:12]=1.[CH2:24]=O.S(=O)(=O)(O)O.[BH4-].[Na+].[OH-].[Na+].[Cl-].[Na+]>C(Cl)(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:23])[C:10]([C:13]([N:16]([CH3:24])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([CH3:15])[CH3:14])=[N:11][N:12]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)Nc1ccccc1
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN(c1ccccc1)C(C)(C)c1nnc(-c2ccccc2Cl)n1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a THF (7 ml) solution of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}aniline (200 mg) were added 36% formaldehyde solution (0.14 ml) and 1.5M sulfuric acid (0.05 ml) and, after stirring at room temperature for 10 minutes, sodium borohydride (81 mg) was added thereto, followed by stirring at room temperature for 10 minutes. After a 1M aqueous sodium hydroxide solution was added to the reaction solution, the reaction solution and chloroform were added to a saturated aqueous sodium chloride solution and then the organic layer was separated. Furthermore, the organic layer was dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=99:1) and the resulting solid washed with hexane to obtain 72 mg of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}-N-methylaniline (colorless solid).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>C(O)C>[CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)COc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cccc2cnccc12
Reaction time: 12 h

Procedure:
In 10 ml of acetonitrile, 1.0 g of 5-hydroxyisoquinoline and 1.52 ml of ethyl bromoacetate were added in the presence of 2.07 ml of DBU and the resultant mixture was refluxed for 8 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in 1N-HCl, washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and subjected to a silica gel column chromatography (chloroform) to give 1.46 g of ethyl 5-isoquinolyl-oxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 6.5 ml of 1N-NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N-HCl and the precipitated crystals were filtered, washed with water and dried to give 0.68 g of the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)=[N:8][C:9]=1S(C)(=O)=O.Cl.[CH3:31][CH:32]([OH:34])[CH3:33]>>[NH2:3][C:4]1[N:5]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)=[N:8][C:9]=1[O:34][CH:32]([CH3:33])[CH3:31]
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
In a sealed tube, NaH (60% in oil suspension) (31.1 mg) was added 2-propanol (0.6 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and an aqueous layer was removed by decantation to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6-(5-amino-6-isopropoxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (102 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([NH:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:36]=2)[CH2:28][CH2:27]1)(OC(C)(C)C)=O>>[CH2:43]([N:42]1[C:37]2[CH:36]=[C:35]([O:34][CH2:33][CH2:32][N:29]3[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]3)[CH:40]=[CH:39][C:38]=2[N:41]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)[CH2:44][CH2:45][CH3:46]
Reactant: O=Cc1ccc(OCCc2ccc(Cl)cc2)cc1
Reactant: CCCCNc1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2)nc2ccc(OCCN3CCNCC3)cc21
Yield: 59.6 %

Procedure:
A mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-benzaldehyde (0.08 g)and 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (0.10 g) was subjected to General Procedure K. Ethanol was removed in vacuo and the residue purified on silica gel with 1–2% MeOH/DCM. The BOC-group was removed employing General Procedure T1 to give 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole (0.081 g).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:19][C@H:11]2[CH2:12][N:13]([C:15](=[O:18])[NH:16][CH3:17])[CH2:14][C@@:10]2([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:19][C@H:11]2[CH2:12][N:13]([C:15]([NH:16][CH3:17])=[O:18])[CH2:14][C@@:10]2([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9]1
Reactant: CNC(=O)N1C[C@@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product from Step A (0.08 g, 0.156 mmol) in TFA (1.5 mL) and DCM (1.5 mL) was stirred at rt for 1.5 h. The volatile organic compounds were removed by evaporation, and the residue was diluted with DCM and evaporated again to give the product as a TFA salt. LC/MS: C19H24F3N5O2: m/z 412.5 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:25][CH3:26])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]1=[O:24])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@@H:2]([CH2:25][CH3:26])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccnc2C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccnc2C)C1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 175.8 %

Procedure:
A solution containing the product from Example 15B (2.3 g, 6.37 mmol) in dichloromethane (15 mL) was treated with trifluoracetic acid (15 mL), stirred at 25° C. for 5.5 hours and concentrated to give the title compound (3.42 g) as the trifluoroacetic acid salt, which was used without further purification.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][C@H:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C[C@H]1CCCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@H]1CCCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (20.9 mg, 65.4%), MS (ISP) m/z=457.3[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and (R)-2-(tetrahydro-2H-pyran-2-yl)acetic acid
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:40]12[CH2:32][CH:37]([CH2:38][CH2:39]1)[CH2:36][CH:35]2[CH2:34][NH:33][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: O=C(NCC1CC2CCC1C2)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting bicyclo[2.2.1]hept-2-ylmethamine for 3-phenylpropan-1-amine and 6-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (bs, 1H), 8.92 (d, J=42.7 Hz, 1H), 8.61 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.29 (d, J=9.3 Hz, 1H), 8.10 (d, J=9.3 Hz, 1H), 7.47-7.41 (m, 1H), 5.07-4.74 (m, 4H), 3.23-2.84 (m, 2H), 2.30-2.02 (m, 3H), 1.86-1.57 (m, 2H), 1.58-0.99 (m, 6H); MS (ESI(+)) m/e 393 (M+H)+.
Reaction SMILES: [N:1]1([C:11]2[C:12]([CH2:17][NH:18][CH2:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:28]=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[N:30]1[CH2:39][CH2:40][CH2:41][CH:42]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:1]1([C:11]2[C:12]([CH2:17][N:18]([CH2:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=3)[CH2:42][CH2:41][CH2:40][CH2:39][N:30]3[C:31](=[O:38])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:29]3=[O:28])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnc(CNCc2ncccc2N2CCCc3ccccc32)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN2C(=O)c3ccccc3C2=O)Cc2ncccc2N2CCCc3ccccc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of [3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine in CH2Cl2 and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (1.36 g, 6.28 mmol) with NaBH(OAc)3 gave 2-{4-[[3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-isoindole-1,3-dione as a yellow fluffy solid. 1H NMR (CDCl3) δ 1.35-1.50 (m, 4H), 1.95-1.80 (m, 2H), 2.03 (s, 3H), 2.22 (s, 3H), 2.50-2.65 (m, 2H), 2.65-2.95 (m, 2H), 3.27-3.40 (m, 2H), 3.45-3.55 (m, 2H), 3.65-3.80 (m, 4H), 5.99 (d, 1H, J=7.7 Hz), 6.59 (t, 1H, J=7.7 Hz), 6.81 (t, 1H, J=1.3, 7.7 Hz), 6.95 (d, 1H, J=7.7 Hz), 7.07 (s, 1H), 7.21 (dd, 1H, J=4.6, 7.9 Hz), 7.50 (dd, 1H, J=1.0, 7.9 Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.9 (s, 1H), 8.53 (dd, 1H, J=1.0, 4.6 Hz). Deprotection with H2NNH2H2O following General Procedure E gave N1-[3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-N1-(3,5-dimethyl-pyridin-2-ylmethyl)-butane-1,4-diamine as a free base.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[CH3:41])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:18]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:39]3[CH:38]=[C:16]([CH:15]=[CH:14][C:40]=3[CH3:41])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=3)=[O:18])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(NC2CC2)nn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (as prepared above) in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 68-69° C.; 1H NMR (300 MHz, CDCl3) δ: 8.84 (1H, s), 7.99-8.01 (2H, d, J=6.0 Hz), 7.95-7.98 (1H, d, J=9.0 Hz), 7.82-7.85 (1H, d, J=9.0 Hz), 7.71-7.73 (1H, d, J=6.0 Hz), 7.40-7.43 (1H, d, J=9.0 Hz), 7.29-7.32 (1H, d, J=9.0 Hz), 6.99-7.02 (1H, d, J=9.0 Hz), 5.85 (1H, s), 3.63 (2H, s), 2.53 (8H, brs), 2.34 (3H, s), 2.03 (3H, s), 1.43 (1H, m), 0.86-0.88 (2H, m), 0.61-0.63 (2H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H32F3N6O: 549.2584. found: 549.2568.
Reaction SMILES: Cl.C[NH:3][C@H:4]([C:23]([OH:25])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[O:14])=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[ClH:21].[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@@H:4]([C:23]([OH:25])=[O:24])[NH2:3])=[CH:7][CH:8]=1)=[O:14]
Reactant: CN[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 42.5 °C
Yield: 200.2 %

Procedure:
To a solution of methyl 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine hydrochloride salt (30 mmol, 12.1 g) in ethanol (300 mL) was added 1 N sodium hydroxide (90 mL). The mixture was heated to 40-45° C. for 1 h at which point TLC analysis of the reaction mixture indicated the absence of starting material and it was cooled to room temperature. The solvent was removed under vacuum and the residue was extracted with ether (2×100 mL) to remove neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid to pH 2 to give a clear solution. The solution was lyopholized under high vacuum to afford 11.7 g (100%) of the title compound as a white amorphous solid. HR MS (C16H15Cl3N2O3): Obs. mass, 354.2014. Calcd. mass. 354.2053 (M+H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:18][C:17]3[NH:16][C:15]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:19](=[O:22])[NH:20][N:21]=[C:8]([C:9]=3[C:10]=45)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[CH3:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].CN(C)CCN1C2CC(C)(C)CC3=NNC(=O)C4C(C=23)=C1C=CC=4>>[CH:1]1([C:4]([N:6]2[CH2:18][C:17]3[N:16]([CH2:27][CH2:26][N:24]([CH3:25])[CH3:23])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:19](=[O:22])[NH:20][N:21]=[C:8]([C:9]=3[C:10]=45)[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32
Reactant: CN(C)CCCl
Agent: CN(C)CCn1c2c3c4c(cccc41)C(=O)NN=C3CC(C)(C)C2
Product: CN(C)CCn1c2c3c4c(cccc41)C(=O)NN=C3CN(C(=O)C1CC1)C2

Procedure:
Compound 48 was prepared from 2-(cyclopropanecarbonyl)-2,3,4,9-tetrahydro-2,4, 9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and N,N-dimethylamino-2-chloroethane according to the procedures similar to those for Compound 28. 1H NMR (DMSO-d6) δ 10.0 (s, 1H), 7.67 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.23 (dd, 1H, J=8.4, 7.8 Hz), 5.22 (s, 1H), 4.98 (s, 1H), 4.55 (s, 1H), 4.28-4.35 (m, 3H), 2.58-2.62 (m, 2H), 2.19 (s, 6H), 2.09-2.13 (m, 1H), and 0.79 (s, 4H). MS (ESI) m/e [M+1]+ 366.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]3)[C:7](=[O:20])[C:6]3([CH3:25])[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1.[CH:26]1([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[O:31])[CH2:28][CH2:27]1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:26]1([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH:12]5[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]5)[C:7](=[O:20])[C:6]5([CH3:25])[CH2:21][O:22][CH2:23][CH2:24][N:5]5[C:4]=4[N:3]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:28][CH2:27]1
Reactant: CC12COCCN1c1nc(Cl)ncc1N(C1CCS(=O)(=O)CC1)C2=O
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC12COCCN1c1nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc1N(C1CCS(=O)(=O)CC1)C2=O
Yield: 70.6 %

Procedure:
A mixture of 2-chloro-5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one (6.50 mg, 0.017 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (8.63 mg, 0.029 mmol), saturated aqueous NaHCO3 (0.75 ml) and PdCl2(dppf) (1.10 mg, 1.34 μmmol) in 1,4-dioxane (1 ml) was irradiated in the microwave at 110° C. for 30 minutes The reaction mixture was diluted with THF and passed through 0.45 mM PTFE syringe filter (washed with small amount of THF). The filtrate was purified by preparative HPLC (eluting with a gradient of 15-40% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). The fractions containing the desired product were combined and were evaporated under reduced pressure. Then NaHCO3 aqueous solution was added (in order to adjust the pH to basic) and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (6.2 mg, 0.012 mmol, 70% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 0.36-0.45 (m, 2 H) 0.59-0.69 (m, 2 H) 1.32 (s, 3 H) 1.93-2.17 (m, 2 H) 2.51-2.60 (m, 1 H) 2.85-3.76 (m, 9 H) 3.91-3.99 (m, 1 H) 4.01-4.10 (m, 1 H) 4.14-4.25 (m, 1 H) 4.45-4.62 (m, 1 H) 6.58 (br. s., 1 H) 7.49-7.56 (m, 2 H) 8.16-8.24 (m, 2 H) 8.49 (s, 1 H) 8.75 (s, 1 H). MS [M+H] found 527.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(Cl)(Cl)Cl>CO>[Br:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)=[O:21])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of 4-(p-tolyloxy)piperidine (765 mg), 6-bromonicotinic acid (808 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.7 g) were added chloroform (5 mL) and methanol (5 mL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.5 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Reactant: COc1ccccc1Br
Product: COc1ccccc1Nc1nc2cccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Yield: 37.7 %

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methoxyphenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100 mg, 0.35 mmol) and 1-bromo-2-methoxy benzene (52 μL, 0.42 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methoxyphenyl)-amine (52 mg, 38%) as a yellow powder following purification on a 12 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=88° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.78 (br s, 1H), 8.79 (m. 1H), 8.36 (d, J=7.1 Hz, 1H), 8.20 (d, J=7.1 Hz, 1H), 8.12 (d, J=7.1 Hz, 1H), 8.00 (s, 1H), 7.89 (t, J=12.9, 8.2, 1H), 7.72 (m, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.05 (d, J=5.9 Hz, 1H), 6.92 (m, 2H), 3.87 (s, 3H), 3.32 (s, 3H). MS=395 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH:32](=[C:10]1/[CH2:9][N:8]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12][C:11]/1=[O:14])/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 1-(triphenylmethyl)piperidin-4-one (4.22 g) in benzene (50 ml) was added pyrrolidine (1.02 ml) at room temperature, and the resulting mixture was refluxed for 3 hours. After cooling to room temperature, benzaldehyde (1.26 ml) was added to the reaction mixture, and the resulting mixture was furthermore refluxed for 2 hours. After refluxing, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (3.92 g, yield: 74%) as a yellow oil.