Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:12])[N:10]=[N:11][C:6]=2[CH:5]=[C:4]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])[CH:3]=1.S(=O)(=O)(O)N.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](N)=[CH:29][CH:28]=1>>[CH3:19][C:14]1[C:13]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]3[N:8]=[C:9]([NH:12][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[N:10]=[N:11][C:6]=3[CH:5]=2)=[C:17]([CH3:18])[O:16][N:15]=1
Reactant: Cc1noc(C)c1-c1cc(C)c2nc(N)nnc2c1
Reactant: COc1ccc(N)cc1
Agent: NS(=O)(=O)O
Product: COc1ccc(Nc2nnc3cc(-c4c(C)noc4C)cc(C)c3n2)cc1
Temperature: 180 °C
Yield: 32.1 %

Procedure:
The mixture of 5-methyl-7-(3,5-dimethylisoxazol-4-yl)benzo[e][1,2,4]triazin-3-amine (compound 7 on scheme (CXXVIII)) (107 mg, 0.42 mmol), sulfamic acid (81.4 mg, 0.84 mmol), and 4-methoxybenzenamine 8 (774 mg, 6.3 mmol) was heated at 180° C. overnight. The product was purified by chromatography (SiO2/CH2Cl2) and the title product (48.7 mg, 32%) was obtained as a yellow solid. 1H NMR (CD2Cl2): δ 2.34 (s, 3H); 2.49 (s, 3H); 2.70 (s, 3H); 3.84 (s, 3H); 6.99 (d, J=8.9 Hz, 2H); 7.57 (s, 1H); 7.83 (d, J=8.9 Hz, 2H); 8.03 (s, 1H); 8.10 (br, 1H). MS (ESI+): m/z=362.1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C@:17]3([CH3:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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].C(Cl)Cl>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C@:17]4([CH3:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18]4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:7]=2)=[CH:39][N:40]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@](C)(N2CCc3c(Cl)nc(N4CCOCC4)nc32)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Temperature: 120 °C
Yield: 87.8 %

Procedure:
To a solution of tert-butyl(3R)-3-[4-chloro-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (150 mg, 0.354 mmol) in dioxane (3 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (104 mg, 0.471 mmol), and 1 M aqueous Na2CO3 (1.3 mL, 51.3 mmol). Nitrogen was bubbled through the suspension for a few minutes before PdCl2(dppf)2-DCM (24 mg, 0.029 mmol) was added. The vial was crimp sealed and the reaction was heated at 120° C. for 30 min in a microwave reactor. The mixture was partitioned between EtOAc and aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-10% (MeOH with 10% NH4OH)/(EtOAc/DCM, 1:1) to give 150 mg (88%) of the title compound as a crisp foam (˜85% pure). This material was taken into the next step without further purification. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 8.72 (s, 2 H), 6.60 (br s, 2 H), 3.80-3.62 (m, 11 H), 3.54 (q, J=8.9 Hz, 1 H), 3.42-3.34 (m, 1 H), 3.33-3.23 (m, 1 H), 3.09 (t, J=8.1 Hz, 2 H), 2.44-2.34 (m, 1 H), 2.08-1.99 (m, 1 H), 1.42 (s, 9 H), 1.31 (s, 3 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[O:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=1>>[NH2:18][C:19]1[O:20][C:21]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:26])=[C:22]([CH3:24])[N:23]=1
Reactant: Cc1nc(N)oc1C(=O)O
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: Cc1nc(N)oc1C(=O)NC(C)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 41 %

Procedure:
The title compound is prepared in 41% yield (92 mg, a white solid) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (171 mg, 0.59 mmol, Amine-5, single enantiomer) and 2-amino-4-methyloxazole-5-carboxylic acid (100 mg, 0.70 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [N:1]1[CH:6]=[N:5][CH:4]=[N:3][CH:2]=1.Cl.[F:8][C:9]1[CH:10]=C(NN)[CH:12]=[CH:13][CH:14]=1>C(O)C>[F:8][C:9]1[CH:10]=[C:2]([N:1]2[CH:6]=[N:5][CH:4]=[N:3]2)[CH:12]=[CH:13][CH:14]=1
Reactant: NNc1cccc(F)c1
Reactant: c1ncncn1
Agent: Cl
Solvent: CCO
Product: Fc1cccc(-n2cncn2)c1
Yield: 89.7 %

Procedure:
A mixture of 1,3,5-triazine (1 g, 12.3 mmol) and 3-Fluorophenylhydrazine hydrochloride (2 g, 12.3 mmol) in ethanol (20 mL) is heated at reflux overnight. After concentrating, ethyl acetate is added, the mixture is washed with aqueous bicarbonate followed by saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 1.8 g of crude 1-(3-Fluorophenyl)-1,2,4-triazole. 1H NMR (CDCl3): δ 8.57 (s, 1H), 8.12 (s, 1H), 7.46-7.51 (m, 3H), 7.08-7.15 (m, 1H). LCMS 164.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]4[CH:27]=3)=[CH:14][CH:13]=2)=[C:6]([O:28][CH2:29][CH2:30][F:31])[CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.CCOC(C)=O.C(Cl)Cl>CCO>[F:31][CH2:30][CH2:29][O:28][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]3[CH:27]=2)=[CH:16][CH:17]=1)[NH2:1]
Reactant: Cc1ccc2nc(-c3ccc(/C=C/c4ccc([N+](=O)[O-])cc4OCCF)cc3)cn2c1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc(N)cc4OCCF)cc3)cn2c1
Yield: 47.9 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-(4-{(E)-2-[4-nitro-2-(2-fluoroethoxy)phenyl]ethenyl}phenyl)-6-methylimidazo[1,2-a]pyridine (81 mg, 0.194 mmol) and tin (II) dichloride dihydrate (219 mg, 0.970 mmol) in EtOH (12 ml) to give the title compound (36 mg, 48%) as an orange solid after work-up and flash chromatography (2:1 EtOAc/DCM).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH2:8][C:7]=2[CH:29]=1
Reactant: BrCc1ccccn1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Clc1ccc2c(c1)CN(Cc1ccccn1)Cc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To a mixture of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.064 g, 0.15 mmol) and potassium carbonate (0.062 ml, 0.45 mmol) in acetonitrile (1 ml) was added 2-(bromomethyl)pyridine hydrobromide (0.040 ml, 0.16 mmol) at room temperature. Stirring for 72 h at 50° C. was followed by partitioning between 1 M aqueous sodium hydroxide solution (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50-ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.044 g, 63%) as light brown solid. MS m/e: 486 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([OH:24])=[CH:21][C:20](=[O:25])[NH:19][C:18]=3[S:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.I[Si](C)(C)C>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([OH:24])=[CH:21][C:20](=[O:25])[NH:19][C:18]=3[S:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=c1cc(O)c2c(-c3ccc(OCc4ccccc4)cc3)csc2[nH]1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=c1cc(O)c2c(-c3ccc(O)cc3)csc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.6 %

Procedure:
To 349 mg (1.00 mmol) of 3-(4-benzyloxy-phenyl)-4-hydroxy-7H-thieno[2,3-b]pyridin-6-one from Example 7d in 10 mL of CH2Cl2 was added 0.7 mL (4.9 mmol) of iodotrimethylsilane. The reaction was stirred at ambient temperature for 48 h, then concentrated in vacuo. The residue was suspended in 10 mL of water, and 5% NaHSO3(aq.) was added to discharge the I2 color. The insoluble material was filtered, washed with water, then diethyl ether, and dried on the filter to give 183 mg (70%) of a tan solid. MS (ESI) m/e 259.9, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 5.69 (s, 1H) 6.72 (m, 2H) 6.85 (s, 1H) 7.24 (m, 2H) 9.39 (s, 1H) 10.79 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][CH:25]1[CH2:27][C:26]1([F:29])[F:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1([F:29])[CH2:27][CH:25]1[CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(CC2CC2(F)F)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 40 °C
Yield: 72.7 %

Procedure:
A mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.29 g, 1.00 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (0.21 g, 1.20 mmol), cesium carbonate (0.65 g, 2.00 mmol) and N,N′-dimethylformamide (2.5 mL) was heated at 40° C. for 2 h and filtered while hot. The filtrate was allowed to cool to ambient temperature and water was added, causing a precipitate to be deposited. The solid was collected by filtration, washed with water and dried under vacuum. The residue was recrystallized from ethanol/diethyl ether to afford 1′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.28 g, 73%) as a colourless solid: mp 162-164° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35 (ddd, J=7.8, 7.8, 0.9 Hz, 1H), 7.23 (dd, J=7.9 Hz, 1H), 7.17 (d, J=6.9 Hz, 1H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.51 (d, J=1.9 Hz, 1H), 6.13 (d, J=6.2 Hz, 1H), 4.71 (dd, J=9.3 Hz, 1H), 4.69 (dd, J=9.3 Hz, 1H), 4.17 (dd, J=3.7 Hz, 2H), 4.10 (dd, J=3.4 Hz, 2H), 3.87 (d, J=6.9 Hz, 2H), 2.33-2.14 (m, 1H), 1.74-1.60 (m, 1H), 1.48-1.29 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.5 (d, 4JC-F=15.9 Hz), 154.5 (d, 6JC-F=1.4 Hz), 144.1 (d, 6JC-F=1.9 Hz), 141.9, 137.7 (d, 5JC-F=3.9 Hz), 131.7 (d, 6JC-F=2.3 Hz), 128.8, 123.5, 122.9 (d, 6JC-F=1.6 Hz), 121.2 (d, 5JC-F=4.1 Hz), 114.3 (q, 1JC-F=283.4 Hz), 110.9 (d, 2JC-F=18.1 Hz), 109.1, 98.7 (d, 5JC-F=3.6 Hz), 79.2 (d, 5JC-F=3.7 Hz), 64.1, 63.5, 57.1 (d, 6JC-F=2.4 Hz), 36.6 (t, 3JC-F=5.9 Hz), 20.1 (t, 2JC-F=17.4 Hz), 14.7 (t, 2JC-F=10.7 Hz); MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.O.C(OCC)(=O)C.[ClH:33].[CH3:34][CH:35]1[O:40][CH:39]([CH3:41])[CH2:38][NH:37][CH2:36]1>>[ClH:33].[CH3:41][CH:39]1[O:40][CH:35]([CH3:34])[CH2:36][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:38]1
Reactant: CC1CNCC(C)O1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CN(CCCCCCCCOc2ccc(-c3ccc(C(=O)O)cc3)cc2)CC(C)O1

Procedure:
A suspension of 4-[4-(8-bromooctyloxy)phenyl]benzoic acid (1 g) in 2,6-dimethylmorpholine (3.06 ml) was refluxed for 30 minutes. The reaction mixture was added to a mixture of water and ethyl acetate and adjusted to pH 2.0 with conc. HCl. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-(2,6-dimethylmorpholin-4-yl)octyloxy]phenyl]benzoic acid hydrochloride (0.95 g).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>S(=O)(=O)(O)O>[C:12]1([CH:11]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH:7]([CH3:9])[CH3:8])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)c1ccccc1C(C)c1ccccc1

Procedure:
Aralkylation of cumene with styrene was carried out in the presence of sulfuric acid catalyst. From the reaction product, a fraction mainly containing 1-phenyl-1-(isopropylphenyl)ethane was obtained by distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1ccc(F)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29](F)[CH:30]=2)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:23]1=[O:43]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:30]=2)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:23]1=[O:43]
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccccc2F)CC1
Yield: 100.3 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.083 mL, 0.75 mmol), triethylamine (0.106 mL, 0.75 mmol), and 1-(2-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example F-1, 0.1 g, 0.25 mmol) provided 0.12 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C1CSCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCSCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and thiomorpholine in DMSO at ambient temperature.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[OH:25]O.[OH-].[K+].Cl>CO.CCOC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([NH2:18])=[O:25])=[C:9]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: OO
Reactant: N#Cc1c(-c2ccccc2)n(-c2ccc(O)cc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1c(-c2ccccc2)n(-c2ccc(O)cc2)c2ccccc12

Procedure:
1-(4-Hydroxy-phenyl)-2-phenyl-1H-indole-3-carbonitrile (Example 46, 10 mg, 0.03 mmol) was dissolved in 1 ml of MeOH. H2O2 (1 ml, 35% by weight in H2O) and 2M KOH (0.5 ml) were added and the reaction mixture was heated to reflux over night. The mixture was acidified with 1M HCl and EtOAc was added. The phases were separated and the organic solvents were evaporated. The crude product was purified by reversed phase preparative HPLC to give the title amide. ES/MS m/z: 329.1 (M+H), 327.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.34 (m, 1H), 7.46 (m, 2H), 7.40-7.37 (m, 3H), 7.24-7.18 (m, 2H), 7.12 (m, 2H), 7.07 (m, 1H) and 6.85 (m, 2H).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)c1
Solvent: CO
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 14 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(3-methoxyphenyl)pyridazin-4(1H)-one (crude 640 mg, 2.14 mmol) in 20 mL of methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(3-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (106 mg, 14% for two steps) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18]>>[CH2:20]([O:19][C:17]([C:16]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4][CH:2]([CH3:1])[NH:3][CH:15]=1)=[O:18])[CH2:21][CH3:22]
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: CCCOC(=O)C(=O)CBr
Product: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1ccccc21

Procedure:
2-Methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester was prepared in the manner described in Example 1A using α-methyl tryptamine and n-propyl 3-bromopyruvate; MS (ESI): 285 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1)[NH2:23]
Reactant: NN
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cn1
Yield: 64 %

Procedure:
6-Chloro-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.49 g) and hydrazine monohydrate (4 mL) were suspended in ethanol (8 mL), and the suspension was heated to reflux for 15 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was then collected by filtration and washed with ethyl acetate. The solid was dried under reduced pressure to obtain the title compound (0.31 g) as a white solid (yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[C:14]3=[O:43])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[C:14]3=[O:43])=[CH:11][CH:12]=2)=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CC(c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(CCN2CCNCC2)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-butyl 4-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazo-lidin-1-yl)ethyl)piperazine-1-carboxylate (15 mg, 0.023 mmol) is dissolved in a mixture solvent of DCM (0.2 mL) and TFA (0.2 mL). The reaction mixture is stirred at room temperature for 15 min before removal of the solvent. The residue is purified by reparative LC/MS to provide the title compound; HPLC-MS calculated for C28H28ClF3N4O2 (M+H+) 545.2, found 545.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[CH3:17][CH:18]1[CH2:27][C:26]2[C:25]([OH:28])=[CH:24][CH:23]=[CH:22][C:21]=2[O:20][CH2:19]1>CN(C)C=O>[CH3:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:28][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[O:20][CH2:19]1
Reactant: CC1COc2cccc(O)c2C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1COc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2C1
Temperature: 110 °C
Yield: 195.9 %

Procedure:
In a microwave vial, 3-methyl-3,4-dihydro-2H-chromen-5-ol (Intermediate 117, 53 mg), potassium carbonate (134 mg, 0.968 mmol) and 2-chloro-5-nitropyridine (51.2 mg, 0.323 mmol) were dissolved in N,N-dimethylformamide (2 ml) to give a light brown solution. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 hour. After cooling, the reaction mixture was quenched with 5 ml of water and diluted with 10 ml of Et2O. Phases were separated by a separating funnel. The aqueous phase was extracted with 3×10 ml of Et2O. The collected organic phase were dried using a hydrophobic frit and evaporated under vacuum to give the title compound as a brown oil (181 mg).