Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:4]([OH:16])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8].N[C@@H](CCCC)[C@H](O)CNS(C1C=CC=CN=1)(=O)=O.[C:40](=O)([O:60]C1C=CC([N+]([O-])=O)=CC=1)[O:41][C@H:42]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[CH:51][CH:50]=1)[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:16][C@H:4]([C@@H:3]([NH:2][C:40](=[O:60])[O:41][C@H:42]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[CH:51][CH:50]=1)[C:43]([CH3:45])([CH3:46])[CH3:44])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)[C@@H](COc1ccc(-n2ccnc2)cc1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](N)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)O[C@H](COc1ccc(-n2ccnc2)cc1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
To 154 mg (0.31 mmol) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide in 3 mL of dimethylformamide, 132 mg (0.31 mmol) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl 4-nitrophenyl carbonate was added, followed by 0.25 mL (1.43 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred for 18 h at room temperature. It was concentrated, a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an methanol:chloroform solution (1:9) to yield 101.3 mg (57%) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate and (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. ES-LCMS m/z 574 (M+H) Rt=2.7 min.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Br[CH2:10][CH2:11][O:12][CH3:13].O>CN(C=O)C>[CH3:13][O:12][CH2:11][CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH3:3]
Reactant: Cc1ncc[nH]1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1ccnc1C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
NaH (60%, 620 mg) was added to a solution of 2-methyl-1H-imidazole (1.06 g, 12.95 mmol) in DMF (8 mL). After stirring for 15 minutes, 1-bromo-2-methoxyethane (2.16 g, 15.54 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80° C. under microwave irradiation for 60 minutes. Water (1 mL) was added and all solvents were removed by high vacuum. EtOAc was added to the residue, stirred for 15 minutes, filtered and concentrated in vacuo to afford the title compound as a colourless oil (604 mg, 33%) that was used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:34])[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([NH:14][C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][C:16]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:13])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:42]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:34])[C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([NH:14][C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][C:16]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:13])[CH2:10][CH2:11]1)(=[O:44])[CH3:43]
Reactant: CN(CCCN)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[({Trans-4-[(3-aminopropyl)(methyl)amino]cyclohexyl}-carbonyl)amino]-N-(5-chloropyridin-2-yl)furo[3,2-b]pyridine-2-carboxamide (113 mg) obtained in Example 121 and triethylamine (65 μl) are dissolved in chloroform (5 ml), and thereto is added acetyl chloride (25 μl) under ice-cooling. The mixture is warmed to room temperature and stirred for 1 hour. To the reaction solution is poured saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=10/1). The resulting solid is suspended in n-hexane-diisopropyl ether, and collected by filtration to give the title compound (90 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:38]([NH2:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:40])[CH3:39]>CN(C=O)C.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([NH:47][C:38]([CH3:40])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:39])=[O:10]
Reactant: CC(C)(N)c1ccccc1
Reactant: COCOc1cc(C(=O)O)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1OC
Yield: 79.3 %

Procedure:
In a similar manner to Step 11 of Example 137, 3-methoxymethoxy-4-methoxybenzoic acid (6.41 g, 30.2 mmol) was dissolved in DMF (100 mL), and the solution was treated with EDCI (5.75 g, 30.0 mmol), HOBT monohydrate (4.05 g, 30.0 mmol) and cumylamine (8.63 mL, 60.0 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-methoxymethoxy-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (7.89 g, yield 80%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([Br:36])[CH:35]=1)[CH2:7][O:8][C@H:9]1[C@H:18]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1.[CH3:37]I>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([Br:36])[CH:35]=1)[CH2:7][O:8][C@H:9]1[C@H:18]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]([CH3:37])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:23][CH2:24]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN([C@@H]2c3ccccc3OC[C@H]2OCc2cc(Br)cc(Br)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN([C@@H]2c3ccccc3OC[C@H]2OCc2cc(Br)cc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.2 g of sodium hydride (60% in oil) is added to 1 g of the compound obtained in Step B of Example 9 and 0.42 ml of methyl iodide in 10 ml of tetrahydrofuran, maintaining the temperature of the reaction mixture at 0° C. After 15 minutes at that temperature, the mixture is stirred for 48 hours at ambient temperature, diluted with water and extracted with ethyl acetate. After conventional treatment, the expected product is isolated.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:21]>>[CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([Cl:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Product: O=C(Cl)C(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To 20 mL of SOCl2 was added in portions 3.14 g (13.1 mmol) of di-benzylacetic acid and the solution stirred at room temperature overnight. The SOCl2 was removed under reduced pressure and the residue taken up in Et2O and the solvent removed again. There was obtained 3.18 g (94.1% yield) of the product as an oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.[O:23]1CCC[CH2:24]1>>[F:8][C:7]1[C:2]2[NH:1][C:24](=[O:23])[N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:3]=2[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cc(F)c(N)c(NC2CCN(C3CCOCC3)CC2)c1
Reactant: C1CCOC1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Reaction time: 0.5 h

Procedure:
A mixture of (2-amino-3-fluoro-5-methylphenyl)[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amine (0.5 g), N,N′-carbonyldiimidazole (0.66 g) and tetrahydrofuran (7 ml) was heated to reflux. After 30 minutes, tetrahydrofuran (3 ml) was added, and the mixture heated at reflux for a further 1½ hours. The reaction mixture was filtered and washed with tetrahydrofuran (10 ml), then the solid was dried at 40-45° C. under high vacuum to give the title compound (0.323 g).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([OH:34])=[CH:23][N:22]=3)[C:5]=2[CH3:35])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][CH2:44][N:45]([CH3:47])[CH3:46].CC(=O)CC>CN(C=O)C>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:34][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[CH:23][N:22]=3)[C:5]=2[CH3:35])[CH2:3][CH2:2]1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCN(C)C)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 50 °C

Procedure:
80 mg of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol 2-2-1 (0.048 mmol, 1.0 eq) were dissolved in 1.9 mL of dry DMF and 33.5 mg potassium carbonate (0.24 mmol, 5.0 eq) and 10.5 mg 2-chloro-N,N-dimethylethanamine (0.073 mmol, 1.5 eq) were added. The reaction mixture was stirred over night at 50° C. Then butan-2-one was added and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography and HPLC provided 10 mg (0.02 mmol, 37%) of analytically pure target compound.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][CH2:9][C:10]1[C:11]([F:18])=[C:12]([C:14]([F:17])=[CH:15][CH:16]=1)[NH2:13]>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:13][C:12]1[C:11]([F:18])=[C:10]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:9][NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: NCc1ccc(F)c(N)c1F
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (400 μL, 2.86 mmol) followed by pivaloyl chloride (60 μL, 0.52 mmol) are added to 3-aminomethyl-2,6-difluoro-aniline (120 mg as HCl salt) in THF (10 mL) and stirred at rt overnight. The reaction mixture is diluted with EtOAc and sat. NaHCO3-solution, the organic layer is washed with water and brine, dried and concentrated to give the sub-title compound.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:28].C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH2:27]([C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[CH3:28]
Reactant: CCc1ccc(C(=O)c2ccccc2)cc1CC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CCc1ccc(C(=CC#N)c2ccccc2)cc1CC

Procedure:
3-(3,4-Diethylphenyl)-3-phenylacrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-diethylbenzophenone (0.95 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 2 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 8% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried and then dried in vacuo to afford 0.6 g (57%) of a mixture of the E and Z isomers as a white solid: mp 63-64° C.; 1H NMR (CDCl3) δ 7.51-6.99 (m, 16H), 5.72 (s, 2H), 2.76-2.55 (m, 8H), 1.32-1.14 (m, 12H); 13C NMR (CDCl3) δ 163.3, 144.7, 142.2, 137.3, 136.5, 130.2, 129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 127.2, 126.2, 118.2, 93.9, 93.7, 25.5, 25.3, 15.2, 15.0.
Reaction SMILES: C(=O)([O-])[O-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[C:23]2[O:27][CH:26]=[N:25][CH:24]=2)[N:8]=1.Cl[N:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[NH:30]1>CN(C=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:7]([O:6][CH3:5])[N:8]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][N:29]3[N:30]=[C:31]([O:37][CH3:38])[CH:32]=[C:33]([O:35][CH3:36])[NH:34]3)[C:17]=2[C:23]2[O:27][CH:26]=[N:25][CH:24]=2)[N:10]=1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2-c2cnco2)n1
Reactant: COC1=CC(OC)=NN(Cl)N1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2-c2cnco2)N1
Temperature: 25 °C

Procedure:
To DMF solution containing 0.14 g pottasium carbonate and 0.15 g 5-[2-(4,6-dimethoxypyrimidine-2-yloxy)-6-hydroxyphenyl]oxazole, was added at once DMF solution containing 0.13 g 2-chloro-4,6-dimethoxytriazine. The solution reacted was stirred for a night at room temperature. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, affording the objective substance in an amount of 0.22 g.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]1[C:37]([NH2:42])=[N:38][CH:39]=[CH:40][CH:41]=1.[NH4+].[Cl-]>C(Cl)Cl>[O:6]=[C:4]([NH:42][C:37]1[C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:41][CH:40]=[CH:39][N:38]=1)[C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncccc1Nc1ccccn1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccn1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Boc-L-Ala-OH (1.214 g, 6.42 mmol) and N-methylmorpholine (0.741 mL, 6.74 mmol) in DCM (16.04 mL) was added isobutyl chloroformate (0.839 mL, 6.42 mmol). The resulting cloudy light yellow mixture was stirred at −10° C. After 15 min at −10° C., to the mixture was then added a solution of N3-(pyridin-2-yl)pyridine-2,3-diamine (0.5974 g, 3.21 mmol) in DCM (16 mL) at −10° C. with stirring. The resulting mixture was allowed to warm to rt with stirring. After 15.5 h at rt, to the mixture was added satd. NH4Cl (50 mL). The organic layer was separated. The aqueous mixture was extracted with DCM (50 mL×1). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAC in hexane for 14 min, then 50 to 100% gradient of EtOAc in hexane over 14 min, and then 100% isocratic of EtOAC for 30 min as eluent to give (S)-tert-butyl 1-oxo-1-(3-(pyridin-2-ylamino)pyridin-2-ylamino)propan-2-ylcarbamate as a light pink foamy solid: LC-MS (ESI) m/z 358.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].C(=O)([O-])O.[Na+]>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:39](=[O:41])[CH3:40])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1
Reactant: CC(=O)Cl
Reactant: COc1nccc2c1c(-c1ccc(C3CCNCC3)cc1)nn2-c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1nccc2c1c(-c1ccc(C3CCN(C(C)=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (120 mg), triethylamine (0.080 mL) and N,N-dimethylaminopyridine (1.7 mg) in THF (4 mL) was added acetyl chloride (0.080 mL). The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (117 mg).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:20][CH:21]=2)=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 3B. MS m/z 473 (M+1).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=1.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:54][CH:55]=[CH:56][N:57]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:48]=1>>[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:57][CH:56]=[CH:55][N:54]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61][C:24]2[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=2)[N:48]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CN(C)CCOc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(C)CCOc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
(2-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro(2-pyridyloxy)}ethyl)dimethylamine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and [2-(6-chloro-3-nitro(2-pyridyloxy))ethyl]dimethylamine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][CH2:20][S:21][CH3:22])[C:16]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:26][C:15]=2[S:14]1.O>O1CCOCC1>[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][CH2:20][S:21]([CH3:22])=[O:9])[C:16]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:26][C:15]=2[S:14]1
Reactant: CSCCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)CCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reaction time: 72 h
Yield: 27.2 %

Procedure:
90% m-chloroperbenzoic acid (2.5 g) is added in the course of about 15 minutes, at a temperature close to 20° C., to 2-imino-3-(3-methylthiopropyl)-6-trifluoromethoxybenzothiazoline (4.2 g) in solution in a mixture (100 cc) of water and dioxane (40/60 by volume). The reaction mixture is stirred at the same temperature for 72 hours. After adding to distilled water (500 cc) and neutralising with 1N sodium hydroxide solution, the reaction mixture is extracted with dichloromethane. After drying over magnesium sulphate and concentrating to dryness under reduced pressure and then purifying by chromatography on a silica column using a mixture of ethyl acetate and methanol (80/20 by volume) as eluent, (RS)-2-imino-3-(3-methylsulphinylpropyl)-6-trifluoromethoxybenzothiazoline (1.2 g) melting at 114° C. is obtained.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:27][O:28][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:26].FC1C(C#[N:37])=CC2C3(COC=2C=1)C1C(=CC=CC=1)N(CC1C=CC=CC=1C(F)(F)F)C3=O>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:5]3[CH:6]=[C:7]4[C:2](=[CH:3][C:4]=3[O:28][CH2:27]2)[NH:37][N:9]=[CH:8]4)[C:11]1=[O:26]
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3[nH]ncc3cc12

Procedure:
Following the procedure as described in EXAMPLE 46 and making non-critical variations using 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3-indole]-5-carbonitrile to replace 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3-indole]-5-carbonitrile, 1′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′ (1′H)-one was obtained (33%): mp 117-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 10.21 (br s, 1H), 8.60-7.59 (m, 1H), 7.79 (s, 1H), 7.70-7.65 (m, 1H), 7.31-6.89 (m, 7H), 5.24-4.77 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 160.7, 155.4, 149.6, 142.3, 141.7, 137.1, 134.9, 132.3, 129.0, 126.3, 123.7, 123.6, 122.8, 121.7, 119.1, 115.6, 109.7, 89.6, 80.6, 57.3, 46.1; MS (ES+) m/z 369.2 (M+1).