Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=NC=CC=1OC1C=CC(N)=CC=1F)C.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=C[C:36]([CH2:37][NH:38][C:39]2N=CN=[C:41]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH:52][C:53]([NH:55][C:56](=[O:65])[CH2:57][C:58]4[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=4)=[O:54])=[CH:48][C:47]=3[F:66])[CH:40]=2)=[CH:35][CH:34]=1.[ClH:69].CCOCC>C(Cl)Cl.CO>[ClH:69].[CH2:35]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][C:41]=1[O:45][C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:53]([NH:55][C:56](=[O:65])[CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)=[O:54])=[CH:48][C:47]=1[F:66])[CH3:34]
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: CCc1cnccc1Oc1ccc(N)cc1F
Agent: Cl
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CCc1cnccc1Oc1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 36 %

Procedure:
A solution of 4-(3-ethylpyridin-4-yloxy)-3-fluorobenzenamine (23 mg, 0.10 mmol) in CH2Cl2 (1 mL) was treated with a solution of 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.33 mL, 0.11 mmol) and the mixture was stirred at room temperature for 2.5 h. The mixture was concentrated under vacuum and the residue triturated with 1:1 isopropyl ether/EtOAc to give a yellow solid. The product was treated with absolute MeOH (1 mL) and 2 M HCl/Et2O (1 mL), stirred at room temperature for 5 min and concentrated under vacuum to give the title compound (15 mg, 36%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.57 (s, 1H), 8.41 (s, 1H), 8.26 (d, 1H, J=5.6 Hz), 7.76 (dd, 1H, J=2.0, 12.7 Hz), 7.40-7.28 (m, 4H), 7.19-7.14 (m, 3H), 6.54 (d, 1H, J=5.6 Hz), 3.73 (s, 2H), 2.72 (q, 2H, J=7.6 Hz), 1.23 (t, 3H, J=7.6 Hz); MS(ESI+): m/z 412.20 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[C:34]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl.C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O.CN(C=O)C>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([NH:42][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([C:7]3[C:6]([S:3]([N:2]([CH3:1])[CH3:21])(=[O:4])=[O:5])=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:20][CH:19]=2)=[CH:43][CH:44]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CN(C)S(=O)(=O)c1cccnc1-c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)c1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Reaction time: 1.5 h

Procedure:
The product from Example 44B (0.917 g, 2.99 mmol) and DMF (0.03 mL) were combined in CH2Cl2 (9 mL) and treated with (COCl)2 (0.32 mL, 3.7 mL). After stirring for 90 minutes, the mixture was diluted with toluene (2 mL) and concentrated to dryness. The residue was dissolved in CH2Cl2 (9 mL) and treated with pyridine (0.36 mL, 4.5 mmol), DMAP (catalytic amount), and 4-tert-butylaniline (0.57 mL, 3.6 mmol). After stirring for 1 hour, the mixture was diluted with water and extracted with CH2Cl2. The organics were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (75% ethyl acetate in hexanes) to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ 8.84 (dd, 1H), 8.44 (dd, 1H), 7.98 (d, 2H), 7.83 (br s, 1H), 7.72 (d, 2H), 7.58 (d, 2H), 7.51 (dd, 1H), 7.41 (d, 2H), 2.43 (s, 6H), 1.33 (s, 9H); MS (m/z) 438.
Reaction SMILES: Cl.[CH3:2][C@H:3]([NH2:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>CC(C)=O>[C:24]([NH:13][C@@H:3]([CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-(-)-α-methyl-4-nitrobenzylamine hydrochloride (7.96 gm, 48 mmol) in acetone (20 mL) was added 5N sodium hydroxide (10 mL, 50 imol) and the solution was cooled in an ice bath. Solutions of benzylchloroformate (9.8 mL, 53 mmol) in acetone (10 mL) and 5N sodium hydroxide (11 mL, 55 mmol) were simultaneously added over 0.5 hr and the reaction was then allowed to warm to rt over 16 hrs. The reaction was poured into a mixture of ice water and ether and the layers were separated. The ether layer was washed with water and brine and the aqueous layers were consecutively extracted with a second portion of ether. The pooled ether layers were dried over sodium sulfate and evaporated to give 14.3 gm (quantitative) of clean title compound which was used without purification.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[N:42]=[CH:41][N:40]([C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:39]=3)=[CH:35][CH:36]=2)[C:31]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[N:30]1>ClCCl>[CH:1]1([CH2:7][C:8]([NH:68][C:64]2[CH:65]=[CH:66][CH:67]=[C:62]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[C:34]([C:38]5[N:42]=[CH:41][N:40]([C:43]([C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)[C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[N:39]=5)[CH:33]=4)[N:29]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][O:23]4)[N:30]=3)[CH:63]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclohexylacetic acid (0.071 g, 0.498 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.105 g, 0.548 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. (Yield not calculated) ES-MS (m/z) 727 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][O:12]S(C)(=O)=O)[S:10][C:6]=2[CH:5]=1.[Cl-].[NH4+:20]>CN(C)C=O>[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][O:12][C:4]3[CH:18]=[CH:17][C:7]([NH:20][C:11](=[O:12])[CH3:9])=[CH:6][CH:5]=3)[S:10][C:6]=2[CH:5]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)OCc1nc2ccc(F)cc2s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2nc3ccc(F)cc3s2)cc1
Reaction time: 0.05 h
Yield: 28 %

Procedure:
18.8 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 64.6 mg of4-acetamidophenol in 1.3 ml of dimethylformamide cooled in an ice-water bath, and the resulting mixture stirred at the same temperature for 3 minutes. A solution of 122.8 mg of 6-fluoro-2-methanesulfonyloxymethylbenzothiazole [prepared as described in step (c) above] in 0.4 ml of dimethylformamide was then added to the reaction mixture. The temperature of the resulting mixture was then elevated to room temperature and the mixture was stirred for 3 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and an aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 38.3 mg (yield 28%) of the title compound as a solid having a melting point of 204° to 205° C.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([OH:40])=[O:39])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C>CC(C)=O.C(O)(=O)C>[CH2:6]([O:5][C:1]([O:2][CH2:3][O:40][C:38](=[O:39])[C@H:37]([OH:41])[CH2:36][N:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[F:42])=[CH:23][CH:22]=1)[NH:26][C:27]([C:29]1[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=1)=[O:28])=[O:8])[CH3:7]
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: CCOC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1
Temperature: 65 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A mixture of chloromethyl ethyl carbonate (17.9 mg, 129 μmol) and NaI (19.4 mg, 129 μmol) in acetone (0.7 mL, 10 mmol) was heated at 65° C. for 1 hour. The mixture was then cooled to room temperature and a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg) and DIPEA (15.0 μL, 0.1 mmol) in acetone (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2.0 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a white solid. The solid was dissolved in acetic acid (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (5.8 mg, purity 94%). MS m/z [M+H]+ calc'd for C25H25ClFN3O9, 566.13. found 566.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1)=[C:25]=[O:26]>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([N:24]3[C:4](=[O:5])[C:6]4[CH:7]=[N:8][C:9]5[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]=4[N:16]([CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[C:25]3=[O:26])=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)OCO4)c(=O)n(C3CCCC3)c12
Yield: 76.5 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (33 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 5-isocyanato-benzo[1,3]dioxole (0.5 mmol) following general procedure C. LCMS: m/z 432 [M+1]+.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[NH:4].C(N(CC)CC)C.[C:36](Cl)(=O)[CH2:37][CH3:38]>ClCCl>[CH2:37]([C:38]1[O:1][N:2]=[C:3]([C:5]2[N:6]=[N:7][C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])=[O:28])[CH2:15][CH2:16]3)=[CH:9][CH:10]=2)[N:4]=1)[CH3:36]
Reactant: CCC(=O)Cl
Reactant: N=C(NO)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(-c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To an ice cold solution of N-hydroxy-6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxamidine (0.200 g, 0.500 mmol) in dichloromethane (6 mL) was added triethylamine (0.5 mL), followed by then addition of propionyl chloride (0.05 mL, 0.55 mmol). The mixture was warmed up to room temperature and then stirred for 30 minutes. The solvent was removed in vacuo. The crude residue and cesium carbonate (0.200 g) were suspended in a mixture of 1,4-dioxane/water (1:1, 8 mL) and then heated to reflux overnight. The reaction mixture was cooled and concentrated to remove 1,4-dioxane and diluted with water (10 mL). The product was extracted with ethyl acetate (2×10 mL). The organic layers were combined, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography and recrystallization from ethyl acetate/hexanes. The title compound was obtained as a white crystals in 52% yield (0.113 g). m.p. 204° C. 1H NMR (300 MHz, CDCl3) 7.93 (d, J=9.6 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.68-7.50 (m, 2H), 7.32 (d, J=7.6 Hz, 1H), 6.97 (d, J=9.6 Hz, 1H), 4.11-3.90 (m, 6H), 3.34 (t, J=5.1 Hz, 2H), 2.95 (q, J=7.6 Hz, 2H), 1.44 (t, J=7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 181.4, 167.6, 166.5, 142.0, 134.3, 134.2, 132.3, 129.4, 127.2, 127.1, 127.1, 126.8, 126.8, 126.7, 111.7, 46.4, 44.6, 44.2, 41.2, 20.3, 10.7. MS (ES+) m/z 433.0 (M+1).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Cl[CH2:14][C:15]1[C:16]([CH3:21])=[N:17][O:18][C:19]=1[CH3:20].[CH3:22][C:23]1[N:24]=[C:25]([N:38]2[C:42](=[O:43])[NH:41][N:40]=[CH:39]2)[S:26][C:27]=1[C:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29]>>[CH3:21][C:16]1[C:15]([CH2:14][N:41]2[C:42](=[O:43])[N:38]([C:25]3[S:26][C:27]([C:28]([NH:30][CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:29])=[C:23]([CH3:22])[N:24]=3)[CH:39]=[N:40]2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2cnn(Cc3c(C)noc3C)c2=O)sc1C(=O)NCc1cccnc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(chloromethyl)-3,5-dimethylisoxazole to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 45% yield: mp 233-234° C. (ethyl acetate/hexane): 1H NMR (300 MHz, CDCl3) δ 8.74 (br s, 1H), 8.60 (br s, 1H), 8.22 (s, 1H), 7.87-7.80 (m, 1H), 7.52-7.31 (m, 1H), 6.51 (t, J=5.8 Hz, 1H), 4.74 (s, 2H), 4.64 (d, J=5.8 Hz, 2H), 2.64 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H); MS (ES+) m/z 426.1 (M+1).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CS(C)=O.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:7]([O:8][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1=CCCCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C1=CC(COCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 19.8 g (0.177 mol) cyclohexene-1-methanol, and 150 mL of DMSO. Sodium hydride (4.90 g, 95% in purity; 0.194 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 1 hr, 30.2 g (0.177 mol) of benzylbromide was slowly added to the above mixture over 15 min. The reaction was carried out at 60° C. for 2 hrs. The reaction mixture was cooled to room temperature and was added to water (200 mL), and then extracted with chloroform (3×200 mL), washed with water (2×250 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:26]([N:29](CC2C=CC(OC)=CC=2OC)[C:30]2[S:34][N:33]=[CH:32][N:31]=2)(=[O:28])=[O:27])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][N:23]=[N:22][CH:21]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:26]([NH:29][C:30]2[S:34][N:33]=[CH:32][N:31]=2)(=[O:27])=[O:28])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][N:23]=[N:22][CH:21]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Cc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-pyridazin-4-yl-4-(trifluoromethyl)benzyl]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 34, 54 mg, 0.083 mmol) was dissolved in dichloromethane (0.75 mL) and cooled to 0° C. Trifluoroacetic acid (32 μL, 0.41 mmol) was added as a solution in dichloromethane (0.25 mL) and the reaction stirred for 2 hours warming slowly to room temperature. The solvent was removed in vacuo and the residue re-dissolved in methanol. Once again the solvent was removed in vacuo. The material was suspended in methanol and filtered through Celite™. The reaction mixture was concentrated in vacuo and purified by the basic preparative HPLC method to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O:16]([C:18]#[N:19])[Na].FC(F)(F)C(O)=O>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:18](=[O:16])[NH2:19])[CH2:5][O:4]1
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reactant: N#CO[Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 15 grams of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.0625 mols), 8.12 grams NaOCN (0.125 mols), and 75 ml methylene dichloride is stirred at 25°-35° C. while 14.3 grams trifluoroacetic acid is added dropwise. The mixture is stirred for 16 hours at 40° C. The product is filtered and the filter cake washed with methylene dichloride. The filtrate is washed with water and dried over Na2SO4 prior to vacuum-stripping. The reaction product is recrystallized from 1 part benzene to yield 2,2-bis(trifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 52°-54° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccnc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
To a stirred solution of (2-chloropyridin-4-yl)methanol (0.500 g, 3.496 mmol) in dichloromethane (15 mL), triethylamine (0.424 g, 4.195 mmol) and methanesulfonylchloride (0.440 g, 3.846 mmol) were added at 0° C. and stirred at room temperature for 2-3 h. The reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated in vacuo to give (2-chloropyridin-4-yl)methyl methanesulfonate (0.530 g, 68%); MS: 221.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:19][C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[S:13]([NH:12][C:10]([NH:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)=[O:11])(=[O:15])=[O:14])=[O:20])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCc2ccccc2)n1

Procedure:
To 1.75 g of 2-(4,6-dimethylpyrimidin-2-ylaminocarbonylsulfamoyl)benzoic acid was added 0.51 g of triethylamine in 10 ml tetrahydrofuran and 0.88 g of benzyl bromide in 10 ml of tetrahydrofuran. The mixture was heated to reflux for 1.5 hours, filtered and the tetrahydrofuran evaporated in-vacuo. The residue was extracted with hot 1-chlorobutane, diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and the solvents evaporated in-vacuo. The resultant residue was crystallized from 1-chlorobutane to a melting point of 157°. This product showed absorption peaks in the infrared region at 1720, 1600, 1560 cm-1 consistent for the desired ester and absorption by nuclear magnetic resonance at 2.45', singlet, for CH3 ; 5.3 singlet, CH2 on benzyl; 6.65' singlet CH of pyrimidine and aryl peaks at 7-8%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
A mixture of DMSO (7.8 mL, 109.3 mmol) and methylene chloride (100 mL) was cooled to −78° C. Oxalyl chloride (4.8 mL, 54.7 mmol) was added to this solution via syringe. The mixture was stirred at −78° C. for 30 min. A solution of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (10.0 g, 49.7 mmol) in methylene chloride (30 mL) was added dropwise to this solution (temperature remained below −70° C.). The mixture was stirred for 30 min. Triethylamine (28 mL, 200 mmol) was added dropwise over 20 min. The mixture was stirred at −78° C. for 1 h and was allowed to warm to room temperature and stirred for 45 min. The mixture was diluted with water, and the layers separated. The organic layer was washed with water, dried Na2SO4), filtered, and concentrated to give 3-oxopiperidine-1-carboxylic acid tert-butyl ester (10.2 g) as a yellow, brown liquid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27]C)[N:24]=[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:22]=4)[CH:18]=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].BrC1C=C(C2C=C(N)N=C(C3C=CC=CN=3)C=2)C=NC=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[C:25]([NH2:27])[N:24]=[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:22]=4)[CH:18]=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1
Agent: Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Product: CC(C)N1CCC(n2cc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)cn2)CC1

Procedure:
This compound is prepared analogously to {5″-[1-(1-Isopropyl-piperidin-4-yl)-1H-pyrazol-4-yl]-[2,2′;4′,3″]terpyridin-6′-yl}-methyl-amine (Example 2.175) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with 5″-Bromo-[2,2′;4′,3″]terpyridin-6′-ylamine (Example 1.31).