Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][CH2:22][C:23](=[O:25])[NH2:24])=[CH:14][CH:13]=1)(C)(C)C.[ClH:27]>C1COCC1.O1CCOCC1>[ClH:27].[ClH:27].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]([NH2:24])=[O:25])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNCC(N)=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NCCCCc1ccc(OCCNCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 3 (0.25 g, 0.68 mmol) was dissolved in THF (3 mL), treated with 4 N HCl in dioxane (10 mL) and the reaction was stirred at room temperature for 2 hours. After this time, TLC analysis indicated a complete reaction. The reaction mixture was concentrated under vacuum, and methanol (2 mL) was added to the resulting residue. The resulting precipitate was collected by vacuum filtration and further dried in a vacuum oven to provide 4 (0.154 g, 67% overall yield for two steps) as a light brown solid. 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.65 (m, 2H), 2.95 (m, 2H), 3.27 (m, 2H), 3.52 (t, 2H), 3.90 (s, 2H), 4.30 (t, 2H), 6.92 (d, 2H), 7.18 (d, 2H). m/z (ESI) 266.
Reaction SMILES: [CH3:1][NH:2][C:3]1C=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[NH:34]1CCCCC1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:7][N:34]=1
Reactant: C1CCNCC1
Reactant: CNc1ccc(-c2nc3ccc(O)cc3s2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNc1ccc(-c2nc3ccc(O)cc3s2)cn1
Yield: 99.4 %

Procedure:
2-[4-(N-monomethyl)aminophenyl]-6-hydroxybenzothiazole (45, 520 mg, 2.03 mmol) was dissolved in tetrahydrofuran (15 mL) and (BOC)2O (974 mg, 4.46 mmol) and N,N-dimethylaminopyridine (DMAP; 496 mg, 4.06 mmol) were sequentially added thereto. After agitating the resulting reaction mixture for 16 hours at room temperature and removing the solvent under reduced pressure, the mixture was dissolved again in dichloromethane (40 mL). Then, after adding piperidine (4.0 mL, 40.6 mmol), the reaction mixture was agitated for 1 hour at room temperature and ammonium chloride aqueous solution was added. After extracting the organic compound with dichloromethane and removing water using sodium sulfate, column chromatography yielded the target compound 2-[2-(N-monomethylamino)pyridin-5-yl]-6-hydroxybenzothiazole (12-4, 519 mg, 72%) as a white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Br.[NH2:9][C:10]1[S:11][C:12]([Br:15])=[CH:13][N:14]=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O>[Br:15][C:12]1[S:11][C:10]([NH:9][C:5](=[O:7])[CH3:6])=[N:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(Br)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.9 ml (42.3 mmol) of acetic anhydride are added to a solution of 10 g (38.5 mmol) of 2-amino-5-bromothiazole hydrobromide in 100 ml of dichloromethane and 11 ml (77 mmol) of triethylamine, cooled to 0° C. The reaction medium is stirred for 30 minutes at 0° C. and then for 18 hours at room temperature. After addition of water, the pH is adjusted to pH 8 with aqueous 1M sodium hydroxide solution and the reaction medium is extracted with dichloromethane. The dichloromethane phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is used in step b without purification.
Reaction SMILES: O[NH:2][CH2:3][C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:5].[CH:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](O)[CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1.CC[O:43]C(C)=O>>[CH:17]1[C:18]([NH:6][C:7]([C:13]([OH:15])=[O:14])=[O:43])=[CH:19][CH:20]=[C:21]([N+:22]([OH:24])=[O:23])[CH:16]=1.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:5]
Reactant: NCCCC[C@H](NC(=O)CNO)C(=O)O
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: NCCCC[C@H](NC(=O)CN)C(=O)O
Product: O=C(O)C(=O)Nc1ccc([N+](=O)O)cc1
Reaction time: 0.08 h

Procedure:
To a magnetically stirred solution of HO-GlyLys [ε-CBz] [α-Lys] [Boc]2 (430 mg, 0.65 mmol) and EtOAc (10 ml) was added, in the following order, p-nitrophenol (99 mg, 0.71 mmol) and DCC (147 mg, 0.71 mmol). After stirring at Rt for ca. 5 mins, the reaction mixture became a slurry due to the formation of a gel like precipitate. Stirring was continued at Rt for a further 22 h. The crude reaction mixture was diluted upon the addition of EtOAc (15 ml) then filtered. The filtrate was concentrated under reduced pressure to give an orange/yellow coloured solid. After subjection of the crude material to silica gel flash chromatography (EtOAc), the product PNPO-GlyLys [ε-CBz] [α-Lys] [Boc]2 (Rf 0.4) (344 mg, 66%) was obtained as an off white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[N+:22]([O-])=O)#[N:2].[C:25](OC(=O)C)(=[O:27])[CH3:26].C1C[O:35][CH2:34][CH2:33]1>[Ni]>[C:25]([NH:22][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=[CH:8][C:3]=1[CH2:1][NH:2][C:34](=[O:35])[CH3:33])(=[O:27])[CH3:26]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c([N+](=O)[O-])c2)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Product: CC(=O)NCc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(C)=O
Reaction time: 12 h
Yield: 75 %

Procedure:
To a solution of compound 18 (2.0 g, 6 mmol) in THF (30 mL) was added acetic anhydride (4.5 mL, 48 mmol), followed by the addition of Ra—Ni (˜0.4 g), and the mixture was subjected to hydrogenation in a Parr apparatus at 60 psi for 12 h. After filtering over the pad of celite, the solution was concentrated to get a brown oil material, which was resolved over silica column eluting with EtOAc:hexanes (4:6) and then changing to (6:4) to get 1.75 g (75%) of 19 as an off-white gum. IR (KBr) νmax. cm′: 3311, 3160 (NH), 3062 (Ar—H), 1691 (C═O), 1611, 1512, 1412 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.39 (s, 9H, (CH3)3C); 1.98 (s, 3H, CH3); 2.21 (s, 3H, CH3); 3.03 (m, 4H, 2CH2); 3.53 (m, 4H, 2CH2); 4.29 (d, 2H, J=6.7 Hz, CH2); 6.73 (d, 1H, J=2.4 Hz, H-2); 6.84 (dd, 1H, J=8.8, J=2.4 Hz, H-6); 7.85 (d, 1H, J=8.8 Hz, H-5); 9.48 (s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=22.96 (CH3), 24.06 (CH3), 28.37 (CH3)3C), 40.87 (CH2), 43.50 (CH2), 49.73 (CH2), 79.95 (CH3)3C), 117.14 (C-2), 118.65 (C-4), 124.56 (C-6), 129.59 (C-3), 129.94 (C-5), 147.95 (C-1), 154.67 (C═O), 169.41 (C═O), 171.29 (C═O). Calculated (%) for C20H30N4O4 (390.23); C: 61.52, H: 7.74, N: 14.35. found (%); C: 61.43, H: 7.82, N: 14.26.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)OC(C)(C)C)[N:10]=2)[N:7]=1.CCOCC.[ClH:24]>O1CCOCC1>[ClH:24].[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 3B was synthesized according to a procedure analogous to that described in International Patent Publication No. WO 2008/06192 (Takeda Pharmaceutical Company Limited), which is incorporated by reference herein in its entirety. Specifically, tert-butyl 6-iodoimidazo[1,2-b]pyridazin-2-ylcarbamate (3A, 5.9 g, 16.38 mmol) was dissolved in 4N HCl in dioxane (60 mL) and stirred at ambient temperature for 4 hours. Ether (140 mL) was added to the reaction and a brown precipitate formed. The precipitate was filtered and washed with ether to give 6-iodoimidazo[1,2-b]pyridazin-2-amine hydrochloride in quantitative yield. This material was used without purification. ESI-MS:m/z 261.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:15]([O:22][C:23]1[C:28](F)=[CH:27][C:26]([Cl:30])=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:28]2[C:23]([O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:24][CH:25]=[C:26]([Cl:30])[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc(Cl)cnc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)cnc2OCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
To 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.35 g, 2.0 mmol) in NMP (3 mL) was added 60% NaH in mineral oil (0.08 g, 2.0 mmol). After 20 min at rt, the reaction was heated to 50° C. for 20 min, cooled to rt and the title compound from step A (0.40 g, 1.7 mmol) in NMP (1 mL) was added. The reaction was then heated in a microwave reactor at 145° C. for 1 h, cooled to rt, poured into H2O and extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (2-15% EtOAc in hexanes) gave 0.34 g (51% yield) of the title compound as a white solid. 1H NMR (CDCl3): 7.74 (d, J=2.1 Hz, 1H), 7.46 (d, J=7.0 Hz, 2H), 7.39-7.30 (m, 3H), 6.77 (d, J=2.1 Hz, 1H), 5.42 (s, 2H), 4.87-4.82 (m, 1H), 4.26 (dd, J=10.5, 6.4 Hz, 2H), 4.05 (dd, J=10.3, 4.2 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH3:18].[Li][CH2:20]CCC.CI>C1COCC1>[CH3:14][O:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]=1[CH3:20]
Reactant: CCCOc1ccc(OCOC)cc1OCOC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCOc1ccc(OCOC)c(C)c1OCOC
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 4b (165 mg, 0.64 mmol) in anhydrous THF (520 μL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 390 μL, 0.97 mmol) in anhydrous THF (420 μL) at room temperature. After 1 hour, the solution was cooled to −78° C. and methyl iodide (160 μL, 2.58 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 5b as a yellow oil (166 mg, 95%): 1H NMR (CDCl3, 500 MHz) 6.66 (d, J=9.0 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 3.80-3.77 (m, 2H), 3.49 (s, 3H), 3.47 (s, 3H), 2.14 (d, J=7.1 Hz, 3H), 1.73-1.69 (m, 2H), 0.94 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 148.5, 148.5, 147.3, 145.6, 126.7, 123.0, 112.8, 110.8, 110.4, 99.2, 57.7, 57.6, 21.2, 10.9, 10.0; IR (film) νmax 2957, 2924, 2853, 1738, 1597, 1487, 1468, 1391, 1335, 1231, 1157, 974, 798 cm1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H22O5, 271.1545. found, 271.1558.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([OH:26])=O)[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:38][S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH3:28])(=[O:36])=[O:37])=[O:26])[O:21][C:22]=3[CH3:23])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: Cc1ccccc1S(N)(=O)=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1

Procedure:
Compound (173) was prepared from compound (171) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt=10.63 mins, m/z (ES+)=527 (M+H for C27H24F2N2O5S).
Reaction SMILES: CC(C(CCC[CH2:15][N:16]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:17]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)C(O)(O)C([O-])=O)(C)C.[OH-].[Na+].[C:48]([O:51]CC)(=[O:50])[CH3:49].[C:54]([O-:57])(=[O:56])[CH3:55].[Ca+2:58].[C:59]([O-:62])(=[O:61])[CH3:60]>C(#N)C.O.C1CCCCC1>[CH3:23][CH:21]([C:20]1[N:16]([CH2:15][CH2:60][C@@H:59]([OH:61])[CH2:55][C@@H:54]([OH:57])[CH2:49][C:48]([O-:51])=[O:50])[C:17]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH3:22].[CH3:23][CH:21]([C:20]1[N:16]([CH2:15][CH2:55][C@@H:54]([OH:56])[CH2:60][C@@H:59]([OH:62])[CH2:49][C:48]([O-:51])=[O:50])[C:17]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH3:22].[Ca+2:58]
Reactant: CC(=O)[O-]
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCCCC(C(C)(C)C)C(O)(O)C(=O)[O-]
Reactant: CCOC(C)=O
Agent: [Ca+2]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: O
Solvent: CC#N
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Reaction time: 0.5 h

Procedure:
20 gm of R—(R*,R*)]-1,1-dimethylethyl-2-(4-fluorophenyl)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoate was taken in 400 mL of acetonitrile to obtain clear solution at 40° C. to 45° C. The reaction mixture was cooled to 25° C. to 30° C. and 2.60 gm of NaOH solution in 100 mL of water was added within 15 min and stirred for 30 min. Acetonitrile was distilled under vacuum to obtain white slurry or solid. The compound thus obtained was further cooled at 10° C. to 15° C. 400 mL of water was added followed by slow addition of 400 mL of ethyl acetate to dissolve the solution. 10.46 gm of calcium acetate solution in 244 mL of water was added to obtain hazzy solution at 10° C. to 15° C. The reaction mixture was stirred for 2 hrs at 35° C. to 40° C. and cooled to 30° C. to 35° C. The organic layer was separated and washed with water and filtered through hyflow bed followed by washing with ethyl acetate. The organic phase was distilled to remove ethyl acetate completely till powder or lump of material was obtained. The solid thus obtained was treated with 100 mL of cyclohexane and stirred for 30 min. The product was filtered, washed with cyclohexane and dried at 30° C. to 35° C. to obtain amorphous atorvastatin calcium.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](O)(=O)C(O)=O.[CH:28]1([NH:31][NH2:32])[CH2:30][CH2:29]1.C(C1C=C(NS(C)(=O)=O)C(OC)=C(NC(=O)C2C=CC(C)=C(N3C=C(C4C=NN(C(C)C)C=4C4CC4)N=N3)C=2)C=1)(C)(C)C>>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:31]([CH:28]3[CH2:30][CH2:29]3)[N:32]=[CH:22][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(O)C(=O)O
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NNC1CC1
Agent: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnn(C(C)C)c4C4CC4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: CCOC(=O)c1cnn(C2CC2)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
N-Boc-4-(2-Cyclopropyl-4-ethoxycarbonyl-2H-pyrazol-3-yl)-piperidine was prepared from N-Boc-4-(2-ethoxycarbonyl-acetyl)-piperidine and cyclopropyl hydrazine oxalate in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (Example 49).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH2:17].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH:17][CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4]
Reactant: COc1ccc(CCN)cc1OC
Reactant: OC(CBr)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCNCC(O)c2cccs2)cc1OC
Temperature: 25 °C

Procedure:
A solution of the halohydrin, α-(bromomethyl)-2-thiophenemethanol (11.4 g, 0.055 mole), described in Example 4, and the primary amine, 3,4-dimethoxyphenethylamine (15 g, 0.083 mole), in 200 ml toluene is heated at reflux for 12 hr. The mixture is cooled to 25° C, shaken with 10% NaOH an the layers separated. The aqueous layer is extracted with chloroform and the combined organic phases washed with water and brine, dried (K2CO3) and concentrated. The resulting dark brown oil is purified by chromatography on silica gel to give the title compound as an oil; nmr (CDCl3) 2.9 (m, 6H), 3.45 (2H), 3.85 (s, 6H), 5.05 (m, 1H), 6.7 - 7.3 (m, 6H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:4])=[O:3].[NH2:37][C:38]([NH2:40])=[S:39]>CN(C)C=O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:38]([S:39][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[NH:37])[NH2:40]
Reactant: NC(N)=S
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(COS(C)(=O)=O)C4)C(=O)NC2=O)c2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CSC(=N)N)C4)C(=O)NC2=O)c2ccccc21
Yield: 69.5 %

Procedure:
A solution of 100 mg of the pyrroledione product of Example 6 and 75 mg of thiourea in 5 ml of dimethylformamide was heated to 80° C. under a nitrogen atmosphere for 18 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2). The residue was triturated with ethyl acetate to give 80 mg of 3-[8-[(amidinothio)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]-indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione methanesulfonate of melting point 200°-205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[NH2:21][C:22]1[S:26][C:25]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[N:24][C:23]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:21][C:22]1[S:26][C:25]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[N:24][C:23]=1[C:35]([NH:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:36]
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2sncc2N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2sncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
tert-butyl 4-(4-aminoisothiazol-5-yloxy)piperidine-1-carboxylate (1D4) (47 mg, 0.156 mmol), 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (1E) (40 mg, 0.156 mmol), HATU (71 mg, 0.187 mmol) and DIEA (84 μL, 0.468 mmol) were mixed in DMF (5 mL), stirred at 50° C. for 1 hour, cooled to room temperature, diluted with ethyl acetate (50 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to afford the product tert-butyl 4-(4-(5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)isothiazol-5-yloxy)piperidine-1-carboxylate (1A) (17 mg, 0.031 mmol).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([N:12]([CH3:32])[C:13]([CH2:15][N:16]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)C(=O)C(F)(F)F)=[O:14])[CH:6]=1.C(O)(=O)C>CO.O>[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([N:12]([CH3:32])[C:13](=[O:14])[CH2:15][NH:16][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:6]=1
Reactant: Cc1cc(C)nc(N(C)C(=O)CN(C(=O)C(F)(F)F)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cc(C)nc(N(C)C(=O)CNc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Lithium hydroxide monohydrate (56 mg, 1.34 mmol) was added to a solution of N-{[(4,6-Dimethyl-pyridin-2-yl)-methyl-carbamoyl]-methyl}-2,2,2-trifluoro-N-(4-nitro-phenyl)-acetamide (550 mg, 1.34 mmol) in methanol (20 mL) at 0° C. and stirred for 1 h. The pH was adjusted to approximately pH 6 by the addition of acetic acid. Methanol was evaporated in vacuo to yield a solid residue, which was stirred in water and filtered to afford N-(4,6-dimethyl-pyridin-2-yl)-N-methyl-2-(4-nitro-phenylamino)-acetamide (350 mg, 53%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][Si](C)(C)C)[CH:14]=3)=[CH:12][C:3]1=2.C(=O)([O-])[O-].[K+].[K+]>CO>[C:19]([C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:25])([CH3:1])[C:3]=3[CH:12]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4,4-dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.7 g, 2 mmol) and potassium carbonate (2 g, excess) in anhydrous methanol was stirred at rt under nitrogen for 4 hours. The mixture was treated with ice-water (100 mL) and extracted with ethyl acetate (2×80 mL). The organic layers were washed with brine and dried with MgSO4. The solvent was removed and the title compound was obtained as a off-white solid (0.4 g, 72%): mp 171-172° C. 1H-NMR (DMSO-d6) δ 10.3, (s, 1H), 7.78 (bs, 1H), 7.72-7.69 (m, 1H), 7.6-7.57 (m, 2H), 7.49-7.43 (m, 2H), 6.97 (d, 1H, J=7.98 Hz), 4.25 (s, 1H), 1.67 (s, 6H); MS (EI) m/z 277([M+], 100%), Anal. Calc. For C18H15NO2.0.2 EtOAc: C, 76.56; H, 5.67; N, 4.75. Found: C, 76.34; H, 5.4; N, 4.7.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[CH3:15][C:16]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].CC(C)=O.CO>C(Cl)Cl>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:5]=1[CH2:4][C:1](=[O:3])[N:19]([CH2:18][C:17]1[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:16]=1[CH3:15])[C:7]2=[O:9]
Reactant: Cc1ccc(CN)c(C)c1
Reactant: O=C(O)Cc1c(Cl)cccc1C(=O)O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(CN2C(=O)Cc3c(Cl)cccc3C2=O)c(C)c1
Temperature: 180 °C
Yield: 72.7 %

Procedure:
A mixture of 2-carboxymethyl-3-chlorobenzoic acid (1.91 g, 8.9 mmol) and 2,4-dimethylbenzylamine (1.35 mL, 9.6 mmol) was placed in a vented vial and heated in an oil bath maintained at 180° C. After heating for 64 hours the reaction was allowed to cool to ambient temperature, then taken up in a mixture of CH2Cl2, acetone, and methanol. The solution was mixed with silica gel and then concentrated under reduced pressure to afford a free flowing solid. This solid was loaded onto the top of a silica gel column and eluted with a gradient from 0% to 14% ethyl acetate/hexane to afford 5-chloro-2-(2,4-dimethylbenzyl)-4H-isoquinoline-1,3-dione (2.03 g, 73% yield) as a yellow solid: 1H-NMR (400 MHz, CDCl3): δ 8.17 (1H, dd, J=7.8, 1.3 Hz), 7.65 (1H, dd, J=7.8, 1.3 Hz), 7.42 (1H, app. t, J=7.8 Hz), 6.98 (1H, br s), 6.96-6.92 (1H, m), 6.91-6.87 (1H, m), 5.16 (2H, s), 4.09 (2H, s), 2.44 (3H, s), 2.26 (3H, s) ppm.