Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=2[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.[Li+].[Cl-].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:51])[CH3:50])=[N:46][CH:47]=2)O1.O>O1CCOCC1>[Cl:31][C:29]1[CH:28]=[CH:27][C:4]2[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=[C:2]([C:42]3[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:51])[CH3:50])=[N:46][CH:47]=3)[C:3]=2[CH:30]=1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc(NC(C)=O)nc3)c3cc(Cl)ccc32)cc1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
5,7-Dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (208 mg, 0.439 mmol), LiCl (56 mg, 1.32 mmol), and CsOH (221 mg, 1.32 mmol) were combined, then a solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (115 mg, 0.439 mmol) in 1,4-dioxane (3 mL) was added followed by water (300 uL). The mixture was purged with nitrogen, then tetrakis(triphenylphosphinepalladium(0) (51 mg, 0.044 mmol) was added and the flask was lowered into a 100° C. oil bath and heated at 100° C. for 3 h. The mixture was allowed to cool, then diluted with ethyl acetate and rinsed with water 2× then brine and dried (MgSO4). Chromatography eluting with 40-50% ethyl acetate in hexanes to give a colorless oil (210 mg, 83% yield). MS (ES+) m/z 573.1 (M+1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[S:34]1[CH:38]=[N:37][N:36]=[C:35]1[N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH:25][C:46](=[O:47])[CH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:35]2[S:34][CH:38]=[N:37][N:36]=2)[CH2:40][CH2:41]1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)CC1CCN(c2nncs2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(c2nncs2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example A169, step B using 6-chloro2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and [1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting materials in 27% yield. LCMS for C27H28ClN8OS (M+H)+: m/z=547.2.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CS(C)=O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Agent: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
1-Benzyl-5-methylisatin was suspended in DMSO (100 mL) and cooled to 0° C. Hydrazine hydrate (5 mL) was added dropwise over 5 min. After addition, the resulting clear red solution was heated at 120° C. for 2 h then 140° C. for 5 h. After cooling to rt, it was poured into a IL Erlenmeyer flask, rinsed with H2O (50 mL) and ice was added until a total volume about 300 mL. 2 M HCl (50 mL) was added and the mixture was extracted with EtOAc (200 mL×2, then 100 mL), and the organic layer was dried (Na2SO4). Removal of solvents followed by drying under high vacuum for 2 days gave the title compound as a dark red solid (12.53 g, quantitative yield over 2 steps, contained some DMSO residue). 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 7.09 (s, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.91 (s, 2H), 3.60 (s, 2H), 2.31 (s, 3H); MS ESI 238.0 [M+H]+, calcd for [C16H15NO+H]+ 238.1.
Reaction SMILES: C1(O[C:8](=O)[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33]CN[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([N:9]2[CH2:8][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)[CH2:29][CH2:30]2)[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1N1CCN(c2cccc(O)c2)CC1
Yield: 78 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1(C)C=CC=CC=1.CCCCCC>[I:36][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCCC(C)CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)CCI
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a stirring solution of 43 (5 g, 32 mmol), imidazole (2.59 g, 38 mmol, 1.2 eq) and triphenylphosphine (9.11 g, 35 mmol, 1.1 eq) in toluene (100 ml) under nitrogen was added iodine (10.44 g, 41 mmol, 1.3 eq). The reaction mixture was stirred for 18 hours then filtered. The filtrate was washed with 5% sodium thiosulfate solution (3×100 ml) then dried (Na2SO4) and concentrated in vacuo to give a white solid. This solid was taken up in hexane (20 ml), cooled and filtered. The filtrate was then concentrated in vacuo to give 45 (6 g, 71%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[CH3:1][O:2][C@H:3]([C:4]1[O:6][N:62]=[C:61]([NH:60][C:55]2[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]3[C:43](=[O:65])[N:42]([CH3:41])[C:51]4[C:46]([CH:45]=3)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=4)[CH:54]=2)[N:64]=1)[CH3:7]
Reactant: CO[C@@H](C)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@@H](C)c1nc(Nc2ccc(C)c(-c3cc4cnc(C)cc4n(C)c3=O)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-2-methoxypropanoic acid (40 mg, 0.4 mmol) in DMF (4 mL) were added DIPEA (65 μL, 0.4 mmol) and HATU (0.14 g, 0.4 mmol). After stirring at rt for 15 min, 17 (0.13 g, 0.4 mmol) was added as a solution in DMF (1 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 3 h. Subsequently, the reaction was cooled to rt, partitioned with EtOAc (30 mL) and 5% aq NaHCO3 (20 mL). The aqueous layer was extracted with fresh EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and reduced to dryness. The crude material was purified by flash column chromatography on silica with DCM/2% MeOH as eluant to give (S)-3-(5-(5-(1-methoxyethyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A76) as a clear white glassy solid. 1H NMR (400 MHz, d6-DMSO) δ 9.94 (s, 1H), 8.81 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 7.40 (dd, J=8, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 4.68 (d, J=6 Hz, 1H), 3.65 (s, 3H), 3.45 (s, 3H), 2.61 (s, 3H), 2.07 (s, 3H), 1.49 (d, J=6 Hz, 3H). MS m/z 406.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:31](=[O:33])[NH2:32]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:31](=[O:33])[NH2:32]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1Cl
Yield: 98.9 %

Procedure:
A solution of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester (46 mg, 0.1 mM) in 3 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was triturated with diethyl ether/hexanes, then dried in vacuo to afford 40 mg (98%) of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ12.9 (br s, 1H), 7.55 (s, 1H), 7.5 (d, 1H, J=8 Hz), 7.45 (s, 1H), 7.4-7.3 (m, 3H), 7.25 (t, 1H, J=8 Hz), 7.1-7.0 (m, 3H), 6.6 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3430, 1735, and 1635. MS (ES) m/e 407, 409.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[S:37])=[O:34])=[CH:29][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (82 mg, yield 98%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:24]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@@H:36]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:27]2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:23]([O:57][C@@H:58]2[O:74][C@H:73]([CH2:75][O:76][C:77](=[O:84])[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C@H:71]([OH:72])[C@H:69]([OH:70])[C@H:59]2[O:60][C:61](=[O:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@@H:22]([CH2:85][O:86][C:87](=[O:94])[C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[O:21][C@H:11]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.C([C:103](CC)(CC)[C:104]([O-])([O-])[O-:105])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[C:1]([O:9][C@@H:10]1[C@@H:24]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@@H:36]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@@H:27]2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:23]([O:57][C@@H:58]2[O:74][C@H:73]([CH2:75][O:76][C:77](=[O:84])[C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[C@H:71]([O:72][C:104](=[O:105])[CH3:103])[C@H:69]([OH:70])[C@H:59]2[O:60][C:61](=[O:68])[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C@@H:22]([CH2:85][O:86][C:87](=[O:94])[C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[O:21][C@H:11]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCCCCCCCO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](O)[C@H](O)[C@H]2OC(=O)c2ccccc2)[C@H](O[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](OC(C)=O)[C@H](O)[C@H]2OC(=O)c2ccccc2)[C@H](O[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Compound 22 (5 g) was dissolved a 1:1 mixture of benzene and triethylorthoacetate (110 mL), containing 4-toluenesulfonic acid (0.2 g), and the mixture was stirred for 1 h at room temperature. The acid was neutralized with triethylamine, and the mixture evaporated to dryness. The residue was dissolved in 80% aqueous acetic acid (75 mL) and stirred for 40 min at room temperature. The acetic acid was evaporated under diminished pressure and the last traces were removed by co-evaporation with toluene to yield 23 (4.7 g, 91.3%); [α]D, -4.5° (c 0.8, chloroform), t.l.c. (5:1 ethyl acetate-toluene). 13C NMR (CDCl3): δ170.98 (COCH3), 166.75, 166.33, 166.18, 165.07 (4×PhCO), 102.03, 101.08 (C-1, C-1'), 98.16 (C-1 fuc), 80.07, 78.23 (C-3, C-4), 74.69, 73.53, 73.24 (3×PhCH2), 70.66 [OCH2 (CH2)6 ], 63.23, 61.42 (C-6, C-6'), 32.25-23.14 [(CH2)6CH3 ], 21.20 (COCH3), 17.49 (C-6 fuc), and 14.63 (CH3).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10]N=[N:8][C:7]=2[O:6][CH2:5]1.[CH3:13][C:14]1N=C2OCC(=O)C2=CC=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[N:8][C:13]([CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: Cc1ccc2c(n1)OCC2=O
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2nc(C)ccc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 6-methylfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (1/1) gives the desired product as white solid;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[Cl:20]N1C(=O)CCC1=O>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[C:5]2[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCN(C(=O)c2cc3cc(Br)ccc3[nH]2)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2[nH]c3ccc(Br)cc3c2Cl)CC1
Reaction time: 18 h
Yield: 58.2 %

Procedure:
(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 3, 0.27 g) in dichloromethane (3 mL) at ambient temperature was treated with N-chlorosuccinimide (0.103 g) and stirred for 18 h. The reaction mixture was diluted with ether, washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.16 g). 1H NMR (400 MHz, CDCl3): δ 2.35 (3H), 2.52 (4H), 3.78 (4H), 7.23 (1H), 7.35 (1H), 7.74 (1H), 9.84 (1H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19]C1C=C2C(=CC=1)NC(=O)C2=O>>[F:19][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:18])[C:2]([OH:1])=[C:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(F)cc12

Procedure:
Intermediate 21 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 5-fluoroindoline-2,3-dione. LC-MS (ESI) m/z 251.9 (M+H), RT=1.74 min (Method B).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH3:15])=[C:10]([C:12](O)=[O:13])[N:11]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>CN(C=O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH3:15])=[C:10]([C:12]([NH:28][C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[O:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(C(=O)O)c(C)s2)s1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(C(=O)Nc3nnn[nH]3)c(C)s2)s1
Temperature: 70 °C
Yield: 97.1 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-5-methyl-4-thiazolecarboxylic acid (300 mg) and CDI (304.9 mg) in dry DMF (3 ml) was allowed to react at room temperature for 1 hour. Then a solution of 5-aminotetrazole (128 mg) in dry DMF (2 ml) was added dropwise and the mixture was heated at 70° C. for 3 hours. The solvent was removed from the reaction mixture, and the residue was treated with water and acidified with 2N-HCl under ice-cooling. The produced solids were filtered with suction, washed sufficiently with water and dried to give pale yellow solids of 2-(5-methyl-2-thienyl)-5-methyl-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (372.9 mg, 97%), m.p. 278°-280° C. (from methanol-THF-water).
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Cl.[NH2:13][CH2:14][C:15]#[N:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[C:14]([CH2:15][NH:16][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:10]([OH:9])=[O:11])=[O:8])#[N:13]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: N#CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+)-trans-Cyclohexane-1,2-dicarboxylic anhydride (100 mg, 0.65 mmol) was weighed into a 10 mL round bottom flask and aminoacetonitrile hydrochloride (135 mg, 1.46 mmol) and 4-(dimethylamino)pyridine (7.5 mg, 61 μmol) added. After adding tetrahydrofuran (2.0 mL) and triethylamine (0.20 mL, 1.4 mmol), the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between 1 M aqueous hydrochloric acid (30 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give (1R,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexanecarboxylic acid (as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C)=[C:5]([C:20]([O:22]COC(=O)C(C)(C)C)=[O:21])[CH:6]([CH3:19])[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9].[CH:32](OC(C)C)(C)C>O>[CH3:32][N:3]1[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[O:9])[CH:6]([CH3:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1
Reactant: CC(C)OC(C)C
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Solvent: O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(C(=O)O)=CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
In 30 ml of isopropyl ether saturated with water was dissolved 1.32 g of the bis(pivaloyloxymethyl) 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate obtained in Example 18, and 300 mg of Lipase B was added thereto, followed by stirring at room temperature for 8 hours. Any insoluble matter was removed by filtration and washed with acetone. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane =1/3) to obtain 741 mg (yield: 76%) of (+)-1,4-dihydro-1,4,6-trimethyl-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[F:28][C:26]([F:27])([F:29])[C:23]1[N:21]2[N:22]=[C:17]([N:3]3[CH2:4][C@@H:5]4[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:1]([CH2:7][CH2:6]4)[CH2:2]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CNC2
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc3nnc(C(F)(F)F)n3n1)C2

Procedure:
A mixture of tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give tert-butyl (1S,5R)-3-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][N:20]=[N+:21]=[N-:22])[CH2:16][CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Yield: 73.3 %

Procedure:
The mesylate from step i (32.6 g, 110 mmol) was treated with sodium azide (21.45 g, 330 mmol) in DMF at 80° C. for 24 hrs. The solvent was evaporated, the residue was taken up in DCM, filtered and washed with saturated NaHCO3 (aq). The solution was dried with Na2SO4 and concentrated to a brown oil which was purified by flash chromatography using a gradient of ethyl acetate and hexane to afford the title compound as a white solid (19.55 g, 73%).
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:84])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:33]([O:78][CH3:79])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@@H:42]([C@@H:45]([CH3:77])[C:46](=[O:76])[NH:47][C@@H:48]([CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:49](=[O:68])[NH:50][CH2:51][CH2:52][NH:53][C:54](=[O:67])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C@H:60]3[C@@H:64]([CH3:65])[NH:63][C:62](=[O:66])[NH:61]3)[O:43][CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:33]([O:78][CH3:79])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@@H:42]([C@@H:45]([CH3:77])[C:46](=[O:76])[NH:47][C@@H:48]([CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:49](=[O:68])[NH:50][CH2:51][CH2:52][NH:53][C:54](=[O:67])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C@H:60]1[C@@H:64]([CH3:65])[NH:63][C:62](=[O:66])[NH:61]1)[O:43][CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])([CH3:84])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCNC(=O)CCCCC[C@@H]1NC(=O)N[C@@H]1C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCNC(=O)CCCCC[C@@H]1NC(=O)N[C@@H]1C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Yield: 53.1 %

Procedure:
Following general procedure A using #256 (5 mg, 0.004 mmol, 1.0 eq.) and piperidine (0.02 mL, 0.2 mmol, 50 eq.) in 0.7 mL of DMF followed by purification (Method J) afforded #257 (2 mg, 50%) as a colorless glass. LC-MS (Protocol Q1): m/z 1164.8 [M+H+], retention time=0.99 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.44-8.52 (m), 8.06-8.20 (m), 7.96-8.01 (m), 7.69-7.83 (m), 7.20-7.28 (m), 7.11-7.19 (m), 3.38-3.83 (m), 3.19-3.26 (m), 3.03-3.12 (m), 2.98 (s), 2.91 (s), 2.75 (s), 2.65-2.70 (m), 2.01-2.36 (m), 1.65-1.87 (m), 1.39-1.57 (m), 1.13-1.37 (m), 1.04-1.08 (m), 0.74-1.01 (m).