Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][OH:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:42]([CH3:51])([CH3:50])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C)C=O.C(OCC)(=O)C.O>[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([CH3:51])[CH3:50])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 0.05 h

Procedure:
A mixture of 9.88 g of the hydrochloride of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetate and 8.28 g of potassium carbonate in 25 ml of dry dimethylformamide was cooled in a bath at -10° C. for 10 minutes and 19 ml of raw tert.-butyl 2-bromo-2-methyl-propionate were added thereto over 3 minutes. The mixture was stirred for 16 hours during which it solidifed into a mass which was poured into a mixture of 400 ml of distilled water and 200 ml of ethyl acetate. The mixture was stirred and decanted and the organic phase was washed with water. The aqueous phase was extracted twice with 100 ml of ethyl acetate and the combined organic phases were dried and vacuum filtered. The filtrate was evaporated to dryness to obtain an oil residue which was added to 240 ml of petroleum ether. The mixture was cooled and crystallization was effected. The mixture was vacuum filtered after 30 minutes to obtain 10.8 g of the syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(1-tert.-butoxycarbonyl-1-methylethyl oxyimino)-acetate melting at 134° C.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=2[O:10]1>>[O:17]1[C:16]2[CH:15]=[CH:14][C:13]([C:2]3[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=3)=[CH:12][C:11]=2[O:10][CH2:9]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2ccc3c(c2)OCO3)CCC1
Yield: 85 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 3,4-methylenedioxyphenylboronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 80% ethyl acetate/hexanes) yielded the product (164 mg, 85%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.07-7.00 (m, 2H), 6.81 (d, J=8.0 Hz, 2H), 6.31 (s, 1H), 5.99 (s, 2H), 2.70 (t, J=5.5 Hz, 2H), 2.45 (t, J=6.3 Hz, 2H), 2.12 (quintet, J=6.3 Hz, 2H). 13C (75 MHz, CDCl3): 199.7, 159.0, 149.2, 148.2, 132.8, 124.2, 120.7, 108.4, 106.3, 101.6, 37.4, 28.3, 23.0. LCMS (ESI): mass calcd for (C13H12O3) m/z 216.08; measured [M+H]+: m/z 216.95.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)[CH:12]=2)[C@@H:9]([O:28]C(=O)C)[C@H:8]([CH2:32][O:33]C(=O)C)[C@@H:7]([O:37]C(=O)C)[C@@H:6]1[O:41]C(=O)C)(=O)C.[OH-].[Na+].Cl>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:10]2[C@@H:9]([OH:28])[C@H:8]([CH2:32][OH:33])[C@@H:7]([OH:37])[C@H:6]([OH:41])[C@H:5]2[OH:4])=[CH:12][C:13]=1[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:27])[CH3:26])=[CH:23][CH:24]=1
Reactant: CC(=O)OC[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3O)ccc2Cl)cc1
Reaction time: 1.5 h
Yield: 149.7 %

Procedure:
To a solution of (1S,2R,3R,4S,5R,6R)-4-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)cyclohexane-1,2,3,5-tetrayl tetraacetate (38) (300 mg, 47.6 μmol) in MeOH (5 mL) was added sodium hydroxide (29 mg, 72 μmol) and stirred for 1.5 h under reflux. The mixture was acidified to pH 6 with 1 N hydrochloric acid and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC to provide 30 mg of the desired compound. 1H-NMR (400 MHz, CD3OD): δ 7.90 (2H, d, J=8.4 Hz), 7.35 (3H, m), 7.22 (H, d, J=1.6 Hz), 7.18 (1H, d, J=8.4, 1.6 Hz), 4.17 (2H, s), 3.91 (2H, d, J=3.2 Hz), 3.66 (1H, t, J=10.4 Hz), 3.49-3.40 (2H, m), 3.30 (1H, m), 2.57-2.52 (4H, m), 1.55-1.50 (1H, m); MS (ESI+): 421 [M+H]+, 443 [M+Na]+, (ESI−): 465 [M+HCOO]−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[CH3:34])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[F:33][CH:31]([F:32])[O:30][C:26]1[CH:25]=[C:24]([S:21]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:22])=[O:23])[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[5-(3-Difluoromethoxy-benzenesulfonylamino)-2-methyl-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.097 g, 0.195 mmol) was dissolved in 5 mL of dichloromethane. A solution of 0.293 mL of 2N hydrochloric acid in diethyl ether was added and the mixture stirred for 16 h at room temperature. The solvents were evaporated, the residue purified via reversed phase HPLC and fractions containing the product were combined. The pH was adjusted to 9 with aqueous sodium bicarbonate and the aqueous layer extracted with dichloromethane. The organic phase was then dried over magnesium sulphate, filtered and evaporated to dryness. The residue was treated with a solution 2N hydrochloric acid in diethyl ether and the mixture evaporated to dryness to yield the title compound (0.017 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=O)=[CH:2]1.[N:21]1(OC(N(C)C)=[N+](C)C)[C:25]2C=C[CH:28]=[CH:29][C:24]=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(N)CCC>>[CH2:25]([NH:21][C:12](=[O:14])[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[CH2:24][CH2:29][CH3:28]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCN
Product: CCCCNC(=O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid (100 mg, 0.3784 mmol.) in 2 ml of DMFd were added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoborate (121.5 mg, 0.3784 mmol.), N-hydroxybenzotriazole (51.1 mg, 0.3784 mmol) and N,N-diisopropylethylamine (129.2 μl, 0.7568 mmol). After stirring at room temperature for 30 min., 34.5 μl (0.3784 mmol.) of n-butylamine were added and the obtained solution was stirred at room temperature, for 24 hours. The resulting mixture was concentrated by evaporation of the solvent in vacuo, the residue was diluted with dichloromethane washed with 1 N NaOH, 1 N HCl, brine, dried over sodium sulphate and evaporated. The residual solid was triturated with Et2O to afford 49 mg of the title compound as a white solid (yield 41%) m.p. 177-179° C. (dec.)
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].ClCCl.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])(=[O:5])=[O:4]
Reactant: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
Step 2 is a step of conversion of hydroxyl to a trifluoromethanesulfonate (triflate). Compound (B3-c) may be obtained by reaction with trifluoromethanesulfonic anhydride in a solvent such as dichloromethane in the presence of a base such as triethylamine or pyridine, or by reaction with compound (B3-e) in the presence of triethylamine or dimethylaminopyridine.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:17]2[CH:22]=[C:21]([I:23])[C:20]([O-:24])=[C:19]([I:25])[CH:18]=2)=[C:8]2[CH:14]=[C:13]([I:15])[C:11](=[O:12])[C:10]([I:16])=[CH:9]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+].[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:55])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([N+:52]([O-])=O)[CH:47]=2)[NH2:44])[CH2:38][CH2:37]1)=[O:35])[CH3:32].[H][H]>C(O)C.[Pd]>[CH:1]1[CH:6]=[C:5]([C:7]([C:8]2[CH:9]=[C:10]([I:16])[C:11]([O-:12])=[C:13]([I:15])[CH:14]=2)=[C:17]2[CH:18]=[C:19]([I:25])[C:20](=[O:24])[C:21]([I:23])=[CH:22]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+:29].[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:42](=[O:55])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH2:52])[CH:47]=2)[NH2:44])[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1C(I)=CC(=C(c2cc(I)c([O-])c(I)c2)c2ccccc2C(=O)[O-])C=C1I
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc(N)c2)CC1

Procedure:
TIPPS-3-nitro-(L)-phenylalanine-4-ethoxycarbonylpiperazide (157 g; 176 mmol) was dissolved in 800 ml of ethanol, admixed with 19.7 g of 10% palladium on activated carbon catalyst and hydrogenated for 3 days by slowly passing through hydrogen. After filtering off the catalyst, the solvent was evaporated under vacuum and the crude product was chromatographically purified over silica gel.
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([NH:21][C@H:22]([CH2:29][CH3:30])[CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:8][C:9]=2[NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.N[C@@H](CC)C(O)C(C)(C)C>CCCCO.CS(C)=O>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([NH:21][C@@H:22]([CH2:29][CH3:30])[CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:8][C:9]=2[NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Agent: CC[C@H](N)C(O)C(C)(C)C
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (3RS,4R)-4-{9-Isopropyl-6-[(pyridin-3-ylmethyl)-amino]-9H-purin-2-ylamino}-2,2-dimethyl-hexan-3-ol (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4S)-4-amino-2,2-dimethyl-hexan-3-ol (43 mg, 2.81 eq, 0.29 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 5.4 mg (13%). (53% de 4S,3R: 47% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ0.99-1.03 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.57 & 1.59 (2×d, 6H, J=6.79 & 6.79 Hz, —CH(CH3)2), 1.70-1.93 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.55 (d, 1H, J=2.05 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.77-3.90 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.58-4.70 (m, 1H, —CH(CH3)2), 4.82-4.94 (m, 2H, —HNCH2-Pyr), 5.31-5.45 & 6.12-6.34 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.26-7.40 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (s, 1H, Pyr-H), 7.75 (d, 1H, J=7.42 Hz, Pyr-H), 8.46-8.81 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (70). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.
Reaction SMILES: Cl.[OH:2][C@@H:3]([CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH:27][CH3:28])[CH2:23][CH2:22]4)[C:10]=3[C:9]1=2)[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:38]>CN(C)C=O.O>[OH:2][C@@H:3]([CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:22][CH2:23][CH:24]([N:27]([CH3:28])[CH2:36][C:37](=[O:38])[N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[CH2:25][CH2:26]4)[C:10]=3[C:9]1=2)[C:4]([NH2:6])=[O:5]
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Reactant: O=C(CCl)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1

Procedure:
Into a 50-mL round-bottom flask, a solution of (2S)-2-hydroxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide hydrochloride (110 mg, 0.26 mmol, 1.00 equiv), potassium carbonate (179 mg, 1.30 mmol, 5.03 equiv) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (152 mg, 1.03 mmol, 4.00 equiv) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 4×20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product was purified by flash preparative HPLC under the following conditions (IntelFlash-1): column: silica gel; mobile phase; Detector, UV 254 nm. This resulted in (2S)-2-hydroxy-3-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (63.8 mg, 49%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 5.28 (m, 1H), 4.17-4.14 (m, 1H), 3.59-3.32 (m, 7H), 3.15-2.98 (m, 2H), 2.76-2.70 (m, 2H), 2.52-2.33 (m, 7H), 2.04-1.89 (m, 6H), 1.74-1.53 (m, 5H). MS: m/z 502 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=1.C(N1CCOCC1)C.[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[O:36]1[CH2:37][CH2:38][CH:33]([CH2:32][NH:31][C:20]([C:13]2[C:14]([C:16]([F:17])([F:19])[F:18])=[N:15][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:11][CH:12]=2)=[O:22])[CH2:34][CH2:35]1
Reactant: NCC1CCOCC1
Reactant: O=C(O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC1CCOCC1)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) in dimethylformamide (2 ml) was added successively N-ethylmorpholine (33 μl), 4-aminomethyltetrahydropyran (12 mg), 1-hydroxybenzotriazole hydrate (18 mg) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (20 mg). The solution was stirred for 3 h and allowed to stand overnight. Dimethylformamide was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 5% sodium bicarbonate solution (2.5 ml), water (2.5 ml), 5% citric acid solution (2.5 ml) and brine (2×2.5 ml), dried (MgSO4) and evaporated to afford the title compound (34 mg) NMR (DMSO-d6) δ 1.20 (2H, m), 1.58 (2H, d), 1.70 (1H, m), 3.10 (2H, t), 3.23 (2H, t), 3.84 (2H, dd), 7.46 (1H, dd), 7.57 (1H, d), 7.71 (1H, d), 8.59 (1H, t), 8.63 (1H, s), 10.00 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:3]=1[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])[CH:9]=[CH:10][CH:11]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:2]([CH3:1])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1C=Cc1cccc(CCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1/C=C/c1cccc(CCC(=O)N2CCNCC2)c1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a stirred solution of tert-Butyl 4-(3-(3-(2,6-Dimethylstyryl)phenyl)propanoyl)piperazine-1-carboxylate (12) (0.450 g, 1.00 mmol) in methylene chloride (6 mL) was added trifluoroacetic acid (3 mL) at room temperature. After 1 h, the reaction mixture was basified by slow addition of saturated aqueous sodium bicarbonate (30 mL) followed by 10% aqueous potassium carbonate to pH 10. The resulting mixture was extracted with hexanes (3×50 mL) and the combined extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by Preparative HPLC (Method 1) to give (E)-3-(3-(2,6-dimethylstyryl)phenyl)-1-(piperazin-1-yl)propan-1-one (13) (0.147 g, 42%) as a colorless oil. Rf 0.58 (silica gel, 50:40:10 ethyl acetate/hexanes/7N ammonia in methanol); 1H NMR (500 MHz, CD3OD) δ 7.41 (s, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.18 (d, J=16.7 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.03 (s, 3H), 6.57 (d, J=16.7 Hz, 1H), 3.53 (t, J=5.1 Hz, 2H), 3.41 (t, J=5.1 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.71 (m, 4H), 2.59 (t, J=5.1 Hz, 2H), 2.34 (s, 6H); 13C NMR (75 MHz, CD3OD) δ 173.5, 142.8, 139.3, 138.3, 137.3, 135.4, 130.1, 129.1, 129.0, 128.3, 127.9, 127.7, 125.5, 47.9, 46.7, 46.4, 43.6, 35.5, 32.9, 21.3; ESI MS m/z 349 [M+H]+; HPLC (Method 5)>99% (AUC), tR=10.63 min. HRMS Calcd for C23H28N2O [M+H]: 3492280. Found: 349.2275.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[CH3:19][N:20]([C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)[C:16]([C:3]1[CH:4]=[N:5][N:6]([CH:7]([C:8]([F:9])([F:11])[F:10])[C:12]([F:14])([F:13])[F:15])[C:2]=1[CH3:1])=[O:18]
Reactant: Cc1c(C(=O)O)cnn1C(C(F)(F)F)C(F)(F)F
Reactant: CNc1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N(C)c2ccnnc2)cnn1C(C(F)(F)F)C(F)(F)F
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
A mixture of 300 mg 5-methyl-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyrazole-4-carboxylic acid, 127 mg N-methylpyridazin-4-amine, 710 mg O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate [HATU] and 220 mg triethylamine in 30 ml THF was stirred at 20-25° C. for about 24 h, then evaporated. The residue was taken up in 21 ml CH2Cl2, washed with 3×14 ml water, dried over Na2SO4, then evaporated. Purification by flash chromatography (CH2Cl2/MeOH) gave 130 mg of the title compound (90% purity).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:16]1[C:25]([CH3:26])=[N:24][C:23]2[C:18](=[CH:19][C:20]([F:28])=[C:21]([F:27])[CH:22]=2)[N:17]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:27][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:28])[N:17]=[C:16]([NH:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)[C:25]([CH3:26])=[N:24]2
Reactant: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester (0.524 g) was dissolved in trifluoroacetic acid (15 ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white solid (0.289 g), MH+ 293.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C([O-])([O-])=O.[K+].[K+].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>CN(C=O)C.O>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:9]2[C:8](=[O:11])[N:6]3[N:7]=[C:2]([Cl:1])[C:3]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[C:4]([C:12]4[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=4)[C:5]3=[N:10]2)=[CH:36][CH:35]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Temperature: 75 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (750 mg, 1.92 mmol), prepared as described in Example 1F, in DMF (10 mL) was added K2CO3 (270 mg, 1.95 mmol) and 4-(trifluoromethyl)benzyl bromide (460 mg, 1.92 mmol). The reaction mixture was stirred at 75° C. for 1 h under Argon. It was cooled to RT diluted with water (50 mL) and the solid was collected by filtration. The solid was washed with water (25 mL×2) and dried in a vacuum oven at 50° C. overnight to give the title compound, 2-(4-(trifluoromethyl)benzyl)-6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (990 mg, 94%) as yellow powder. HPLC: 4.23 min; MS: M+H=549.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.Br[C:12]1[N:17]=[C:16]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:15]=[N:14][CH:13]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[C:16]([N:18]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]4)[CH:15]=[N:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(Cl)cc43)n2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.0 mmol; 307 mg), tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate (2.199 mmol; 785.5 mg), N,N′-Dimethylethylenediamine (4.0 mmol; 352.4 mg; 0.398 mL), cuprous iodide (2.0 mmol; 380.72 mg), and potassium carbonate (2.1990 mmol; 307 mg) in 1,4-Dioxane (15 mL) was purged with Argon, then sealed and stirred at 110° C. overnight. The mixture was cooled to room temperature, then filtered through Celite. The filtrate was concentrated; the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate as an off-white solid (217.2 mg, 25%). MS (ESI) m/z: δ 430 [M+H]+