Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].[C:14](#[N:16])[CH3:15].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]([CH3:11])([CH3:12])[C:3](=[O:13])[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: COCCOCC(C)(C)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCOCC(C)(C)C(=O)CC#N
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A solution of 3-(2-methoxy-ethoxy)-2,2-dimethyl-propionic acid methyl ester (3.08 g, 16.21 mmol) and acetonitrile (1.19 mL, 22.69 mmol) in toluene (6 mL) is added dropwise to the refluxing suspension of 60% sodium hydride in mineral oil (907.6 mg, 22.69 mmol) in toluene (18 mL). After the addition, the reaction mixture is stirred at reflux for 3 h. After this time, the reaction mixture is cooled to room temperature and the aqueous layer is neutralized to pH˜7 by adding 1M aqueous HCl solution. The aqueous layer is extracted with ethyl acetate 3 times. The organic layers are combined, washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield the title compound. Yield: 94.2%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (6H, s), 3.38 (3H, s), 3.47 (2H, s), 3.50-3.55 (2H, m), 3.57-3.62 (2H, m), 3.80 (2H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[N:2]1.[ClH:18].[CH3:19][NH:20][CH3:21].[BH4-].[Na+]>CO.C(OCC)(=O)C>[ClH:18].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][N:20]([CH3:21])[CH3:19])=[N:2]1
Reactant: CNC
Reactant: O=Cc1ccccc1-c1noc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
In one portion, a total of 2.0 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde was added to a solution of 8.0 g of dimethylamine hydrochloride in 70 ml of methanol. The reaction mixture was stirred at room temperature for 16 h, after which 2.0 g of sodium borohydride were added. After stirring at room temperature for another 24 h, the solids were filtered off, and the residue was washed with dichloromethane. The combined filtrate was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The resulting solid was purified by chromatography on silica gel, eluting with ethyl acetate, affording 0.89 g. This solid was dissolved in ethyl acetate, and triturated with a solution of hydrogen chloride in methanol. This solution was evaporated to dryness under reduced pressure and the residue was crystallised from ethanol/diethyl ether/hexane, yielding 0.54 g of pure 2-(1,2-benzisoxazol-3-yl)-N,N-dimethyl-benzenemethanamine hydrochloride, melting at 190° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1)C.[OH-].[K+].CO>CO.O>[CH3:16][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][CH2:5][C:4]([OH:17])=[O:3])[CH2:12][CH2:11]1)([CH3:14])[CH3:15]
Reactant: CCOC(=O)CC[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring solution of trans-4-(1,1-dimethylethyl)cyclohexanepropanoic acid ethyl ester (3.58 g, 14.9 mmol) in CH3OH (198 mL) at 0° C. were added 10% KOH/MeOH (46 mL), followed by H2O (30 mL). The mixture was stirred at room temperature 5 h, then diluted with H2O (20 mL) and concentrated. The residue was diluted with H2O (20 mL) and ice chips and the mixture was acidified to pH 2 with 3N HCl. The aqueous solution was extracted with ethyl ether (4×150 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4) and concentrated to give crystalline trans-4-(1,1-dimethylethyl)cyclohexanepropanoic acid (3.09 g, 14.5 mmol) in 98% yield mp 105°-107° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][C:11]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)C)(C)(C)C.C(OC(=O)NCC1C=C(Br)C=CC=1OC1C=CC(Cl)=C(Cl)C=1)(C)(C)C.C1CCN2C(=NCCC2)CC1.C(N1CCNCC1)(C)C.F[B-](F)(F)F>C1COCC1>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][C:11]1[CH:12]=[CH:13][C:14]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:22][CH2:23]2)=[O:17])=[CH:15][C:10]=1[CH2:9][NH:7][CH3:6]
Reactant: CC(C)N1CCN(C(=O)c2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)CC1
Agent: CC(C)(C)OC(=O)NCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)N1CCNCC1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNCc1cc(C(=O)N2CCN(C(C)C)CC2)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 56 %

Procedure:
[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazine-1-carbonyl)-benzyl]-methyl-carbamic acid tert-butyl ester. To a solution of [5-bromo-2-(3,4-dichloro-phenoxy)-benzyl]-carbamic acid tert-butyl ester (327.0 mg, 0.71 mmol) in THF (2 mL) were added DBU (0.30 mL, 2.0 mmol), 1-isopropyl piperazine (0.30 mL, 2.5 mmol), Hermann's catalyst (31.9 mg, 0.034 mmol), tri-t-butylphosphium tetrafluoroborate (26.4 mg, 0.091 mmol), and Mo(CO)6 (211.0 mg, 0.80 mmol). After 6 min in a microwave reactor at 125° C., the mixture was cooled to rt and concentrated. Purification by FCC gave the desired product (212.5 mg, 56%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:32]O.O>C(O)(=O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N+:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:31])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)[O-:32])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(N=Nc2ccc(OC(=O)CCOCCCC)cc2)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCOc1ccc(N=[N+]([O-])c2ccc(OC(=O)CCOCCCC)cc2)cc1
Reaction time: 30 h

Procedure:
0.81 g of the 4'-hexyloxy-4-α-butoxypropanoyloxyazobenzene was dissolved in 40 ml of glacial acetic acid and the mixture was stirred under heating at 50°-60° C. About 5 ml of 31% H2O2 aqueous solution was added dropwise to the mixture in about 6 hours. The mixture was further left standing for 4 hours at 50°-60° C., for 30 hours at room temperature, charged into 400 ml of deionized water and extracted with ether. The extract was washed with 50 ml of 5% Na2CO3 aqueous solution and deionized water, and then dried with anhydrous Na2SO4. After distilling off ether; the resultant yellow crystal was recrystallized in ethanol to obtain 0.3 g of 4'-hexyloxy-4-α-butoxypropanoyloxyazoxybenzene showing the following properties:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[O:28][CH3:29])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:32])=[CH:12][C:13]([CH3:31])([CH3:30])[NH:14]2.[OH-].[Na+].C(OCC)(=O)C>C(O)C.[Zn]>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([O:28][CH3:29])=[C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:33]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:34])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:31])([CH3:30])[CH:12]=[C:11]3[CH3:32])[CH:24]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N)cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 110 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-5-nitrophenyl)-2,2,4-trimethyl -1,2-dihydroquinoline (Compound No. 14-48, 100.4 mg, 0.217 mmol) was dissolved in 4N aqueous NaOH solution (405 μL, 1.62 mmol)-ethanol (5 mL), and zinc (292.9 mg, 4.48 mmol) was added thereto, and then the reaction mixture was stirred at 110° C. overnight. Ethyl acetate (20 mL) was added to the reaction mixture and the unsoluble materials were filtered. After ethyl acetate (50 mL) was added to the filtrate, the whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (12.1 mg) as a yellow amorphous product. (Yield 13%)
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)[CH:24]=[CH:23][N:22]=1
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc(C(F)(F)F)c3)CC2)C1
Temperature: 120 °C
Yield: 62 %

Procedure:
Sodium t-Butylate (6.24 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 4-bromo-2-(trifluoromethyl)pyridine (2.08 mmol, 1.0 eq.) in toluene (15 ml) and the reaction mixture was then degassed with N2. BINAP (0.12 mmol, 0.06 eq.) and Pd(OAc)2 (0.04 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 2% methanol in methylene chloride), in order to obtain the desired product. Yield: 62%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[C:12]1([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.CC(C)=O>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:1][C:22]([NH:21][S:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:20])=[O:19])=[O:23])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(N(C)C)nc(N)n1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2)n1
Reaction time: 4 h

Procedure:
To a suspension of 15.2 g of 2-amino-4-dimethylamino-6-methylpyrimidine in 400 ml of methylene chloride at ambient temperature was added slowly 18.3 g of benzenesulfonylisocyanate. After stirring for four hours the mixture was stripped in-vacuo and the white semisolid residue triturated with ethyl ether and isolated by filtration. The solid was then slurried in hot acetone, cooled and refiltered to yield the solid named above which decomposed at 180°-182°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=424.1, tR (minutes, Method F)=3.19. [α]D20=+16.4 (c=6.80 mg/mL,CHCl3)
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:48][C@H:49]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (2.5 g, 12.11 mmol) and Et3N (4.3 mg, 43 mmol) in MeCN (50 ml) was added HATU (4.83 mg, 12.72 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((R)-amino(phenyl)methyl)phenyl(methyl)phosphinate hydrochloride, 23-c, (3.5 g, 12.1 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=2/1) to provide the product, 23-d, (4 g, 69%).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:14](O)[CH3:15]>>[CH2:14]([CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]([OH:8])=[O:7])[CH3:15]
Reactant: CCO
Reactant: O=C(O)CC[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCC(C[N+](=O)[O-])C(=O)O

Procedure:
To a solution of 2 gr of 3-nitropropionic acid (41) in 30 mL of ethanol add catalytic amount of concentrated sulphuric acid (0.8 mL) and reflux overnight. Then add water and extracted with ethylacetate. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride and water. Purification from column gives ethyl 3-nitropropionic acid (26) as pale yellow liquid with boiling point 92° C. at 2.5 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:34]1([NH:40]O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:40][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: ONC1CCCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(ONC1CCCCC1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (300 mg, 1.03 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (251 mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour. In one portion N-cyclohexylhydroxylamine hydrochloride (469 mg, 3.09 mmol) was added and the solution was stirred for 2 hours at room temperature. To the resulting solution was added water (15 mL). The insoluble material was filtered and dried to give the title compound (286 mg, 72% yield, m.p. 220° C.).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[CH:15][C:14]=1[N+:32]([O-:34])=[O:33].CCCCCC>CS(C)=O>[N+:32]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([O-:34])=[O:33]
Reactant: O=C(Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1)C(F)(F)F
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Dimethyl malonate (9.6 mL) was added dropwise to a stirred suspension of 3.2 g of 60% sodium hydride in mineral oil in 40 mL of anhydrous dimethylsulfoxide under nitrogen. The mixture was stirred for 10 minutes and 2-fluoro-5-(3-trifluoroacetamidophenyl)nitrobenzene in 20 mL of dimethylsulfoxide was added. The resulting dark red mixture was heated to 100° C. for 2 hours. The reaction was quenched by pouring into 100 mL of saturated ammonium chloride solution and extracted twice with 50 mL of ethyl acetate each time. The organic phase was washed with 50 mL each of saturated ammonium chloride solution, water, and brine, dried over anhydrous sodium sulfate and concentrated to a yellow oil. The oil was chromatographed on a column of silica gel eluting with a 1:4 mixture of ethyl acetate:hexane to give 4.4 g (50% yield) of dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]malonate as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([C:21](=[O:23])[CH3:22])=[CH:19][N:18]=[C:17]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35]OC(OC)N(C)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[C:20](=[CH:19][N:18]=[C:17]4[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH:25]=[CH:26][C:16]4=3)[C:21](=[O:23])[CH:22]=[CH:35]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCN(Cc2ccccc2)CC1
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCN(Cc4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
1-{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}ethanone (343 mg, 0.720 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 170° C. for 6 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL) and stirred with 1 M hydrochloric acid (3 mL) at 80° C. for 1 hour. After addition of saturated aqueous sodium hydrogen carbonate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1 (v/v)) to give the title compound (299 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:30](=[O:31])[CH:29]([CH3:33])[CH3:28])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CC(C)C(=O)Cl
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) and pyridine (0.09 ml) in dichloromethane (3 ml) was added 2-methylpropanoyl chloride (0.1 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, and washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was washed with diisopropyl ether to give the title compound as a pale-yellow powder (0.21 g, 60%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(C(=O)OC(C)(C)C)CCO4)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CNCCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-butyl 2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine-4-carboxylate (21.9 g, 54.69 mmol) was dissolved in CH2Cl2 (300 ml), and TFA (5.3 g, 82.04 mmol) was added, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the next reaction was advanced.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1nc2ccccc2s1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nc5ccccc5s4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-benzothiazole-2-carbaldehyde was carried out according to General Synthetic Method 5. 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 6-[4-(1,3-benzothiazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[OH:9])[CH:5]=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][CH2:21][CH2:20]2.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.[Cu]I>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=3)=[O:9])[CH:3]=1)[CH2:21][CH2:20]2
Reactant: Cn1ccnc1C(O)c1cncc(Br)c1
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ccnc1C(=O)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 150 °C
Yield: 2.5 %

Procedure:
(5-Bromo-pyridin-3-yl)-(1-methyl-1H-imidazol-2-yl)-methanol (150 mg, 0.56 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (90 mg, 0.49 mmol) (intermediate A-2), CuI (30 mg, 0.16 mmol), Cs2CO3 (330 mg, 1.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.08 mL, 0.64 mmol) were dissolved in dioxane (4.0 mL). The resulting mixture was heated at 150° C. for 2 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×75 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give the title compound (4.5 mg, 2.5%) as light yellow oil. MS: 367.1 (M+H+).