Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]3([CH2:14][O:15][CH2:16][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:12]3.O>CO>[C:11]12([C:10]3=[C:5]([OH:4])[CH:6]=[CH:7][CH:8]=[C:9]3[CH2:16][O:15][CH2:14]1)[CH2:13][CH2:12]2
Reactant: COCOc1cccc2c1C1(CC1)COC2
Solvent: CO
Solvent: O
Product: Oc1cccc2c1C1(CC1)COC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 5-{[(methyloxy)methyl]oxy}-1H-spiro[2-benzopyran-4,1′-cyclopropane] (Intermediate 135, 380 mg) in methanol (10 mL) HCl 10% in water (1.048 mL, 3.45 mmol) was added and the reaction mixture was stirred overnight at 50° C. The combined solvents were evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane/ethyl acetate as eluents from 100:0 to 8:2. This afforded the title compound as a white solid (260 mg).
Reaction SMILES: C([O:8][CH2:9][N:10]1[C:25](=[O:26])[C:24]2[C:23]3[C:22]4[C:17](=[C:18]([O:27]CC5C=CC=CC=5)[CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]=3[C:14]3[N:35]([C@:50]4([C:70](=[O:72])[CH3:71])[O:58][C@H:57]([CH2:59][OH:60])[C@@:55]([C:61](=[O:63])[CH3:62])([OH:56])[C@:53]([C:64](=[O:66])[CH3:65])([OH:54])[C@@:51]4([C:67](=[O:69])[CH3:68])[OH:52])[C:36]4[C:37]([O:42]CC5C=CC=CC=5)=[CH:38][CH:39]=[CH:40][C:41]=4[C:13]=3[C:12]=2[C:11]1=[O:73])C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].C(O)C>[OH:42][C:37]1[C:36]2[N:35]([C@:50]3([C:70](=[O:72])[CH3:71])[O:58][C@H:57]([CH2:59][OH:60])[C@@:55]([C:61](=[O:63])[CH3:62])([OH:56])[C@:53]([C:64](=[O:66])[CH3:65])([OH:54])[C@@:51]3([C:67](=[O:69])[CH3:68])[OH:52])[C:14]3[C:15]4[NH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][C:18]=5[OH:27])[C:23]=4[C:24]4[C:25](=[O:26])[N:10]([CH2:9][OH:8])[C:11](=[O:73])[C:12]=4[C:13]=3[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)[C@@]1(O)[C@](O)(C(C)=O)[C@](C(C)=O)(n2c3c(OCc4ccccc4)cccc3c3c4c(c5c6cccc(OCc7ccccc7)c6[nH]c5c32)C(=O)N(COCc2ccccc2)C4=O)O[C@H](CO)[C@]1(O)C(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)[C@@]1(O)[C@](O)(C(C)=O)[C@](C(C)=O)(n2c3c(O)cccc3c3c4c(c5c6cccc(O)c6[nH]c5c32)C(=O)N(CO)C4=O)O[C@H](CO)[C@]1(O)C(C)=O
Yield: 57.7 %

Procedure:
To 4.5 mg of 6-benzyloxymethyl-1,11-dibenzyloxy-12,13-dihydro-13-(tetraacetyl-β-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione were added 1.5 ml of ethyl acetate and 9 ml of ethanol to make a solution, and the solution was subjected to hydrogenation reaction in the presence of palladium-carbon catalyst (two medical spoonsful) for 3 hours. After the reaction, the palladium-carbon was removed by filtration and washed with methanol and tetrahydrofuran. The filtrate and the washings were concentrated under reduced pressure, the residue was subjected to thin layer chromatography (Kiesel gel 60; developed with chloroform-methanol=19:1), and the desired product was scraped and extracted with methanol to give 12,13-dihydro-1,11-dihydroxy-6-hydroxymethyl-13-(tetraacetyl-β-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (yield: 57.7%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=O)[NH:5][C:6]=1[CH3:7].C(Cl)(=O)C(Cl)=O>CN(C)C=O.N1C=CC=CC=1.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]#[N:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(N)=O)cc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1[nH]c(C#N)cc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 168C (300 mg) in N,N-dimethylformamide (6 mL) and pyridine (0.6 mL) at 0° C. was added dropwise oxalyl chloride (0.35 mL). The mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate and washed with saturated NaHCO3 and water extensively. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography, and eluted with dichloromethane to provide the title compound.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:8][C@H:7]([N:9]=[N+:10]=[N-:11])[CH2:6]1)([O:3]C)=[O:2].O.[OH-].[Na+]>CO>[N:9]([C@@H:7]1[CH2:8][C@H:5]([C:1]([OH:3])=[O:2])[CH2:6]1)=[N+:10]=[N-:11]
Reactant: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)O)C1

Procedure:
To a solution of cis-3-carbomethoxycyclobutylazide (2.8 g, 18.0 mmol) in methanol (8 ml) was added water (8 ml). The resulting cloudy solution was well stirred and treated dropwise (0.5 h) with an aqueous solution of sodium hydroxide (1N, 18.0 ml) at such a rate that the temperature was kept under 28° C. The reaction mixture was stirred at 23° C. for 2 h and the solvents were evaporated in vacuo to a yellow residue which was diluted with water (12 ml). The aqueous solution was washed with ether (2×15 ml), acidified with 1N hydrochloric acid and extracted with dichloromethane (4×30 ml). The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to a colorless oil; 2.29 g, 90%; ir (neat) νmax : 2100 (N3) and 1705 cm-1 (C=O of carboxylic acid); 1Hmr (CDCl3) δ: 11.88 (1H, s, H of carboxylic acid), 3.8 (1H, m, H-1) and 3.2-2.0 ppm (5H, 2H-2, H-3 and 2H-4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH2:38](I)[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:38][CH3:39])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: CCI
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: CCOc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with ethyl iodide
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[N+:5]([C:8]1[CH:9]=[C:10](/[CH:14]=[N:15]/[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>C(#N)C.B(F)(F)F.CCOCC>[CH3:1][C:2]1([CH3:4])[C:17]2[C:16](=[CH:23][CH:22]=[C:19]([C:20]#[N:21])[CH:18]=2)[NH:15][CH:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[CH2:3]1
Reactant: C=C(C)C
Reactant: N#Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C#N)cc21
Temperature: 30 °C
Reaction time: 10 h
Yield: 27.7 %

Procedure:
To a small reactor, isobutene (100 mL, 1.19 mol) was added to a mixture of boron trifluoride etherate (12 mL, 0.96 mmol) and 4-{[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amino}-benzonitrile (30 g, 0.12 mol) in dry acetonitrile (300 mL), sealed. The resultant mixture was allowed to stir at 30° C. for 10 h. The reaction mixture was washed by brine and dried over anhydrous sodium sulfate. It was filtered and concentrated to provide the crude product (30 g). The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford 4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile as yellow solid (10.2 g, yield: 27.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[C:25]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1=CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCCC3)c2)CC1
Temperature: 85 °C
Yield: 45.1 %

Procedure:
A solution of 230 mg (0.647 mmol) 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 6 mL toluene and 3 mL EtOH was treated with 118 mg (0.842 mmol) cyclohept-1-enylboronic acid and 2.60 mL (5.18 mmol) 2.0 M Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 52.3 mg (0.0453 mmol) Pd(PPh3)4, and heated to 85° C. for 23 h. The mixture was diluted with EtOAc (15 mL) and washed with water (1×15 mL) and brine (1×15 mL). The combined aqueous layers were extracted with EtOAc (15 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-18% EtOAc-hexane afforded 108 mg (45%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C19H27N2O2, 315.2 (M−C4H9+2H), found 315.2.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:27][CH2:26][C:23]3([CH2:25][CH2:24]3)[C@H:22]([OH:28])[CH2:21]2)[C:13](=[O:29])[C@@H:12]1[CH3:30])=O)C1C=CC=CC=1>CO.[Pd]>[OH:28][C@@H:22]1[CH2:21][N:20]([CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][NH:11][C@@H:12]([CH3:30])[C:13]2=[O:29])[CH2:27][CH2:26][C:23]21[CH2:24][CH2:25]2
Reactant: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Yield: 99.6 %

Procedure:
A solution of (S)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (950 mg, 2.29 mmol) in methanol (25 ml) was stirred for 5 h under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 243 mg), then insoluble material was removed by filtration and the filtrate evaporated to produce the title compound (642 mg, 100%). Orange oil, MS (ISP)=282.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH2:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.CN(C1C=CC=CN=1)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:1][C:2]1([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH2:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C2(O)CC(=O)C=C2c2ccncc2)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)OC1(c2cccc(C)c2)CC(=O)C=C1c1ccncc1
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-3-pyridine-4-yl-4-m-tolyl-cyclopent-2-en-1-one and it's regioisomer (265 mg, 1.0 mmole) in methylene chloride (5 mL) was added dimethylamino pyridine (183 mg, 1.5 mmole) and acetic anhydride (0.12 mL, 1.2 mmole) at r.t. The reaction mixture was stirred at that temperature for 1 hr before quenching the reaction with 1 mL of methanol. Concentration and purification (silica, hexane/ethyl acetate) gave the title compound as the faster eluting isomer. MS (m/z): Calcd. C19H17NO3(M+): 307, found (M+H)+: 308.1.
Reaction SMILES: Br[CH:2]([C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)OCCCO1)C.[C:22]([O-:25])(=[O:24])C.[K+]>C(N)=O>[CH3:21][O:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:4]([CH3:2])[C:22]([OH:25])=[O:24])[CH:19]=[CH:18]2
Reactant: COc1ccc2cc(C3(C(C)Br)OCCCO3)ccc2c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: NC=O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 53 %

Procedure:
A mixture of 2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxane (3.79 g; 10 mmol), potassium acetate (1.2 g; 12 mmol) and formamide (50 ml) is heated at 170° C. under stirring for 2.5 h. The reaction mixture is worked up as described in example 1a to provide 2-(6-methoxy-2-naphthyl)-propionic acid (yield 53%).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][N:13](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][CH2:11][N:10]1S(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C2C(=CC=CC=2)C=CC=1>C1COCC1>[CH2:1]([CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)C(CCc3ccccc3)C2)cc1
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: c1ccc(CCC2CNCCN2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Add 2-phenethyl-1,4-bis-(toluene-4-sulfonyl)-piperazine (100 mg, 0.2 mmol) in THF (2 mL) to a cooled (−78° C.) suspension of metallic Na (36.8 mg, 1.6 mmol) and naphthalene (230.4 mg, 1.8 mmol) in fresh distilled THF(4 mL) was under nitrogen and stir at −78° C. After 1 hour, TLC indicated the reaction is complete. Hydrolyze the reaction with brine (10 mL) and extract with CH2Cl2 (3×10 mL). Combine the organic layers and dry over Na2SO4 and evaporate. Pass the resulting residue through a SCX column to obtain the title compound as a solid: mass spectrum (electrospray): (m/z)=191.2 (M+1); 1H NMR (CDCl3): δ7.30–7.25 (m, 2H), 7.20–7.15 (m, 3H), 3.00–2.61 (m, 8H), 2.40 (t, 1H, J=11.7 Hz), 1.70 (br, 2H), 1.67–1.60 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C(=O)([O-])[O-].[K+].[K+].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(#N)C>[Br:1][CH2:2][CH2:3][S:20][C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(SCCBr)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
6.94 ml of 1,2-dibromoethane was diluted with 100 ml of acetonitrile, mixed with 11.2 g of potassium carbonate and 5.0 g of 4-nitro-benzenethiol, and stirred at 80° C. for 18 hours. After washing with 300 ml of distilled water and with 300 ml of aqueous NaCl, the resulting organic layer was dried over magnesium sulfate, filtrated, and distilled under a reduced pressure. The residue obtained thus was subjected to column chromatography to obtain 6.9 g of the title compound (yield 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCOc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 3.1 g of 4-nitro-4'-hydroxy-azobenzene, 15 mg of sodium iodide, 2.27 g of 1-bromo-heptane, 1.8 g of potassium carbonate and 20 ml of ethanol is heated under reflux for 60 hours. The solvent is removed in vacuo, water is added and the mixture is exhaustively extracted with methylene chloride. The residue of 4.0 g (brown crystals) of 4-nitro-4'-heptyloxy-azobenzene, which remains after drying with sodium sulfate and removing the solvent by evaporation, is chromatographed on a column of 200 g of silica gel with methylene chloride. By recrystallization of the uniform fractions from acetone/hexane there is obtained the pure compound as orange crystals; m.p. 82.3°-83.2° C., liquid crystalline, conversion at 93.7° C., cl.p. 96.4° C.
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)[C@@H:27]1[N+:28]([O-:30])=[O:29])=[O:9])[CH3:12]
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCC
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCC)[C@@H](c2ccc(OC)cc2)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq) and 1-methoxy-4-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.06 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:3) in 83% yield.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]1[CH2:16]CN2C(=NCCC2)[CH2:8][CH2:7]1.BrCCCCBr>CN(C=O)C>[C:2]1([C:1]#[N:5])([C:3]#[N:4])[CH2:8][CH2:7][CH2:6][CH2:16]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: BrCCCCBr
Product: N#CC1(C#N)CCCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Malononitrile (15.0 g) was dissolved in dry DMF (200 mL) and cooled in an ice bath. Subsequently, DBU (75 mL, 2.2. equiv.) and 1,4-dibromobutane (29.6 mL, 1.1 equiv.) were added dropwise. The ice bath was removed, an extra 100 mL of dry DMF was added, and the mixture was stirred at 80° C. for 2 h. After cooling to ambient temperature, DCM was added and the mixture was washed 5 times with 5% aqueous NaHCO3. The organic phase was dried over Na2SO4 and evaporated under reduced pressure to give 40 g of a black oily substance. This was purified by flash chromatography eluting with PA:EA 9:1 (Rf=0.35, visualized with 12) to give 23.4 g of a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.94-2.03 (m, 4H), 2.41 (t, J=7 Hz, 4H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[NH:22][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:25]([C:23]3[NH:22][N:21]=[C:20]([CH3:19])[CH:24]=3)=[O:26])[CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)[nH]n1
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg, 0.100 mmol, from Step B of Example 1.1), 3-methyl-1H-pyrazole-5-carboxylic acid (18.9 mg, 0.150 mmol), and triethylamine (0.139 mL, 1.00 mmol) in DMF (0.5 mL) was added 1-propylphosphonic acid anhydride solution (50 wt. % in ethyl acetate, 122 μL, 0.200 mmol). The mixture was stirred for 2 h, quenched with water and purified by preparative HPLC/MS. The resultant lyophilate was dissolved in DCM, treated with MP-carbonate resin (˜100 mg). The mixture was stirred for 30 min and filtered to remove the resin. The solvent was removed under reduce pressure to afford the title compound (26.0 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 2.66 (bs, 4H), 3.82 (s, 2H), 3.88 (bs, 2H), 4.02 (bs, 2H), 6.38 (s, 1H), 7.14 (t, J=8.59 Hz, 2H), 7.99-8.09 (m, 2H). Exact mass calculated for Cl17H19FN4O2: 330.2. Found: LCMS m/z=331.3 (M+H+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:31])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:15]([NH:14][CH2:13][CH:12]([OH:31])[CH2:11][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)carbamate (500 mg, 1.18 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, the pH was adjusted to 7˜7.5 with saturated aqueous of NaHCO3 and extracted with EA. The organic layer was concentrated to give the title product that was used in the next step without further purification (450 mg, crude). LCMS (m/z): 326.2 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:10](=[O:28])[N:9]([CH2:29][C:30]2[C:31]([CH3:40])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:8]=1)=O.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:8]2[N:9]([CH2:29][C:30]3[C:31]([CH3:40])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)[C:10](=[O:28])[C:11]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:7]2=[N:6][N:5]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CCl)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CCl)n21
Temperature: 120 °C
Reaction time: 6 h
Yield: 54.2 %

Procedure:
To a round bottom flask was added 2-chloro-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetohydrazide (400 mg, 0.681 mmol) and toluene (10 ml). The mixture was heated at 120° C. for 5 min. After this time, POCl3(1.5 ml) was added and the reaction was stirred at 120° C. for an additional 6 hr. The reaction mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3(20 ml), water (20 ml), and saturated NaCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated chromatography system (12 g silica gel, 20%-40% EtOAc/Hex) to give the product 4-(3-(chloromethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (210 mg) as an off-white solid (54% yield). HPLC retention time 3.148 min (Method A); LCMS (M+1)=569.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][C:7]([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][CH2:10]1)=[O:8].C1N=CN([C:25](N2C=NC=C2)=[S:26])C=1>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][NH:6][C:7]([C:9]2([C:12]([F:13])([F:14])[F:15])[CH2:10][CH2:11]2)=[O:8])=[CH:3][C:2]=1[N:1]=[C:25]=[S:26]
Reactant: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1F
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1ccc(F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Temperature: 50 °C

Procedure:
A mixture of N-(3-amino-4-fluorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (3.17 g; 11.5 mmol) and TCDI (3.07 g; 17.2 mmol) in DCM (50 mL) was heated over night at 50° C. The mixture was concentrated and the residue purified by column chromatography to give the sub-title compound. Yield: 3 g (82%).