Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[S:23][C:24]([C:28]([OH:31])([CH3:30])[CH3:29])=[C:25]([CH3:27])[N:26]=3)[S:21][C:14]=12>>[CH3:27][C:25]1[N:26]=[C:22]([C:20]2[S:21][C:14]3[C:15](=[N:16][CH:17]=[CH:18][C:13]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:19]=2)[S:23][C:24]=1[C:28]([OH:31])([CH3:30])[CH3:29]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(C)(C)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nc(C)c(C(C)(C)O)s5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 2-[2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-propan-2-ol by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.07 (t, 1H), 7.62 (d, 1H), 7.27 (m, 2H), 6.95 (m, 1H), 6.58 (t, 1H), 6.10 (d, 1H), 5.46 (d, 1H), 2.46 (s, 3H), 2.40 (s, 3H), 1.60 (s, 6H); RP18-HPLC RT: 5.17 minutes; API MS: 435 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)N=C=O
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: CC(C)NC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and isopropyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])(=[O:3])[CH3:2].[C:11]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>CO>[C:11]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:2][C:1](=[O:3])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10]2)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C
Yield: 68961.6 %

Procedure:
A solution of 2-acetylphenol (5 g, 0.037 mmol), 1-benzoyl-4-piperidone (7.5 g, 0.037 mmol), pyrrolidine (2.6 g, 0.037 mol) and CH3OH (50 ml) was heated at reflux for 8 hours. After cooling to room temperature overnight, the solid was filtered to yield 8.2 g of 1'-benzoyl-3,4-dihydro-spiro[(2H)-1-benzopyran-2,4'-piperidin]-4-one. The mother liquor was concentrated to dryness and the residue triturated with ether to yield an additional 1.7 g (83% total yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])(C(OCC)=O)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCCC(=O)O)N=C2c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (6 g) is dissolved in diethyl carbonate (100 ml) under a nitrogen stream, and 60% sodium hydride (1.2 g) is added with stirring at room temperature. The mixture is refluxed under heating for 1 hour and cooled to 50° C. with ice water. Ethyl bromobutyrate (4.3 ml) is added. After stirring at 100° C. for 2 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) and crystallized from isopropyl ether to give 3.9 g of (±)-ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyrate as white powdery crystals. (±)-Ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)butyrate (3.5 g) is dissolved in a mixture of ethanol (180 ml) and water (60 ml), and barium hydroxide 8 hydrate (8.4 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 1N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate to give 1.1 g of (±)-4-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyric acid as white powdery crystals, melting point 185°-187° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:31](=[O:34])[CH2:32][CH3:33])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (4.60 g, 15.8 mmol) and N,N-diisopropylethylamine (1.40 mL, 15.8 mmol) in 25 mL of dry methylene chloride was added propionyl chloride (1.40 mL, 15.8 mmol) dropwise at 0° C. After being stirred at room temperature overnight, the reaction mixture was quenched with 30 mL of H2O and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous HCl (5%, 20 mL), NaHCO3 (sat., 2×30 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 as a colorless oil (4.50 g, 82%). IR (film, cm−1) 2975, 2934, 2854, 1690, 1663, 1591, 1496, 1422, 1402, 1365, 1265, 1242, 1176, 1149, 1038, 962,775, 702; 1H NMR (CDCl3, ppm) 7.44–7.22 (m, 5H), 4.09–3.22 (m, 4H), 2.80–2.09 (m, 2H), 2.06 (q, 2H, J=7.5 Hz), 1.75–1.19 (m, 5H), 1.48(s, overlap, 9H), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3](OS(C)(=O)=O)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.[N-:29]=[N+:30]=[N-:31].[Na+].CS(C)=O>O>[N:29]([CH:3]([C:2]([F:28])([F:27])[F:1])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Temperature: 100 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
A mixture of benzyl 4-{3,3,3-trifluoro-2-[(methylsulfonyl)oxy]propoxy}piperidine-1-carboxylate (1.31 g), sodium azide (1.00 g), 15-crown-5-ether (3.39 g) and dimethyl sulfoxide (5 mL) was stirred at 100° C. for 3 days. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (294 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].C(O)(=O)C.O.[C:17]([OH:21])(=[O:20])[CH:18]=[O:19]>O>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][CH:18]([OH:19])[C:17]([OH:21])=[O:20])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(CC(O)C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 23 h
Yield: 38 %

Procedure:
A mixture of 3,4-dichloroacetophenone (3.84 g, 20.3 mmol), glacial acetic acid (20.0 ml), and glyoxylic acid hydrate (1.85 g, 20.1 mmol) was stirred at 90° C. for 23 hours. More glyoxylic acid hydrate (0.93 g) was added, and heating was continued for 41 hours. Water (200 ml) was added, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate/heptane yielded 2.01 g (38%) of 4-(3,4-dichlorophenyl)-4-oxo-2-hydroxybutyric acid. This acid was used to prepare the title amide using General Procedure (D).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH2:21]([N:28]1[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][C:29]1=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:34]([C:31]3[CH:32]=[CH:33][N:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:29](=[O:37])[CH:30]=3)=[O:35])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C

Procedure:
In a 20 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (50 mg, 0.176 mmol), 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (40.3 mg, 0.176 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (81.8 mg, 176 mmol) and N,N-diisopropylethylamine (0.092 mL, 0.527 mmol) were combined with CH2Cl2 (5.00 mL). The reaction mixture was stirred at room temperature, and the crude product was purified using preparative reverse-phase HPLC. MS calcd. for C29H23ClN3O3 [(M+H)+] 496.1, obsd. 496.0.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36].CCN(C(C)C)C(C)C.CNC>C1COCC1>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:2]([CH3:3])[CH3:1])=[O:31])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)C)ccc1N
Reaction time: 18 h
Yield: 59.4 %

Procedure:
HATU (0.296 g, 0.778 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (0.1 g, 0.598 mmol), DIPEA (0.156 mL, 0.897 mmol) and dimethylamine (2M in THF, 0.598 mL, 1.196 mmol) in THF (1.617 ml). The reaction mixture was stirred for 18 hours. The reaction was partitioned between EtOAc and water, the organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 60/40 to 40/60 followed by filtration through an SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a colourless oil (69 mg, 59%).
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH:11]3[CH2:13][CH2:12]3)[C:9]([C:14]3[C:15]([NH2:19])=[N:16][O:17][N:18]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:11]1([N:10]2[C:3]3[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=[C:9]2[C:14]2[C:15]([NH2:19])=[N:16][O:17][N:18]=2)[CH2:13][CH2:12]1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nonc1-c1nc2cncc(Br)c2n1C1CC1
Product: Nc1nonc1-c1nc2cncc(-c3ccccc3)c2n1C1CC1

Procedure:
The title compound was prepared from the product of Step 5 and phenylboronic acid using the method of Example 101; MS (ES+) m/e 319 [M+H]+.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13].C1C=CC(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:29]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13])=[N+:30]=[N-:31]
Reactant: CC1(C)Cc2ccc(C#N)cc2C1O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)Cc2ccc(C#N)cc2C1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of Step B. 3-hydroxy-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (4.98 g, 0.027 mol) in toluene (60 mL) at 0° C. was added DPPA (8.6 mL, 0.040 mol) via syringe dropwise followed by DBU (6.0 mL, 0.040 mol) via syringe dropwise. After stirring at 0° C. for 10 min and rt for 30 min, the mixture was heated at 80° C. for 60 h, then cooled to rt and partitioned between EtOAc (400 mL)/water (100 mL). Resulting layers were separated and the organic layer was washed with water (100 mL), aq HCl (1N, 60 mL×2), water (100 mL), sat. aq. NaHCO3 (80 mL), brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give yellow oil as the crude product. Purification by flash chromatography on silica gel (120 g) eluting with EtOAc/hexane mixtures provided the title compound as a colorless oil (4.12 g, 73% yield). HPLC Ret. time: 3.37 min. LCMS MH+ (m/z) 213.3. 1H NMR: (DMSO-d6, 400 MHz): δ 7.86 (s, 1H), 7.76 (d, 1H), 7.49 (d, 1H), 4.74 (s, 1H), 2.80 (m, 2H), 1.13 (s, 3H), 1.06 (s, 3H).
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:14][C:15]1[C:20](Br)=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2]>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: Brc1ccccc1Br
Reactant: Clc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1ccc(CCCCCCBr)cc1
Yield: 45 %

Procedure:
In the same manner as described in Example 1, a Grignard solution in a mixture containing 450 ml of toluene and 40 ml of tetrahydrofuran was prepared from 58.8 g (0.4 Mol) of 1,4-dichlorobenzene. A solution of 146.4 g (0.6 Mol) of commercially available 1,6-dibromobenzene in 100 ml of toluene and a catalytic amount of dilithium tetrachlorocuprate were added to this solution. The full mixture was refluxed for 7 hours. The precipitate was then filtered off, the filtrate was acidified, and the phases were separated. The organic phase was washed, dried and evaporated, and the residue was fractionated. About 50 g of 1-(6-bromohexyl)-4chlorobenzene (45 percent yield) were obtained at a pressure of 0.2 hPa and at 106° to 109° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-chlorophenylhydrazine hydrochloride (269 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale brown solid (126 mg, 30%).
Reaction SMILES: [C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][CH:10]([O:13][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)CC(O)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC2COC3(CCC(C(C)(C)C)CC3)C2)cc1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of 8-t-butyl-3-hydroxy-1-oxaspiro(4,5)decane (4.24 g, 20 mmol) in THF (50 ml) was added sodium hydride (0.72 g, 24 mmol, 80% in mineral oil) and the mixture was heated to reflux for 3 hours. p-Toluenesulfonylchloride (4.56 g, 24 mmol) in THF (10 ml) was then added and heating was continued for another 3 hours. The solvent was evaporated, toluene and water were added (50 ml, each) and the phases were separated. A pale yellow oil (7.3 g) was isolated from the organic layer which was treated with light petroleum to yield colourless crystals (5.6 g), melting at 101° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([OH:14])[CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reaction time: 18.5 h
Yield: 92 %

Procedure:
Combine (+/-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (2.50 g, 11.6 mmol, prepared in example 3) and Ni2B (8.5 mL of a 0.14M slurry in methanol, 10 mol %) in methanol (14 mL). Stir the slurry under an atmosphere of hydrogen for 18.5 hours. Then replace the hydrogen atmosphere with nitrogen, filter through diatomaceous earth and rinse the solids with methanol (50 mL). Concentrate the filtrate under vacuum (15 mmHg/40° C.) and purify the residue by Kugelrohr distillation (0.6 mmHg/60°-65° C.) to provide the title compound as a colorless oil (2.31 g, 92%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]1.C(N=C=NCCCN(C)C)C>ClCCl>[C:33]([O:32][C:31](=[O:37])[NH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:10]4[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)=[CH:23][CH:22]=2)[CH2:29][CH2:28]1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCCCNc1ccc2ncc(-c3ccc(C(=O)O)cc3)n2n1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)N4CCC(NC(=O)OC(C)(C)C)CC4)cc3)n2n1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
The reaction of the 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoic acid (93 mg, 0.3 mmol), tert-butyl piperidin-4-ylcarbamate (66 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (63 mg, 0.33 mmol) and dichloromethane (3 mL) was maintained at room temperature overnight. The resulting solution was purified by preparative HPLC (neutral) to afford tert-butyl(1-(4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoyl)piperidin-4-yl)carbamate (76 mg, 52% yield) as a yellow solid: 1H NMR (METHANOL-d4) δ: 8.23-8.43 (m, J=8.3 Hz, 2H), 7.85 (s, 1H), 7.63 (d, J=9.9 Hz, 1H), 7.45-7.56 (m, 2H), 6.68-6.87 (m, 1H), 4.55 (d, J=12.1 Hz, 1H), 3.82 (br. s., 1H), 3.59-3.72 (m, 1H), 3.35-3.48 (m, 4H), 3.19 (d, J=15.2 Hz, 2H), 1.92-2.17 (m, 1H), 1.90 (br. s., 1H), 1.72 (m, 2H), 1.35-1.59 (m, 13H), 1.01 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 493.3 [(M+H)+, calcd for C27H37N6O3 493.3].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:21]1([NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:21]1([NH:24][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:27]=2)=[O:42])[CH2:22][CH2:23]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: NC(=O)C1CCCN(c2nncc3cc(Br)ccc23)C1
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCCC(C(N)=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 1-(6-bromophthalazin-1-yl)piperidine-3-carboxamide (0.12g, 0.4 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.1 g, 0.4 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) in 5 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (0.5 mL, 1 mmol). The mixture resulted was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled down to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give (0.11 g) title compound as a pale yellow solid. Found MS (ES+): 430(M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=O)(C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=O)[CH3:27].[OH-].[Na+]>O>[Cl:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][N:11]=1)[NH:8][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])=[CH:27][C:15]2=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Reactant: CC(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2Cl)[nH]c2cnc(Cl)cc12
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
5-(tert-Butoxycarbonylamino)-2-chloroisonicotinic acid (502 mg, 1.84 mmol) was suspended in polyphosphoric acid (9.5 g, 102 mmol) at ambient temperature and stirred for 10 mins causing a bright yellow coloration and visible evolution of gas. 2′-Chloroacetophenone (570 mg, 3.69 mmol) was added and the mixture heated to 150° C. for 2.5 h. The mixture was diluted with cold water (50 mL), and then cooled in ice and treated with solid sodium hydroxide (6.0 g, 150 mmol) to pH ˜7. The mixture was filtered and the recovered oily solids washed with water, dissolved in methanol and reconcentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0.5-20% methanol in DCM) to afford the title compound as a cream solid (29.2 mg, 5.5%). 1H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.12 (s, 1H), 7.64-7.58 (m, 2H), 7.58-7.46 (m, 2H), 6.47 (s, 1H); NH absent. LCMS: M+H+=291 & 293.