Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:2]2[CH2:3][CH2:4][C:5]3[NH:6][C:7]4[CH:8]=[CH:9][C:10]([C:14]([NH:16][CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]5)=[O:15])=[CH:11][C:12]=4[C:13]=3[CH2:1]2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CNCC4)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(F)(F)F)cc2)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (11.63 g, 29.2 mmol) and 4-(trifluoromethyl)benzaldehyde (4.8 mL, 6.12 g, 35.1 mmol) in DCM (200 mL), sodium triacetoxyborohydride (12.4 g, 8.5 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and then poured into saturated sodium bicarbonate solution (300 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated to give an off-white solid. Trituration with ethyl ether provided tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (9 in Scheme 1(c)) as a white solid (13.60 g, 84%). 1H NMR (DMSO-d6, 300 MHZ) 11.03 (br s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 4.22-3.83 (m, 5H), 3.62 (s, 2H), 2.90-2.77 (br s, 6H), 1.82-1.70 (m, 2H), 1.55-1.30 (m, 11H) ppm; MS (ES) 557 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)#[N:17].[OH-].[Ba+2].[OH-].COCCOC>C(OCC)(=O)C.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.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=2)[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Temperature: 80 °C
Yield: 59.9 %

Procedure:
A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.2 g, 0.76 mmol), 3-cyanophenylboronic acid (0.223 g, 1.52 mmol), barium hydroxide (0.285 g, 1.67 mmol), Pd(PPh3)4 (0.088 g, 0.076 mmol), DME (5 mL) and H2O (3 mL) was heated (80° C.) for 6 hours with vigorous stirring under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a plug of celite. The filtrate was diluted with brine; the organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue obtained was purified by flash column chromatography (20% diethyl ether-hexane) to give 75 (0.130 g, 60% yield) as a viscous liquid.
Reaction SMILES: [CH3:1][C@:2]1([C:19]([NH:21][C:22]2([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O[Li].O>>[CH3:1][C@:2]1([C:19]([NH:21][C:22]2([C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[CH2:23][CH2:24]2)=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@@]3(C)CCCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@]1(C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)CCCCN1Cc1ccc(C(F)(F)F)cc1
Yield: 80.4 %

Procedure:
The title compound (E41) (3.9 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from (R)-methyl 4-(1-(2-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D157) (5 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].O[CH2:11][C@@H:12](N)[CH:13](C)C.OCCN.C(=O)C(C)C>>[CH:12]([CH:1]1[NH:5][C@@H:4]([CH:6]([CH3:8])[CH3:7])[CH2:3][O:2]1)([CH3:13])[CH3:11]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CC(C)[C@H](N)CO
Agent: CC(C)C=O
Solvent: NCCO
Product: CC(C)C1N[C@@H](C(C)C)CO1

Procedure:
(L)-Valine methyl ester was reduced to (1S)-1-(hydroxymethyl)-2-methylpropylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2,4diisopropyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-2-methylpropylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-oxazolidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=O)=[CH:7]1)[CH3:2].N1CCCCC1.[Cl-:26].[CH2:27]1[C:35]2[N+:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.C(OCC)(=O)C>C(O)(C)C>[Cl-:26].[CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[C:27]2[C:35]3[N+:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=[CH:7]1)[CH3:2]
Reactant: CCN(CC)C(=O)Cn1cc(C=O)c2ccccc21
Reactant: c1cc[n+]2c(c1)CCC2
Agent: [Cl-]
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Cn1cc(C=C2CC[n+]3ccccc32)c2ccccc21
Reaction time: 24 h

Procedure:
0.800 g of N,N-diethyl-2-(3-formyl-1H-indol-1-yl)acetamide was solubilized in 4.2 ml of isopropanol. 0.238 g of piperidine was added, followed by 0.435 g of 2,3-dihydro-1H-indolizinium chloride dissolved in 7 ml of isopropanol. The reaction mixtures were brought to 80° C. for 24 h, with stirring. 50 ml of ethyl acetate were added in order to precipitate the dye. The precipitate was filtered off, and washed with 3 times with 25 ml of ethyl acetate before being dried under vacuum until a constant weight was obtained. 1.09 g of orange powder were recovered. The analyses were in conformity with the expected structure.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][C:24]1=[O:32].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>C(C(C)=O)C(C)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2ccccc2n1CCBr
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1

Procedure:
Methyl isobutyl ketone, 1.0 g (0.004 mole) of 4-(diphenylmethylene)piperidine, 0.96 g (0.004 mole) of 1-(1-bromo-2-ethyl)-2-benzimidazolone, 0.53 g (0.008 mole) of Na2CO3 and a few crystals of NaI are heated for 9 h at the reflux temperature.
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(C(O)=O)C=CC1=2.S(Cl)(Cl)=O.Cl.NN.[CH3:25][C:26]1([CH3:42])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]2[CH:31]=[C:30]([C:38]([NH:40][NH2:41])=[O:39])[CH:29]=[CH:28][C:27]1=2.[C:43]([C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1)#[N:44]>C1(C)C=CC=CC=1.C(O)(C)C.O1CCCC1.CCOCC.O>[C:43]([C:45]1[CH:53]=[CH:52][C:48]([C:49]([NH:41][NH:40][C:38]([C:30]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:42])([CH3:25])[CH2:35][CH2:34][C:33]([CH3:36])([CH3:37])[C:32]=3[CH:31]=2)=[O:39])=[O:50])=[CH:47][CH:46]=1)#[N:44]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)NN)ccc21
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: Cl
Agent: NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)NNC(=O)c3ccc(C#N)cc3)ccc21
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
23.2 g (0.1 mole) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylic acid and 18 g (0.15 mole) of thionyl chloride in 75 ml of toluene were heated until hydrogen chloride gas was no longer formed. Thereafter, the mixture was evaporated down, toluene was added several times and the mixture was evaporated down again to remove residual thionyl chloride. The residue was dissolved in 75 ml of isopropanol and added dropwise at from -10° to -15° C. to a solution of 7.4 g (0.23 mole) of hydrazine in 200 ml of isopropanol. The mixture was stirred for 15 minutes at -10° C., 150 ml of water and 50 ml of ether were added and the mixture was stirred again vigorously. The mixture was left to stand overnight, after which the solid was filtered off and the filtrate was extracted with water/ether. The organic phase was washed with water, dried over sodium sulfate and evaporated down. 19.7 g (0.08 mole) of the 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylic hydrazide remaining as the residue were dissolved in 100 ml of dry tetrahydrofuran. A solution of 13.5 (0.088 mole) of 4-cyanobenzoyl chloride in 100 ml of tetrahydrofuran was added dropwise at 0° C. The stirred reaction mixture was allowed to reach room temperature in the course of 45 minutes. It was poured onto water, and the precipitated solid was filtered off, washed with ethanol and dried to give 16.4 g of N-(4-cyanobenzoyl)-N'-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl)-hydrazine of melting point 274°-277° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([NH:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:29][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:31][CH:30]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 91.6 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and p-acetylaminoaniline (75 mg, 0.5 mmol) to give 190 mg of the title compound (91%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 9.94 (s, 1H), 9.87 (s, 1H), 7.44~7.52 (m, 4H), 7.23 (bs, 1H), 7.17 (bs, 1H), 5.18~5.26 (m, 1H), 3.07 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.55~2.64 (m, 2H), 2.10 (dm, 1H, J=13.5 Hz), 2.02 (s, 3H), 1.80~1.96 (m, 1H).
Reaction SMILES: F[P:2](F)([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+]>>[F:9][C:3]([P:2]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: FC(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 110 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
230.0 g (0.54 mol) of difluorotris(pentafluoroethyl)phosphorane and 41.2 g (1.089 mol) of sodium borohydride were refluxed with vigorous stirring for 3 hours in a glass flask at a bath temperature of about 110° C. The reaction mixture was subsequently distilled under reduced pressure (2 kPa), and two fractions of the product were collected in cold traps at a temperature of −78° C. and −195° C. respectively. For further purification, the combined products from both traps were distilled under atmospheric pressure under an inert-gas atmosphere, with the fraction in the boiling range 85-87° C. being collected. 194.0 g of pure tris(pentafluoroethyl)phosphine were obtained. The yield was 93%, based on the amount of difluorotris(pentafluoroethyl)phosphorane employed. The resultant product was characterised by means of 19F- and 31P-NMR spectroscopy. The chemical shifts found correspond to those from Example 1a.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(F)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(F)c4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 133 (0.31 g, 0.74 mmol) was subjected to demethylation using pyridine hydrochloride (3.1 g, 26.84 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([Sn](CCCC)(CCCC)CCCC)[N:9]=[N:8]1.Br[C:41]1[C:46]([C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])=[O:48])=[CH:45][CH:44]=[CH:43][N:42]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:35][C:34]([F:37])([F:36])[C:32]1[CH:31]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:1])[F:38])[CH:33]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:41]2[C:46]([C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:55])=[O:48])=[CH:45][CH:44]=[CH:43][N:42]=2)[N:9]=[N:8]1
Reactant: O=C(c1ccccc1Cl)c1cccnc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 113 °C

Procedure:
Combine 4-[3-(3,5-bistrifluoromethylbenzyl)-5-tributylstannanyl-3H-[1,2,3]triazol-4-yl]-pyridine (489 g, 740 mmol) and toluene (1 L), add (2-bromopyridin-3-yl)-(2-chlorophenyl)-methanone (240 g, 810 mmol) in toluene (500 mL). Next, add tris(dibenzylideneacetone)dipalladium (16.95 g, 18.5 mmol) and toluene (300 mL). Add tri-2-furylphosphine (17.35 g, 74 mmol) in toluene (200 mL) and heat the reaction mixture to reflux (113° C.). Upon completion of the reaction, remove the solvent by rotary evaporation and purify the crude product by flash column chromatography (dichloromethane/ethyl acetate gradient). Treat the material with activated charcoal in ethyl acetate, wash with 5% aqueous trithiocyanuric acid trisodium salt solution, and recrystallize (ethyl acetate/hexane) to give the title compound. MS(IS) 588 (M+1). TLC (3% MeOH/CH2Cl2) Rf=0.17. 1H NMR (400 MHz, CDCl3): 5.46 (s, 2H); 7.19 (m, 5H); 7.36 (dd, 1H, J=4.9, 7.8); 7.45 (s, 2H); 7.59 (m, 1H); 7.83 (s, 1H); 7.93 (dd, 1H, J=1.5, 7.8); 8.56 (dd, 1H, J=1.5, 4.9); 8.70 (d, 2H, J=5.9).
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][CH3:13]>C(Cl)Cl>[CH2:9]([CH:10]1[CH:11]([CH2:12][CH3:13])[C:6](=[O:7])[N:5]1[S:2]([Cl:1])(=[O:4])=[O:3])[CH3:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC/C=C/CC
Solvent: ClCCl
Product: CCC1C(=O)N(S(=O)(=O)Cl)C1CC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Chlorosulfonylisocyanate (5.17 ml, 59.4 mmol) in DCM (12 ml) was stirred at 25° C. and treated dropwise with (E)-hex-3-ene (7.39 ml, 59.4 mmol) in DCM (6 ml). The mixture was stirred at RT for 72 hrs. The reaction mixture was heated over 6 hrs at 40° C., before being poured onto ice. The mixture was extracted with DCM (3×100 ml) and the combined organics were washed with water (×1), dried MgSO4 and evaporated to dryness to afford the title compound;
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([O:30]C)[CH:25]=3)=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=3)=[CH:18][N:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(Cc2cnc(SCCCCCCCCc3ccccc3)[nH]c2=O)ccn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1cc(Cc2cnc(SCCCCCCCCc3ccccc3)[nH]c2=O)cc[nH]1
Yield: 7.9 %

Procedure:
A mixture of 2-(8-phenyloct-1-yl)thio-5-(2-methoxypyrid-4-ylmethyl)pyrimidin-4-one (0.40 g, 0.9 mmol), chlorotrimethylsilane (0.23 ml, 1.8 mmol) and sodium iodide (0.27 g, 1.8 mmol) in acetonitrile (30 ml) was heated at reflux for 6 hours. The solvent was evaporated, the residue taken up in dichloromethane, and washed with water and aqueous sodium thiosulphate. Evaporation of the solvent and trituration with ether gave 2-(8-phenyloct-1-yl)thio-5-(2-oxopyrid-4-ylmethyl)pyrimidin-4-one as a white solid (0.03 g). 1H-NMR (d6-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.55 (2H, t), 3.07 (2H, t), 6.07 (2H, m), 7.1-7.3 (6H, m), 7.77 (1H, s); MPt indeterminate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].Cl.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=4)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: Cn1ccc(CCN)cc1=O
Reactant: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)NCCc4ccn(C)c(=O)c4)cc3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.265 mmol), 4-(2-aminoethyl)-1-methylpyridin-2(1H)-one hydrochloride (16 mg, 0.132 mmol), 1-methyl-1H-imidazole (118 mg, 1.45 mmol) and EDCI (276 mg, 1.45 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature for 16 h then extracted with ethyl acetate (50 mL). The combined extracts were washed with water (5 mL×2), then brine (5 mL×2). After drying and concentration, the residue was purified by chromatography (silica gel, 5 g, 200˜300 mesh, methanol:dichloromethane=1:30) to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (27 mg, 21%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.94 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.03-7.94 (m, 4 h), 7.66 (s, 1H), 7.58 (d, 1H, J=6.6 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.23 (s, 1H), 6.13 (d, 1H, J=7.2 Hz), 4.01 (s, 3H), 3.77 (s, 3H), 3.53-3.47 (m, 2H), 3.36 (s, 3H), 2.69 (t, 2H, J=6.6 Hz). LC-MS: [M+H]+, 526, tR=1.367 min, HPLC: 98.9% at 214 nm, 99.36% at 254 nm, tR=4.615 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](OS(C(F)(F)F)(=O)=O)=[CH:24][C:17]=3[C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=1.[C:39]([O:43][C:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O1CCOCC1>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.O>[C:39]([O:43][C:44]([C:46]1[CH:51]=[C:50]([C:25]2[C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:16]3[O:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]=3[CH:24]=2)[CH:49]=[CH:48][CH:47]=1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 90 °C
Yield: 69.3 %

Procedure:
Cesium carbonate (1.54 g, 4.71 mmol) was added to Pd(Ph3P)4 (182 mg, 0.157 mmol), ethyl 2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (1500 mg, 3.14 mmol), 3-(tert-butoxycarbonyl)phenylboronic acid (768 mg, 3.46 mmol). Dioxane (26 mL) and water (5 mL) was added at rt. The reaction was heated to 90° C. overnight. The reaction was allowed to cool was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give to give the titled compound (1.10 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.60 (1H, s), 8.08-8.18 (2H, m), 8.02 (1H, s), 7.95-8.01 (1H, m), 7.88 (1H, s), 7.58-7.70 (2H, m), 7.46 (2H, t, J=8.78 Hz), 4.34 (2H, q, J=7.20 Hz), 1.56 (9H, s), 1.27 (3H, t, J=7.14 Hz). LC-MS retention time: 2.13 min; m/z (MH+): parent does not ionize. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.