Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]3[C:15]([NH:16][C@H:17]4[C@@H:21]([CH3:22])[CH2:20][NH:19][CH2:18]4)=[C:14]([C:23]([NH2:25])=[O:24])[CH:13]=[N:12][N:11]3[CH:26]=2)[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.Br[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([N:19]2[CH2:20][C@H:21]([CH3:22])[C@H:17]([NH:16][C:15]3[C:10]4[N:11]([CH:26]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)[N:9]=4)[N:12]=[CH:13][C:14]=3[C:23]([NH2:25])=[O:24])[CH2:18]2)=[N:36][CH:37]=1)#[N:40]
Reactant: N#Cc1ccc(Br)nc1
Reactant: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CNC[C@@H]4C)c3n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(c5ccc(C#N)cn5)C[C@@H]4C)c3n2)cn1
Yield: 63.8 %

Procedure:
A solution of 2-(1-ethyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, 2 TFA (0.020 g, 0.034 mmol), 6-bromonicotinonitrile (0.013 g, 0.069 mmol) and Hunig's Base (0.030 ml, 0.172 mmol) in DMF (0.3 ml) in a reaction vial was stirred at 100° C. for 5 h. The crude material was purified via preparative LC/MS (Method A). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound of Example 1 (10.0 mg, 0.022 mmol, 63.8% yield). 1H NMR (500 MHz, deuterated 1:1 methanol:chloroform) δ 8.53 (br. s., 1H), 8.51 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.84 (d, J=8.9 Hz, 1H), 6.69 (d, J=7.4 Hz, 1H), 6.32 (br. s., 1H), 4.43 (q, J=7.3 Hz, 3H), 4.19 (br. s., 1H), 4.12-3.91 (m, 2H), 3.70-3.57 (m, 1H), 3.06 (d, J=12.9 Hz, 1H), 1.72 (t, J=7.4 Hz, 3H), 1.43 (d, J=6.9 Hz, 3H). LC/MS (Method F): m/z 456.20 ([M+H]+), Rt. 1.310 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:57][O:58][C:59]1[N:64]=[CH:63][C:62](B(O)O)=[CH:61][CH:60]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:30])[C:2]=2[C:62]2[CH:63]=[N:64][C:59]([O:58][CH3:57])=[CH:60][CH:61]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cn1
Yield: 68 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 92 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (68%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:13]C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].CCOCC.[Na+].[Cl-]>Cl.C(O)C.O>[N:1]([CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: [N-]=[N+]=NC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The compound from step 3 (4.3 g, 15.6 mmol) is dissolved in 30 mL of 4 N HCl in ethanol, and the reaction mixture is stirred for 1.5 hours at room temperature. The solvent is stripped and chased with ether. The residue is dissolved in water, NaCl is added, and the mixture is extracted with ethyl ether, which is discarded. The aqueous layer is adjusted to pH 12 with K2CO3, saturated with NaCl, then extracted with CHCl3. The organic extract is washed with brine, dried (Na2SO4) and filtered. The solvent is removed under vacuum to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[CH3:27][C:28]([N:31]1[C:35]([OH:36])=[CH:34][CH:33]=[N:32]1)([CH3:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.ClCCCl.CC(C)(O)C#N.O.C(N(CC)CC)C>[CH3:27][C:28]([N:31]1[C:35]([OH:36])=[C:34]([C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]=2[Cl:1])[CH:33]=[N:32]1)([CH3:30])[CH3:29]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1-c1ccccc1
Reactant: CC(C)(C)n1nccc1O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)n1ncc(C(=O)c2ccc(S(C)(=O)=O)c(-c3ccccc3)c2Cl)c1O
Reaction time: 8 h

Procedure:
2-Chloro-3-phenyl-4-methylsulfonylbenzoic acid (750 mg, 2.4 mmol), excess oxalyl chloride, and a few drops of N,N-dimethylformamide were dissolved in 1,2-dichloroethane and the mixture was allowed to react with stirring overnight. The mixture was then concentrated by evaporation under reduced pressure. The residue was taken up in about 10 mL of dichloromethane and the resulting solution was cooled with an ice bath. To this was added 410 mg (2.9 mmol) of 1-(1,1-dimethylethyl)-5-hydroxypyrazole and about 2 mL of triethylamine. After about 1 hour, the mixture was diluted with-water and with more dichloromethane and the phases were separated. The organic phase was washed with dilute aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was dissolved in 10 mL of anhydrous 1,2-dimethoxyethane and 1.3 g (9.6 mmol) of sodium carbonate and then about 8 drops of acetone cyanohydrin were added. The mixture was allowed to react overnight and was then diluted with water. The phases were separated and the aqueous phase was extracted with ether, acidified with aqueous hydrochloric acid, and then twice extracted with dichloromethane. The dichloromethane extracts were combined and washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The 900 mg of residue was placed in 15 mL of ethanol and the mixture was heated and then cooled. The precipitate that formed was collected by filtration, washed with ether, and dried in a reduced pressure oven for 1 hour at 80° C. to obtain 682 mg (66 percent of theory) of the title compound as a tan solid melting at 262.5-264° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH:15]=[CH:14][CH:13]=[C:12]2[C:16]([O:18]C)=O)=[CH:5][CH:4]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23].O.C(Cl)Cl>O1CCOCC1.[Cl-].[Na+].O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[NH:24][CH2:21][CH2:22][N:23]2[C:16](=[O:18])[C:12]2[N:11]([CH:15]=[CH:14][CH:13]=2)[CH2:10]3)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(CO)cc1
Reactant: NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=C1c2cccn2CC2(c3ccc(CO)cc3)NCCN12
Yield: 57.8 %

Procedure:
To a solution of methyl 1-{2-[4-(hydroxymethyl)phenyl]-2-oxoethyl}-1H-pyrrole-2-carboxylate (150 mg, 0.55 mmol) in 1,4-dioxane (25 mL) was added ethane-1,2-diamine (0.75 mL, 11 mmol). The solution was heated at reflux for 54 hours. The mixture was concentrated in vacuo to give a yellow oil, which was then portioned between water (30 mL) and CH2Cl2 (30 mL). Brine was added, and the organic layer was separated. The aqueous was further extracted with CH2Cl2 (2×30 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield a yellow solid, which was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0 to 10% methanol in EtOAc) to give 10a-[4-(hydroxymethyl)phenyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as an off-white solid (90 mg, yield: 57%). ESI-MI m/z [M+H]+ 283.9.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1.O>C(O)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[Cl:3][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Cl)nccc12
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
Copper (II) acetylacetonate (253 mg) was suspended in ethanol (10 ml) and sodium borohydride (366 mg) was added in one portion. The mixture was stirred for 5 minutes, by which time a black suspension had appeared. A suspension of 1-chloro-5-nitroisoquinoline (Description 47; 1.01 g, 4.84 mmol) in ethanol (20 ml) was then added over 15 minutes whilst cooling in a water bath; the mixture effervesced. The mixture was stirred at room temperature for 1 hour, then more sodium borohydride (160 mg) was added and stirring continued for a further 1 hour. Water (100 ml) was added then the ethanol was evaporated and the mixture extracted with ethyl acetate (3×50 ml). The combined organic layers were dried (Na2SO4) and evaporated. Purification of the residue by flash column chromatography using 5% methanol-dichloromethane as eluant gave the title compound (210 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(Cl)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (66 mg, 77%), MS (ISP) m/z=345.4 [(M+H)+], mp 218.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1Cl
Yield: 8.4 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-chloro-4-fluorophenylboronic acid (available from Combi-Blocks Inc.; 70 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-fluoro-biphenyl-2-carboxylic acid (8 mg, 8%). LCMS analysis indicated that the material was 93% pure, as measured by UV at 214 nm. LRMS m/z 479.7 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C.O.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl.[Cu]I.CCCCCC.C(OCC)(=O)C.C(O)(=O)C.C(N(CC)CC)C>[C:8]1([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Ic1ccccc1
Reactant: C[C@H](N)C(=O)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(Nc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
A mixture of alanine (356 mg, 4.0 mmol), iodobenzene (816 mg, 4.0 mmol), trans-dichlorobis(tri-o-tolylphosphine)palladium(II) {Pd[P(o-Tol)3]2Cl2} (160 mg, 0.2 mmol), copper(I) iodide (40 mg, 0.2 mmol), K2CO3 (552 mg, 4.0 mmol), benzyltriethylammonium chloride (160 mg, 0.8 mmol), triethylamine (1.6 mL) and water (0.8 mL) in DMF (8 mL) was stirred under nitrogen atmosphere at 100° C. for 20 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), acidified with 6N HCl to the pH=2 to 3. The aqueous layer was extracted with ethyl acetate (50 mL×4). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a red oil. Flash chromatography using hexane/ethyl acetate/acetic acid (95/5/0.5 to 80/20/0.5) to afford 300 mg (45% yield) of the title compound as a pink solid. 1H-NMR (500 MHz, CDCl3/CD3OD=0.5 ml/3 drops) δ 1.45 (d, 3H), 4.02-4.15 (m, H), 6.57-6.70 (m, 3H), 7.11-7.25 (m, 2H); Analytical HPLC: 6.10 min. LC-MS: m/e=166 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>>[CH3:13][C:14]([CH3:18])([CH2:17][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:15][OH:16]
Reactant: CC(C)(CO)CBr
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(CO)CN1CCCC1
Temperature: 25 °C
Yield: 26.2 %

Procedure:
Pyrrolidine (1.82 g, 25 mmol), K2CO3 (3.0 g, 1.04 eq.), 3-bromo-2,2-dimethyl-propan-1-ol (8.45 g, 50 mmol, 2 eq.) were heated together at 90° C. overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (50 ml) and extracted with TBME (3×50 ml). The aqueous phase was basified to pH 14 with 2M NaOH solution and extracted with DCM (3×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.03 g, 26%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](C#N)[C:9](=[O:20])[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15]CC)=O)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)CCCCC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9](=[O:20])[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(C)CC(=O)C(C#N)c1cccc(Cl)c1
Agent: CCCCCC(=O)[O-]
Product: CC1(C)CC(=O)C(c2cccc(Cl)c2)C(=O)C1

Procedure:
This dione was prepared by the acid cyclization of ethyl 6-(3'chlorophenyl)-6-cyano-5-keto-3,3-dimethylhexanoate. Preparation of the hexanoate is described in Part A and of the dione in Part B below.
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([C:8]2[C:9]3[C:4](=[C:3]([C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)[CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[O:14])=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2cccc3c(-c4ccncc4)cccc23)cc1N1CCN(C)CC1
Yield: 17.1 %

Procedure:
A stirred suspension of 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-yl carboxamide hydrochloride salt (E2, 0.35 g, 0.71 mmole) and 4-pyridylboronic acid (85 mg, 0.71 mmole) in 1,2-dimethoxyethane (30 ml) and water (30 ml) containing sodium carbonate (0.38 g, 3.5 mmole) was de-gassed by bubbling argon through for 15 minutes. Tetrakis (triphenylphosphine)palladium (0) (80 mg) was added and the mixture heated at reflux for 30 h. The mixture was concentrated in vacuo to approx. 30 ml volume, then diluted with water (50 ml) and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo to a dark solid. Purification by column chromatography on silica gel eluting with 0-20% methanol/dichloromethane afforded the title compound as a pale yellow oil (55 mg, 17%). This was converted to its hydrochloride salt and solidified from acetone.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:29])[CH3:28])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)C=CN=C1.N[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[CH:27]([N:12]1[C:10]2=[N:11][C:6]([NH:1][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:35][CH:36]=3)=[N:7][CH:8]=[C:9]2[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:13]1=[O:26])([CH3:29])[CH3:28]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1ccc(Cn2c(=O)c3cnc(-n4ccnc4)nc3n(C(C)C)c2=O)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2c(=O)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc3n(C(C)C)c2=O)cc1
Temperature: 180 °C
Yield: 57.7 %

Procedure:
A mixture of 700 mg (1.78 mmol) of 7-(imidazol-1-yl)-1-isopropyl-3-(4-methoxybenzyl)-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 1.02 g (5.35 mmol) of 1-(4-aminophenyl)-4-methylpiperazine is heated at 180° C. for 2 hours. The reaction mixture is cooled, dissolved into chloroform, and chromatographed on silica eluting with 5:95 methanol/chloroform. The resulting material is crystallized from methanol/water to give 530 mg (58%) of the title compound: mp 215-216° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: O=C1CCc2c(ccc(Br)c2Cl)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCc2c(ccc(Br)c2Cl)N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-5-chloro-3,4-dihydroquinolin-2(1H)-one (143-5; 1.2 g, 0.0046 mol) in toluene (20 mL) was added Lawesson's reagent (1.8 g, 0.0046 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound 6-bromo-5-chloro-3,4-dihydroquinoline-2(1H)-thione. MS (M+1): 277.8.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>O>[CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([OH:10])[CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1cc(O)cc(=O)[nH]1
Solvent: O
Product: CCc1cc(O)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
20 g (0.145 mol) of 6-ethyl-4-hydroxy-1-H-2pyridone are suspended in 60 ml of 65% strength HNO3 and heated to 65° C. The strongly exothermic reaction is kept under control by cooling with ice. After the reaction subsides, 120 ml of water are added and the mixture is cooled with ice. After 30 minutes, the precipitate is filtered off with suction and dried.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: NC(=O)C1CCNCC1
Product: NC(=O)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid amide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid amide following General Procedure B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:9]([CH3:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[CH2:13]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[Cl:35][CH2:13][C:3]1[CH:4]=[C:5]([O:8][C@H:9]([CH3:12])[CH2:10][CH3:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC[C@@H](C)Oc1ccc(F)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC[C@@H](C)Oc1ccc(F)c(CCl)c1
Temperature: 78 °C

Procedure:
To a solution of (2-fluoro-5-{[(1R)-1-methylpropyl]oxy}phenyl)methanol (0.091 g, 0.459 mmol) in carbon tetrachloride (4.59 ml) was added triphenylphosphine resin (0.241 g, 0.918 mmol). The reaction was heated to 78° C. overnight in a pressure tube with minimal stirring. The reaction mixture was filtered through a fritted funnel and washed with carbon tetrachloride. The filtrate was concentrated to give the desired product.
Reaction SMILES: C([Li])CCC.[H-].C([Al+]CC(C)C)C(C)C.C(N(C)[C:21]([C:23]1[S:24][CH:25]=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[C:27]=1[CH3:28])=[O:22])(C)(C)C.[BH4-].[Na+]>C1CCCCC1.O1CCCC1.C(O)C>[CH3:28][C:27]1[C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)=[CH:25][S:24][C:23]=1[CH2:21][OH:22]
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)csc1C(=O)N(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1CCCCC1
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)csc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6M in hexanes, 1.1 ml) was added dropwise to a mixture of 1M diisobutylaluminium hydride in cyclohexane (1.77 ml) and tetrahydrofuran at 0° C. under nitrogen. This mixture was allowed to stir for 30 minutes then was added to a cooled (0° C.) solution of N-(tert-butyl)-N,3-dimethyl-4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxamide (intermediate 40, 0.210 g) in tetrahydrofuran (2.5 ml) under nitrogen. After 1.5 hours, a solution of sodium borohydride (0.68 g) in ethanol (5 ml) was added and the reaction was allowed to warm to room temperature. After 2 hours, the reaction was quenched with wet tetrahydrofuran then 2M aqueous hydrochloric acid was added and the mixture was stirred for 15 minutes. Ether was added and the water layer removed. The aqueous was extracted with 2 further portions of ether then the combined organic solution was washed with brine then dried (MgSO4) and concentrated. The crude product was purified by SPE (silica cartdrige) using cyclohexane:ethyl acetate (3:1) as eluent to furnish the title compound as a colourless oil.
Reaction SMILES: FC1C=C(C=C(F)C=1)CNC(=O)C(C)C([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=O.[F:41][C:42]1[CH:43]=[C:44]([CH:56]=[C:57]([F:59])[CH:58]=1)[CH2:45][NH:46][C:47](=[O:55])[CH:48]([CH:52]([CH3:54])[CH3:53])[C:49]([OH:51])=O>>[F:59][C:57]1[CH:56]=[C:44]([CH:43]=[C:42]([F:41])[CH:58]=1)[CH2:45][NH:46][C:47](=[O:55])[CH:48]([CH:52]([CH3:54])[CH3:53])[C:49]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:51]
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Reactant: CC(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CC(C)C(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1

Procedure:
N-(3,5-Difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoguinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-isopropyl-malonamide. MS: m/e=573.3 (M+H+), was prepared in analogy to N-(3,5-difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-malonamide (example 16) from N-(3,5-difluoro-benzyl)-2-isopropyl-malonamic acid.