Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]([Mg]Br)[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:21][CH3:22])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of 4-chloro-N-methoxy-N-methyl-2-phenylamino-benzamide (5.0 g, 17.2 mmol) in tetrahydrofuran (60 mL) was treated dropwise with ethylmagnesium bromide (1M solution in tetrahydrofuran, 70 mL, 70 mmol). Upon completion of addition, the mixture was allowed to slowly warm to 25° C. where it was stirred for 2 h. At this time, the reaction was cooled to 0° C., was quenched with a 1N aqueous hydrochloric acid solution (50 mL) and was then extracted with ethyl acetate (2×300 mL). The combined organics were washed with water (100 mL) and a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica gel; 100-200 mesh, ethyl acetate/hexanes 10-25%) afforded 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (4.15 g, 92.9%) as a yellow oil. 1H NMR (DMSO-d6) δ ppm 10.53 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.34-7.51 (m, 2H), 7.28 (d, J=7.7 Hz, 2H), 7.13-7.23 (m, 1H), 7.07 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.6, 1.9 Hz, 1H), 3.07 (q, J=7.2 Hz, 2H), 1.09 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: OCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Temperature: 110 °C
Yield: 47.1 %

Procedure:
To a solution of 4-(p-fluorobenzoyl)piperidine hydrobromide (0.3 g, 1.04 mmol) in DMF (10 mL) were added 3-bromo-1-propanol (0.11 mL, 1.25 mmol) and potassium carbonate (0.29 g, 2.08 mmol). This heterogeneous solution was heated at 110° C. for 3 h then cooled at 25° C., diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The collected organic phase was washed with water (2×50 mL), dried and concentrated in vacuum. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound as a pale yellow solid (0.13 g, 47%). m.p.=106-108° C. 1H NMR (CDCl3): 1.55-1.68 (m, 2H), 1.68-1.95 (m, SH), 2.05-2.2 (m, 2H), 2.642 (t, J=5.4Hz, 2H), 3.13 (bd, J=11.7Hz, 2H), 3.15-3.3 (m, 1H), 3.808 (t, J=4.8Hz, 2H), 7.137 (t, J=8.4Hz, 2H), 7.95 (dd, J=5.4 & 8.4, 2H). Anal. Calcd. for C15H20FNO2:C, 67.90; H, 7.60; N, 5.28; Found: C, 66.71; H, 7.38; N, 5.44.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=O)=[CH:9][C:8]=1[CH:25]=[C:26]([Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>ClCCl>[Cl:3][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([CH:25]=[C:26]([Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:9]=2)[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(Cl)=Cc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)ccc1Cl
Reaction time: 2 h

Procedure:
13.8 ml of phosphoryl chloride were added dropwise to 12.6 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl]-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, and stirring was carried out for 2 hours at room temperature. Thereafter, 2.1 ml of dimethylformamide were added and stirring was continued for 15 hours at 110-115° C. The reaction mixture was evaporated down under reduced pressure, the residue was added to 150 ml of ice water and the mixture was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed with water, 10% strength sodium bicarbonate and again with water, dried over sodium sulfate and evaporated down. The oil obtained was subjected to flash chromatography (dichloromethane), and the crystalline solid obtained therefrom was stirred with petroleum ether, removed, washed with a little petroleum ether and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH2:17][C@H:16]([CH3:18])[CH2:15][N:14]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]([NH:41][C:42](=[O:62])[C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:51][C@H:50]3[CH3:61])=[N:45][CH:44]=2)=[CH:29][C:30]([O:36][C:37]([F:40])([F:39])[F:38])=[C:31](B(O)O)[CH:32]=1.C(=O)(O)[O-].[Na+].CC1CCCO1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CCOC(C)=O.O>[Cl:26][C:27]1[C:28]([NH:41][C:42](=[O:62])[C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:51][C@H:50]3[CH3:61])=[N:45][CH:44]=2)=[CH:29][C:30]([O:36][C:37]([F:40])([F:39])[F:38])=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[C:10]([C@@H:13]4[CH2:17][C@H:16]([CH3:18])[CH2:15][N:14]4[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[NH:11][CH:12]=3)=[CH:6][CH:7]=2)[CH:32]=1
Reactant: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(B(O)O)cc2Cl)cn1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(Br)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 92.7 %

Procedure:
To a round bottom flask was added (2S,4S)-tert-butyl 2-(4-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (10 g, 24.61 mmol), (R)-(5-chloro-4-(6-(2-methyl-4-pivaloylpiperazin-1-yl)nicotinamido)-2-(trifluoromethoxy)phenyl)boronic acid (14.16 g, 26.1 mmol), sodium bicarbonate (7.24 g, 86 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.17 g, 0.246 mmol), 2 methyltetrahydrofuran (120 mL) and water (44.3 mL) to give a suspension. The reaction mixture was degassed with nitrogen for 10 min then heated at 70° C. overnight. Water (60 mL) was added and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, and evaporated to give crude product (27.3 g). The crude product was purified by flash chromatography (300 g silica gel, 20-100% EtOAc (50 min), then 100% EtOAc (20 min)) to give the title intermediate (18.8 g; 93% yield) HPLC Method B: Retention time 14.99 min.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]=1[CH3:10].[NH3:19]>CO>[CH3:17][C:6]1[C:5]([CH2:4][C:3]([NH2:19])=[O:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: N
Reactant: COC(=O)Cc1c(C)nn(-c2ccccc2)c1C
Solvent: CO
Product: Cc1nn(-c2ccccc2)c(C)c1CC(N)=O
Temperature: 160 °C
Yield: 81 %

Procedure:
6 grams 3,5-dimethyl-1-phenyl-pyrazol-4-acetic acid-methyl-ester and 80 milliliters ammonia solution in methanol were mixed and the mixture heated in an autoclave to 160° C. for 6 hours. The reaction mixture was evaporated to dryness. 4.6 grams 3,5-dimethyl-1-phenyl-pyrazol-4-acetamide, melting at 160°-170° C., were obtained, representing a yield of 81%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH2:13][OH:14])[CH:3]=1.[N+:15]([O-:18])(O)=[O:16]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([N+:15]([O-:18])=[O:16])=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH2:13][O:14][S:9]([OH:11])(=[O:10])=[O:8])[CH:3]=1
Reactant: CS(=O)(=O)Oc1ccc(F)cc1CO
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)Oc1cc([N+](=O)[O-])c(F)cc1COS(=O)(=O)O

Procedure:
To a mixture of 7.53 g (34 mmole) of methanesulfonic acid 4-fluoro-2-hydroxymethyl-phenyl ester and 60 mL of concentrated sulfuric acid at 0 degrees was added dropwise, a cold mixture of 2.5 mL of concentrated nitric acid and 3 mL of concentrated sulfuric acid. The mixture was poured on ice and extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether to give 3.5 g of methanesulfonic acid 4-fluoro-5-nitro-2-sulfooxymethyl-phenyl ester as a white solid. The white solid was heated to reflux for 1 hour with 100 mL of methanol, 2 mL of trimethylorthoformate and 0.10 g of p-toluenesulfonic acid monohydrate. The mixture was neutralized by addition of saturated sodium bicarbonate solution and then concentrated under reduced pressure. The residue was partitioned between 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2.6 g of methanesulfonic acid 4-fluoro-2-hydroxymethyl-5-nitro-phenyl ester as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][CH:14]3[NH:16][CH:10]([CH2:11][C:12](=[O:17])[CH2:13]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][CH:14]3[N:16]([S:26]([C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:30])[F:31])=[CH:25][CH:24]=4)(=[O:28])=[O:27])[CH:10]([CH2:11][C:12](=[O:17])[CH2:13]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CC(c3cccc(Br)c3)CC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CC2CC(c3cccc(Br)c3)CC(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 19 %

Procedure:
7-(3-Bromophenyl)-9-azabicyclo[3.3.1]nonan-3-one (90) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (12.25 g, 50.1 mmol) in pyridine (100 ml) and CH2Cl2 (100 ml) was stirred for 24 h. The solution was concentrated and flash chromatographed with CH2Cl2 as the eluant to yield 2.29 g (19% yield over 4 steps) of compound 91 as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Cl)cc2)cc1
Yield: 61.5 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl)benzenecarboximidamide from Step 1 (8 g, 26 mmol) and sodium bicarbonate (4.36 g, 52 mmol) in isopropanol (240 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating the reaction mixture at 75–80° C. for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (16.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 55/45) to give pure 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (6.7 g, 62%) as a white solid: Anal. Calc'd. for C17H14N2SO3ClF3: C, 48.75; H, 3.37; N, 6.69. Found: C, 48.56; H, 3.22; N, 6.51.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1.CC1(C)C[O:32][B:31](B2OCC(C)(C)CO2)[O:30]C1.C([O-])(=O)C.[K+].N(CCO)CCO>C(O)(C)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:25]([C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([B:31]([OH:32])[OH:30])=[CH:3][CH:4]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])#[N:26]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: OCCNCCO
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A flask containing 6C (83 mg, 0.19 mmol), 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (47.6 mg, 0.211 mmol), potassium acetate (83 mg, 0.84 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (4.4 mg, 0.0060 mmol) was purged with argon. DMSO (1 mL) was added, and the reaction mixture was degassed with three cycles of vacuum followed by argon backfill. The reaction mixture was heated for 2 h at 80° C., cooled to rt, and diluted with water (100 mL). The aqueous solution was extracted with diethyl ether (3×25 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in a mixture of diethyl ether (1 mL), DCM (˜0.1 mL), and EtOAc (˜0.1 mL). Diethanolamine (22 mg, 0.21 mmol) in isopropanol (0.5 mL) was added, and the reaction mixture was stirred overnight at rt. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC (under the standard acidic conditions) to give 6D (44 mg, 57%) as a clear oil. MS (ESI) m/z 425.4 (M+CH3OH—H2O+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[O:28]=[S:29]1(=[O:43])[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1>>[O:43]=[S:29]1(=[O:28])[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:37]=2)[CH2:33][CH2:34]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C28H27N3O5S
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][CH:22]=1)[O:19][CH2:18][C@H:14]1[O:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[CH2:13]1
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Reactant: Oc1cccc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cccc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)c1
Yield: 40.2 %

Procedure:
Compound 23s was synthesised with essentially the same procedure as compound 18s (Example 16), from compound 51 (Example 10; 52 mg, 0.2 mmol), 3-chlorophenol (39 mg, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), and THF (1 ml). The crude residue was purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford the title compound as a colourless oil (30 mg; 40%). Analyses were performed on the free base, and the free base was converted to the HCl salt for testing.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH:33][C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@H]1CCCN1c1cccc(N)n1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC[C@H]4C)n3)c3nccn3n2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (200 mg, 0.6 mmol), (R)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (160 mg, 0.9 mmol), Pd2(dba)3 (36 mg, 0.06 mmol), BINAP (152 mg, 0.24 mmol), Cs2CO3 (592 mg, 1.8 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give (R)-methyl 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (110 mg, 43%) as a yellow solid. LC-MS: [M+H]+, 429.1, tR=2.064 min.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([O:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][N:29]=1)(C)(C)C.[OH-].[K+]>CCO>[C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([C:1](=[O:3])/[CH:2]=[CH:34]/[C:31]3[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:25]([OH:36])=[O:24])=[N:29][CH:30]=3)=[CH:5][CH:6]=2)[CH2:10][CH2:11]1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1ccc(CN2CCN(C(C)=O)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-[4-(4-acetyl-benzyl)piperazin-1-yl]-ethanone (prepared following the procedure described in Preparation 12, 500 mg, 1.92 mmol), (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 448 mg, 1.92 mmol) and 1.7 M KOH (1.2 ml) in EtOH (19 ml) was stirred at room temperature for 6 h and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.1) and the resulting product was dissolved in DCM (1.5 ml) and TFA (0.560 ml). The solution was stirred at room temperature for 3 h and then the solvent was evaporated to give 300 mg (E)-3-(5-{(E)-3-[4-(4-acetyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its bis-trifluoroacetate salt (the compound was used without further purification in the next step).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH:18]([CH3:37])[N:19]([C:23]4[CH:28]=[C:27]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:26]=[C:25]([NH2:36])[N:24]=4)[CH2:20]3)=[CH:15][CH:14]=2)[CH:10]=[N:9]1)(C)(C)C.Cl.[CH3:40][NH:41][CH3:42]>>[NH2:36][C:25]1[N:24]=[C:23]([N:19]2[CH:18]([CH3:37])[CH2:17][C:16]3[C:21](=[CH:22][C:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]([N:41]([CH3:42])[CH3:40])=[O:5])[CH:12]=4)=[CH:14][CH:15]=3)[CH2:20]2)[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[N:26]=1
Reactant: CNC
Reactant: CC1Cc2ccc(-c3cnn(CC(=O)OC(C)(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3cnn(CC(=O)N(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 79 starting from tert-butyl(4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)acetate and dimethylamine hydrochloride. LCMS (M+H)+: m/z=490.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:17][O:18][CH3:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.CCN=C=NCCCN(C)C.Cl.Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:17][O:18][CH3:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1)=[O:12]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COCc1nc(Cl)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5, 20 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL). 4-Dimethylaminopyridine (17.4 mg, 0.14 mmol), EDC.HCl (27 mg, 0.14 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 15.5 mg, 0.07 mmol, 1.00 equiv) were added and the resulting solution was stirred for 12 h at room temperature. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (35% CH3CN up to 50% in 7 min, up to 100% in 3 min, down to 35% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield 15 mg (47%) of the title compound as a white solid. m/z (ES+) 449 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]1([C:37]([OH:41])([C:39]#[CH:40])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(O)c1ccccc1
Product: Cc1cc2ccc(C#CC(C)(O)c3ccccc3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-phenylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (88) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 2-phenylbut-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J=8 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 2H), 7.57 (m, 3H), 7.46 (d, J=8 Hz, 1H), 7.33 (m, 5H), 5.18 (s, 1H), 2.61 (s, 3H), 1.75 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M—OH]+ calcd for C33H30ClO3: 509.1; found: 508.8.