Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1F>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: Fc1cccc(Br)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2c(F)cccc2Br)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Add slowly a solution of 1-methyl-piperidin-4-ol (2.98 g) in DMF (20 mL) into a suspension of sodium hydride (95%) (0.72 g) in DMF (25 mL) at room temperature. Heat the mixture in an oil bath at 65° C. After 30 min., add 1-bromo-2,3-difluoro-benzene (5.0 g) and stir at 65° C. After 2 hr., partition the reaction mixture between water and ether, dry over anhydrous sodium sulfate, and evaporate to give a yellow oil. Separate on a silica gel column (110 g, solvent: ether, ether-2M NH3 in methanol 19:1, 9:1) to obtain 4-(2-bromo-6-fluoro-phenoxy)-1-methyl-piperidine (4.06 g, 54% yield) and the title compound (1.60 g, 21% yield). Mass spectrum (electric spray) m/z=288 (M+1), 290 (M+2+1); 1H NMR (CDCl3): 7.12 (m, 1H), 6.92 (m, 2H), 4.30 (m, 1H), 2.69 (m, 2H), 2.30 (s, 3H), 2.28 (m, 2H), 1.97 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH3:20]>CC(C)=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:17][CH2:18][O:19][CH3:20])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCCBr
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCn1ncc(Cl)c(Cl)c1=O
Temperature: 55 °C
Reaction time: 24 h

Procedure:
To a suspension of 4.00 g (24.2 mmol) of 4,5-dichloro-2H-pyridazin-3-one and 6.70 g (48.5 mmol) of potassium carbonate in 40 ml of acetone were added 4.55 ml (6.74 g, 48.5 mmol, 2 eq.) of 2-bromoethylmethylether. The suspension was stirred for 24 h at 55° C. Then 1 ml (1.48 g, 10.6 mmol) of 2-bromoethylmethylether were added and the mixture was stirred for another 24 h. The reaction was then allowed to cool to room temperature, the solids were filtered off and washed twice with ethyl acetate. The filtrate was concentrated in vaccuo, taken up in methylene chloride and purified by flash chromatography (SiO2, heptane:ethyl acetate 85:15 v/v) to yield the title compound as a white crystalline solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[Si]([N:27]1[CH2:32][CH2:31][N:30](C)[CH2:29][CH2:28]1)(C(C)(C)C)(C)C>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
In a manner similar to that of Example 1, 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (II, R1 : cyclopropyl; X: chloro) is reacted with 1-(t-butylmethylsilyl)piperazine (III, R2 : hydrogen; R3 and R4 : methyl; R5 : t-butyl) to afford a solid compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:24](=O)([O:28]CC)[O:25][CH2:26][CH3:27]>O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:24]([O:25][CH2:26][CH3:27])=[O:28])[CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-benzyloxyacetophenone (90 g, 400 mmol) in diethyl carbonate (500 ml) was added ethanol (1.5 ml) and sodium hydride (60% in oil, 31.8 g, 800 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 4 hrs. To the reaction solution was added 6N hydrochloric acid to stop the reaction, and water (500 ml) was added. The mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-10:1) to give the objective substance (107 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C:14]([CH3:16])=[CH:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[CH:64]=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[C:62](Br)=[CH:61][C:60]=3[Cl:71])=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[C:60]([Cl:71])=[CH:61][C:62]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:12]6[CH:13]=[C:14]([CH3:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:37])[CH:6]([CH3:8])[CH3:7])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[CH:64]=3)=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)N[C@H](C(=O)N1CC(C)=C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC(C)=C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 30 %

Procedure:
To a solution of [(S)-2-Methyl-1-((S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2,5-dihydro-pyrrole-1-carbonyl)-propyl]-carbamic acid methyl ester (100 mg, 0.20 mmol, Preparation 4) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.19 mmol) dissolved in toluene (1.18 mL) and water (0.43 mL) was added potassium carbonate (127 mg, 0.92 mmol). The reaction mixture was sparged under nitrogen for 15 min and Pd(dppf)Cl2 CH2Cl2 (13.55 mg, 0.017 mmol) was added and the reaction mixture was sparged with nitrogen and heated to 90° C. overnight, cooled to RT, diluted with EtOAc and washed with water and brine to produce a dark colored solid, which was purified by silica gel chromatography (12 g silica, EtOAc/hexanes 40 to 100%) to produce the title intermediate (51 mg, 31% yield) as a yellowish colored solid. (m/z): [M+H]+ calcd for C44H50ClF3N8O7 895.34 found 895.3.
Reaction SMILES: [NH2:1][C:2]1C(I)=C(C(O)=O)C(I)=C(C(O)=O)[C:7]=1I.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N:1]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:7][CH:2]=1
Reactant: Cc1ccccc1
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Product: c1ccc2ncccc2c1
Yield: 92.3 %

Procedure:
According to the procedure described in Example 1, the reaction is carried out with the same amounts of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid using toluene instead of meta-xylene, with quinoline, giving a yield of 92.3%.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].Cl>ClCCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:15][C:14]=1[CH3:19]
Reactant: Cc1ccccc1F
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In a mixed solution of 2.0 g of succinic anhydride and 50 ml of 1,2-dichloroethane, 6.7 g of aluminum chloride were added, followed by stirring at room temperature for 40 minutes. To the resulting mixture, 20 ml of 2 -fluorotoluene were added dropwise at room temperature and they were stirred for 20 minutes, followed by further stirring for 20 minutes at an external temperature of 50° C. The reaction mixture was cooled and then poured into ice water to which 5% hydrochloric acid had been added. The resulting mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated. The residue so obtained was recrystallized from chloroform, whereby 3.2 g of the title compound was obtained.
Reaction SMILES: CCCP(=O)=O.[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=2)[CH:8]=1.[CH3:26][N:27]([CH3:42])[CH2:28][C:29]#[C:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:42][N:27]([CH3:26])[CH2:28][C:29]#[C:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:23](=[O:25])[CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N:9]3[C:10]4=[N:11][CH:12]=[CH:13][CH:14]=[C:15]4[N:7]=[CH:8]3)=[CH:21][CH:20]=2)=[CH:33][C:32]=1[C:38]([F:39])([F:40])[F:41]
Reactant: CN(C)CC#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)CC#Cc1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Propylphosphonic anhydride (50% in DMF, 0.69 mL, 1.19 mmol, 2 equiv) is added to a solution of (4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid (Step 7.1) (0.150 g, 0.59 mmol), 4-(3-dimethylamino-prop-1-ynyl)-3-trifluoromethyl-phenylamine (0.138 g, 0.57 mmol, 0.95 equiv), DMAP (10 mg), and Et3N (0.82 mL, 5.93 mmol, 10 equiv) in DMF (2.0 mL), at rt and under an argon atmosphere. The reaction mixture is stirred at rt for 18 h, diluted with EtOAc and washed with H2O. The aqueous layer is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by reversed phase MPLC (CH3CN/H2O/TFA) to provide the title compound as a white solid: ES-MS: 477.9 [M+H]+; single peak at tR=3.20 min (System 1); Rf=0.06 (CH2Cl2/NH3 (2 N in MeOH), 95:5).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Br-].[CH2:33]([Zn+])[CH:34]([CH3:36])[CH3:35]>>[CH3:23][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:22]
Reactant: CC(C)C[Zn+]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Agent: [Br-]
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(CC(C)C)ccc23)cc1C

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 171 from methyl 2-(7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate and isobutylzinc(II) bromide and was isolated as a white solid (11.7 mg, 37%) after reverse phase chromatography: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.27 (s, 1 H), 7.42-7.22 (m, 3 H), 7.16-7.00 (m, 2 H), 5.35 (m, 1 H), 3.70 (s, 3 H), 2.61 (m, 2 H), 2.36 (m, 3 H), 2.32 (m, 3 H), 2.00-1.85 (m, 1 H), 1.07 (m, 9 H), 0.96-0.85 (m, 6 H); LC/MS (m/z) ES+=450 (M+1).
Reaction SMILES: [C:1]([O:5][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:8][NH:9]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:22]([O:21][C:19](=[O:20])[CH:18]([CH2:17][P:6]([CH2:8][NH2:9])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CNCc1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCC(CP(=O)(CN)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 96 h
Yield: 98.6 %

Procedure:
To a solution of di-tert-butyl 2-[((tert-butoxy){[benzylamino]methyl}phosphoryl)methyl]pentane-1,5-dioate (8.20 g, 16.5 mmol) in ethanol (100 mL) was added palladium on carbon (0.50 g), and the suspension was shaken under hydrogen (50 psi) for 4 days. The catalyst was removed by filtration through a pad of Celite. The filtrate was concentrated to give 6.629 g of colorless oil (99% yield): 1H NMR (CD3OD) δ 1.40-1.60 (m, 27H), 1.80-2.00 (m, 3H), 2.2-2.4 (m, 3H), 2.7-3.0 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:11][CH:12]=1
Reactant: Oc1ccccc1F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a mixture of 2-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N,N-dimethylformamide (30 mL) was added sodium hydride (730 mg, 15 mmol, 50% in oil) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was then stirred for 5 hours at 110° C. The reaction mixture was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed twice with water and then washed with saturated aqueous sodium chloride, was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=15:1) to obtain the title compound (940 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.C(OC(C)C)(=O)C.Cl>CCCCCCC.O.O1CCCC1>[OH:13][C:11](=[C:19]1[C:20](=[O:21])[O:22][C:15]([CH3:23])([CH3:14])[O:16][C:17]1=[O:18])[CH2:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC1(C)OC(=O)C(=C(O)Cc2cc(F)c(F)cc2F)C(=O)O1
Temperature: 30 °C
Reaction time: 5 h
Yield: 60.1 %

Procedure:
2,4,5-trifluorophenylacetic acid (30 g), tetrahydrofuran (360 mL), 1,1-carbonyl diimidazole (25.5 g) at about 50° C., and meldrums acid (22.7 g) are combined. The mixture is stirred for about five hours at the same temperature. The reaction mass is then cooled to about 30° C. Isopropyl acetate (180 mL) and water (180 mL) are added and stirred for about 30 minutes. The reaction mass is cooled to about 0° C. and pH is adjusted to about 2.4 using 36% aqueous hydrochloric acid. The organic layer is separated, washed with 0.1 N aqueous hydrochloric acid and distilled off completely. To the residue obtained, n-heptane (140 mL) and isopropyl acetate (70 mL) are charged at about 30° C. and stirred at about 0° C. for about 90 minutes. The separated solid is filtered and washed with a mixture of n-heptane (20 mL) and isopropyl acetate (10 mL). The wet cake is dried at about 50° C. for about 4 hours to afford the title compound. (Yield: 60.1%; purity by HPLC: 98.0%)
Reaction SMILES: Cl.Cl.Cl.[CH:4]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:22][C:23]#[N:24])[CH2:21][NH:20][CH2:19]4)[CH:17]=3)[N:10]3[CH:25]=[CH:26][N:27]=[C:9]3[CH:8]=2)[CH2:6][CH2:5]1.C(#N)C.FC(F)(F)S(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>O>[CH:4]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:22][C:23]#[N:24])[CH2:21][N:20]([CH2:37][C:38]([F:41])([F:40])[F:39])[CH2:19]4)[CH:17]=3)[N:10]3[CH:25]=[CH:26][N:27]=[C:9]3[CH:8]=2)[CH2:6][CH2:5]1
Reactant: N#CCC1(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: O
Product: N#CCC1(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Reaction time: 15 h
Yield: 59.9 %

Procedure:
To a mixture of 2-(3-(4-(7-cyclopropylimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile trihydrochloride (100 mg; 0.233 mmol) and acetonitrile (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (108 mg; 0.466 mmol) and TEA (118 mg; 1.17 mmol). The mixture was stirred in a sealed vial for 15 hours. Water (40 mL) was added and the mixture was extracted into methylene chloride (3×30 mL). The combined extracts were dried (sodium sulfate and magnesium sulfate), filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with methylene chloride/6% ammonium hydroxide in methanol (98:2-96:4 gradient) to give the desired product as a white foam (56 mg). MS (apci) m/z=402.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN([CH:22]=[N:23][NH:24][C:25](OCC)=[O:26])C.CC(O)C>S1CCCC1>[O:26]=[C:25]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:22]=[N:23][NH:24]1
Reactant: CCOC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: CCOC(=O)NN=CN(C)C
Solvent: CC(C)O
Solvent: C1CCSC1
Product: CCOC(=O)N1CCN(c2ccc(-n3cn[nH]c3=O)cn2)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
A mixture of ethyl 4-(5-amino-2-pyridinyl)-1-piperazinecarboxylate (0.18 mol) and ethyl 2-[(dimethylamino)methylene]hydrazinecarboxylate (0.54 mol) in tetrahydrothiophene, 1,1-dioxide (50 ml) was stirred at 150° C. for 3 hours. The mixture was cooled till 100° C., 2-propanol was added until crystallization. The precipitate was filtered and recrystallized from methanol; yielding 30.5 g ethyl 4-[5-(2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl)-2-pyridinyl]-1-piperazinecarboxylate (53.3%); mp. 220.8° C. (interm. 1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([OH:15])=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][CH:13]([OH:15])[C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Product: CC(C)(C)c1ccc(C#CC(O)C#Cc2ccc(C(C)(C)C)cc2)cc1

Procedure:
In the first stage, (A) 4-tert-butylphenylacetylene, organic magnesium halide, and a formic acid derivative are used, thereby obtaining (B) 1,5-bis(4-tert-butylphenyl)-penta-1,4-diyn-3-ol.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6].[CH:15]([NH2:18])([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([NH:18][CH2:2][CH2:3][N:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6])([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: O=C1C(=O)N(CCBr)c2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NCCN1C(=O)C(=O)c2ccccc21

Procedure:
A solution of 4.00 g of 1-(2-bromoethyl)isatin and 13.5 ml of isopropylamine in 160 ml of dry N,N-dimethylformamide was stirred for 1 hour at 80° C. The solution was concentrated under reduced pressure and the residue was dissolved in 50 ml of a 2N-hydrochloric acid. The solution was washed with ethyl acetate, neutralized by adding an aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 3.11 g of 1-(2-isopropylaminoethyl)isatin in an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([OH:45])[CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[O:17])[O:5][CH2:6][C:7]([O:9]C)=[O:8].[Li+].[OH-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([OH:45])[CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)=[CH:27][CH:26]=2)[CH2:22][CH2:23]1)=[O:17])[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
Methyl 2-(3-fluoro-4-{[({4-[4-(2-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)amino]methyl}phenoxy)acetate (0.107 g, 0.2 mmol) was dissolved in tetrahydrofuran. To this solution was added 1N LiOH (2 mL, 0.2 mmol) and stirred at ambient temperature for four days. The solvent was removed in vacuo and the resulting solid lyophilized to yield the title compound (0.075 g, 0.1 mmol).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccccc1I
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A suspension of 2-iodoanisol (3.00 g, 12.8 mmol), 3-chlorophenylboronic acid (2.41 g, 15.4 mmol), and potassium carbonate (3.54 g, 25.6 mmol) in water (10 mL) and methanol (50 mL) was purged with a nitrogen stream for 20 min. To the suspension was added palladium(II) acetate (57.6 mg, 0.2564 mmol) and the solution was stirred at room temperature overnight (18 h). To the reaction was added ethyl acetate (100 mL) and water (100 mL). The layers were separated, the aqueous layer extracted with ethyl acetate (100 mL), and the organic extracts were combined. The organic solution was washed with water (2×150 mL) and brine (150 mL), decolorized with activated charcoal, dried over sodium sulfate, and the solvent removed under reduced pressure. The resulting residue was purified by flash silica gel column chromatography eluting with 10-30% ethyl acetate in hexanes to give I-16 (2.50 g, 89% yield) as colorless oil. 1H NMR (400 MHz CDCl3) 7.53 (t, J=1.8 Hz, 1H), 7.40 (dt, J=7.2 Hz, 1.6 Hz, 1H), 7.38-7.28 (m, 4H), 7.05-6.97 (m, 2H), 3.82 (s, 3H).