Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)([CH2:10]3)[CH2:8]2)(=O)=O.C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CN(C=O)C.O>[CH3:21][C:16]1([C:9]23[CH2:10][CH:11]4[CH2:15][C:7]([CH2:6][N:28]5[CH:32]=[N:31][CH:30]=[N:29]5)([CH2:14][CH:13]2[CH2:12]4)[CH2:8]3)[O:17][CH2:18][CH2:19][O:20]1
Reactant: c1nc[nH]n1
Reactant: CC1(C23CC4CC2CC(COS(C)(=O)=O)(C4)C3)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C23CC4CC2CC(Cn2cncn2)(C4)C3)OCCO1
Temperature: 110 °C
Yield: 83.9 %

Procedure:
A stirred mixture of [3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methyl methanesulfonate (2.4 g, 7.5 mmol) [as obtained from preparation 2], K2CO3 (4.5 g, 34.2 mmol), and 1,2,4-triazole (1.5 g, 22.5 mmol) in DMF (30 mL) was heated to 110° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethylacetate. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain 1-{[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methyl}-1H-1,2,4-triazole (1.82 g) as a viscous liquid in 85% yield. m/z (M+1) 290; IR cm−1 2932, 1668, 1506, 1441, 1373, 1311, 1211, 1140, 1047, 876, 753. 1H NMR (CDCl3) 300 MHz δ 7.99 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 4.03-3.92 (m, 4H), 2.42-2.32 (m, 2H), 1.86-1.79 (m, 1H), 1.74-1.65 (m, 2H), 1.52-1.37 (m, 8H), 1.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[C:18]([O-])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].[Na+]>CCOCC>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH2:12][O:26][CH2:18][C:19]2[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=2)[OH:21])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1O
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)OCCCl
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)OCCOCc1ccccc1O

Procedure:
50 g (0.18 mole) of 1-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-chloro-ethane are mixed with 43.3 g (0.27 mole) of sodium salicylate. The mixture is heated to 195° for 8 hours. The products are taken up in ether, and NaCl is removed by filtration. The diester crystallizes quantitatively from the ether solution.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([CH2:18]OS(C)(=O)=O)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([CH2:18][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2COS(C)(=O)=O
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-benzyloxy-5-methyl-7-methylsulfonyloxymethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (57 mg, 0.14 mmol) in anhydrous DMF under an atmosphere of nitrogen was added piperidine (133 μL, 1.35 mmol). The reaction was stirred at room temperature for 2 hours, heated to 50° C. for 2 hours, and stirred at room temperature overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product as a yellow residue. ES MS (M+H)=413.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:21]([CH:25]=2)[C:22]([OH:24])=O)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:21]([CH:25]=2)[C:22]([NH:40][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)=[O:24])(=[O:16])=[O:15])[CH2:12][CH2:13]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.03 ml, 0.31 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 5-[(4-methyl-1-piperazinyl)sulfonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 72; 120 mg, 0.31 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated to give crude acyl chloride. A solution of this acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (28.9 mg, 0.31 mmol) and diisopropylethylamine (0.05 ml, 0.31 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give crude product as an orange oil. The crude product was crystallized from methanol to yield the title compound as a white solid. 30 mg.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[N:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:13]([NH:35][CH2:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:15])=[C:3]([CH3:16])[N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: NCCCN1CCOCC1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCCCN3CCOCC3)c(C)n(C)c2c1
Yield: 59 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.483 g, 2.20 mmole) with 2.0 M oxalyl chloride in CH2Cl2 (2.2 ml, 4.4 mmole) and 3-morpholin-4-ylpropylamine in a manner as previously described for example 16d to give a white solid (0.445 g, 59%). 1H NMR (300 MHz, CDCl3) δ7.60 (1H, d, J=8.6 Hz), 6.82 (1H, dd, J=2.3, 8.6 Hz), 6.77 (1H, d, J=2.3 Hz), 6.71 (1H, s), 3.87 (3H, s), 3.62 (3H, s), 3.57 (6H, m), 2.69 (3H, s), 2.50 (2H, t, J=6.6 Hz), 2.43 (4H, m), 1.81 (2H, m); ESIMS (MH+): 346.20.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][CH:15]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>O1CCCC1>[F:13][C:14]1[C:15]([B:28]([OH:33])[OH:29])=[CH:16][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:18][N:19]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(c1ccc(F)nc1)N1CCOCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A stirred solution of diisopropylamine (2.152 mL, 15.35 mmol) in tetrahydrofuran (20 mL) was treated with n-butyllithium 1.6M in Hexanes (9.60 mL, 15.35 mmol) at −40° C. The yellow solution was stirred at the same temperature for 1 h and then cooled to −78° C. A solution of 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (2.69 g, 12.79 mmol) in THF (15 mL) was added via cannula over 20 min. The deep-red mixture was stirred at the same temperature for 1.5 h. Then a solution of triisopropyl borate (4.41 mL, 19.19 mmol) in THF (10 mL) was added slowly into the mixture. The resulting mixture was stirred at the same temperature for 30 min and then the cooling bath was removed. After the reaction mixture had warmed to room temperature, the tan mixture was quenched with 1 N NaOH (aq) (15 mL) and stirred. The separated aqueous layer was removed and the flask was rinsed with 1 N NaOH (aq) (2×20 mL) and the organic layer was extracted with 1 N NaOH (2×10 mL). The aqueous layer was collected and carefully acidified with 5N HCl until acidic (pH 5 about 6) and the resulting cloudy mixture was extracted with EtOAc (3×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The product remained in the aqueous layer. The aqueous layer was frozen and the water removed by lyophilization. The mixture was diluted with 1:1 MeOH/DCM and placed into a sonicator for 5 min. The mixture was filtered through a fine-fritted funnel and the filtrate was concentrated in vacuo to give 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (3.120 g, 12.28 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 8.00 (dd, J=8.22, 2.54 Hz, 1H) 7.88 (d, J=2.35 Hz, 1H) 3.68 (t, J=4.69 Hz, 4H) 3.40-3.54 (m, 1H) 2.56 (d, J=10.76 Hz, 2H) 2.35-2.50 (m, 2H) 1.41 (t, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 255.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.[Cu]I>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:20][S:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:11][CH:10]=1
Reactant: NCCCc1ccc(N)cc1
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(CCCNc2ncnc3scc(-c4ccc(F)cc4)c23)cc1
Yield: 30 %

Procedure:
4-(3-aminopropyl)aniline (0.034 g, 0.23 mmol) was added to a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (0.04 g, 0.15 mmol), copper(I) iodide (0.009 g, 0.04 mmol) and potassium carbonate (0.0626 g, 0.453 mmol) in N,N-dimethylacetamide (3 mL) and the resulting mixture was subjected to microwave radiation at 140° C. for 4 hours. The solvent was then removed by evaporation, and the residue was dissolved in ethyl acetate (50 mL), filtered, and the organics were washed with a saturated solution of sodium bicarbonate (30 mL). Concentration and purification by silica gel column chromatography (using 1-3% methanol, 0.06% ammonia in 1:1 ethyl acetate/hexane) afforded N-[3-(4-aminophenyl)propyl]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine as a white solid in 30% yield.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[C:15]([O:21][CH3:22])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[C:32]([O:31][CH3:30])=[CH:37][N:36]([CH3:38])[C:35](=[O:39])[CH:34]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:15]([O:21][CH3:22])=[N:16][CH:17]=1
Reactant: COc1cn(C)c(=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ncc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1cn(C)c(=O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)cnc1OC)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-2-methoxy-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BF) and 5-methoxy-1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (Intermediate AR) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. ESI-MS: tR=1.09 min, [M+H]+ 553/555/557 (LC-MS 1).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:2]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:4])[CH3:3]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2ncccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccccc2)c2ncccc12
Reaction time: 4.5 h
Yield: 57.1 %

Procedure:
27 g of 5-acetyl-8-hydroxyquinoline hydrochloride are dissolved in 540 ml of anhydrous dimethylformamide and 50 g of powdered potassium carbonate are added thereto. 18.4 g of benzyl chloride are added to the mixture at 50° C. under an argon atmosphere, and the mixture is stirred at the same temperature for 4.5 hours and then further stirred at room temperature for 1.5 hours. After the reaction, water is added to the mixture, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, a saturated sodium chloride solution, dried and then evaporated under reduced pressure to remove ethyl acetate. The residue is recrystallized from ethanol. 19.1 g of 5-acetyl-8-benzyloxyquinoline are obtained as brownish prisms. 6.35 g of said product are further recovered from the mother liquor.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.[Na+].[I-:16]>CC(=O)CC.CCOCC>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(CCCCCl)CCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1(CCCCI)CCC1
Yield: 99.4 %

Procedure:
To a solution of ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (21.21 g, 97.0 mmol) in 2-butanone (125 mL) was added NaI (19.07 g, 127 mmol). The reaction mixture was stirred under reflux for 20 h and diluted with Et2O (500 mL). The resulting mixture was washed with aqueous Na2S2O3 (10% (w/w), 250 mL), brine (250 mL), dried (Na2SO4) and evaporated in vacuo to give ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (29.91 g, 99%) as a slightly yellow oil. 1H NMR (CDCl3): δ=4.14 (q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ=176.5, 60.3, 47.5, 36.9, 33.7, 30.1 (2×), 26.0, 15.7, 14.5, 6.8. HRMS calcd for C11H20IO2 (MH+): 311.0508, found: 311.0511.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:23][CH:22]3[CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)=[O:15])=[CH:4][CH:3]=1.CN(C=O)C.Cl[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:37][C:32]1[N:31]=[C:30]([N:20]2[CH2:19][CH:18]3[CH:22]([CH2:23][N:16]([C:14]([C:9]4[N:10]=[C:11]([CH3:13])[S:12][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:15])[CH2:17]3)[CH2:21]2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: Cc1nc(C(=O)N2CC3CNCC3C2)c(-c2ccc(F)cc2)s1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CC3CN(C(=O)c4nc(C)sc4-c4ccc(F)cc4)CC3C2)nc(C)n1
Temperature: 100 °C
Yield: 61.4 %

Procedure:
To a solution of Intermediate 48 (15.8 mg, 0.048 mmol) was added DMF (0.4 mL), 4-chloro-2,6-dimethylpyrimidine (8.2 mg, 0.057 mmol) and cesium carbonate (38.8 mg, 0.119 mmol). The mixture was heated to 100° C. for 18 hours, diluted with water and extract with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by reverse phase HPLC to give the title compound (12.9 mg, 62%). MS (ESI): mass calculated for C23H24FN5OS, 437.5; m/z found [M+H]+438.2. 1H NMR (400 MHz, CDCl3): 7.51-7.41 (m, 2H), 7.06-6.95 (m, 2H), 6.29 (s, 1H), 3.892-3.76 (m, 2H), 3.73-3.51 (m, 3H), 3.44 (dd, J=11.6, 5.0 Hz, 1H), 3.32 (dd, J=11.6, 4.5 Hz, 1H), 3.10 (dd, J=11.3, 5.3 Hz, 1H), 3.02-2.80 (m, 2H), 2.70 (s, 3H), 2.31 (d, J=20.0 Hz, 6H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[S:5]([Cl:8])(Cl)=[O:6].[CH:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2>>[C:9]12([S:5]([Cl:8])=[O:6])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: O=S(Cl)Cl
Reactant: C1C2CC3CC1CC(C2)C3
Agent: [Al+3]
Agent: [Cl-]
Product: O=S(Cl)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aluminum trichloride (40 g, 3 mol) was added slowly to thionyl chloride (200 ml, 2.7 mol), and the mixture was cooled to -20°. Adamantane was added in portions over 21/2 hrs, and the resulting mixture was stirred 1 hr and allowed to warm to room temperature. After the thionyl chloride was removed under vacuum, the residue was diluted with CCl4 ; and the aluminum trichloride was decomposed with ice and water. The layers were separated; and the organic layer was washed (brine), dried (Na2SO4), filtered, and concentrated under vacuum. The residue was distilled under vacuum (1 torr, 133.3 Pascals) with a vigreaux column to give the product (28.8 g; bp 118°-128°) as a waxy solid; TLC, Rf =0.6-0.4, EtOAc:hexanes (15:85).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.Cl.Cl.[CH3:41][N:42]([CH3:47])[CH:43]1[CH2:46][NH:45][CH2:44]1.CN(C)C1CNC1>CC(N(C)C)=O>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:45]3[CH2:46][CH:43]([N:42]([CH3:47])[CH3:41])[CH2:44]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
DIPEA (0.341 mL, 1.96 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 20, 254 mg, 0.61 mmol) and N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 106 mg, 0.61 mmol) in DMA (4 mL) and the mixture was heated to 100° C. for 0.5 h. Further N,N-dimethylazetidin-3-amine (35 mg, 0.19 mmol) was then added and the mixture was heated at 100° C. for a further 2 h and was then left at r.t. overnight. The mixture was purified directly by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (310 mg, 102%) as an orange solid, which was used without further purification; 1H NMR: 2.14 (6H, s), 3.08-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.02-4.11 (2H, m), 6.28 (1H, s), 7.12 (1H, td), 7.30-7.39 (1H, m), 8.12 (1H, s), 8.37 (1H, br s), 8.42 (1H, s), 8.68 (1H, s), 8.83 (1H, d), 8.94 (1H, d); m/z: ES+ MH+ 495.56.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(Cl)cnn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a mixture of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (30.6 g, 120 mmol), prepared as described in Example 244A, 4-chlorophenyl boronic acid (20.6 g, 132 mmol) and tetrakis(triphenylphosphine)palladium (5 g, 4.3 mmol) in toluene (300 mL) under an atmosphere of argon, and was added an aqueous Na2CO3 solution (2M, 66 mL, 132 mmol). The reaction mixture was stirred at 100° C. under argon for 16 h. The reaction was then allowed to cool to RT and was subsequently poured into water (200 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained thick syrup was dissolved in MeOH (100 mL) and the resulting solution kept at 0° C. until white solid precipitated. The solid was collected by filtration, washed with hexanes, and then triturated with EtOAc-hexanes to give the title compound, 2-benzyl-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one (12 g, 30%) as a white powder. LC/MS (method A, general procedure): RT=3.81 min, (M+H)+=331.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH:29]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:29]([N:42]1[CH2:47][CH2:46][N:45]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(c5ccccc5)c5ccccc5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
In DMF (3ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150mg), and to the solution were added 1-benzhydrylpiperazine (127mg) and potassium carbonate (268mg). The mixture was stirred at room temperature for 24 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone-diisopropylether to give N-[4-(4-benzhydryl-1-piperazinyl-methyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 43) (140mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15].COC1C=C2C(CCN(S(Cl)(=O)=O)C2)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([S:14]([Cl:17])(=[O:16])=[O:15])[CH2:8][C:7]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CNCCO2
Reactant: O=S(=O)(Cl)Cl
Agent: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2

Procedure:
This compound was prepared from 1.4 g of 7-methoxy-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine, 0.91 mL of sulfuryl chloride and 4.7 mL of triethylamine using the procedure described for 63f. Yield: 0.23 g (oil), EI-MS: 277 (M+).