Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:25])[CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)[Cl:27]>O1CCCC1.S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:25])[CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([Cl:27])=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCC(=O)Cl)cc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
1.15 g 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetic acid are dissolved in a mixture of 7 ml of methylene chloride and 7 ml of tetrahydrofuran, and 2.2 ml of thionyl chloride are added thereto. After the mixture is refluxed for 2 hours, the solvent is distilled off to give 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetyl chloride as ocherous oil. The product obtained above is dissolved in 10 ml of tetrahydrofuran. The solution and 6 ml of 0.6N an aqueous sodium hydroxide solution are added dropwise to a mixture of 787 mg of 6-aminohexanoic acid, 11 ml of 0.6N an aqueous sodium hydroxide solution, 20 ml of ethanol and 10 ml of ether under stirring at the same time. After the mixture is stirred at room temperature overnight, 50 ml of water and 50 ml of ether are added thereto. The aqueous layer is made acidic with 10% hydrochloric acid, extracted with ethyl acetate, washed, dried, filtered, and evaporated to remove the solvent. Thus obtained pale yellow caramel is purified by silica gel column chromatography (solvent; chloroform, then chloroform: methanol=9:1) to give 1.50 g of 6-{ 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetylamino}-n-hexanoic acid as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:10][CH:9]=1)=[O:7]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)=[O:7]
Reactant: COCCNC(=O)c1ccc(/C=C/C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCNC(=O)c1ccc(CCC(=O)O)cc1

Procedure:
A solution of (E)-benzyl 3-(4((2-methoxyethyl)carbamoyl)phenyl)acrylate (1.0 g, 3.38 mmol) in ethanol (50 ml) is hydrogenated over 10% Pd/C (100 mg) at 50 psi for 24 h. The catalyst is removed by filteration and the solvent removed under vacuum to give 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid as a clear oil that solidifies on standing. MS (ESI) 251 (M+), 1H NMR (CDCl3); 1.24 (t, 3H, J=6.8 Hz), 2.686 (t, 2H, J=7.2 Hz), 3.00 (t, 2H, J=7.2 Hz), 3.39 (s, 3H), 3.57 (t, 2H, J=5.2 Hz), 3.63 (t, 2H, J=5.2 Hz), 3.69-3.74 (m, 1H), 7.27 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz). A mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (400 mg, 0.8 mmol), 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid (251 mg, 1.0 mmol) and TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) (321 mg, 1.0 mmol) and diisopropyl amine (0.42 ml) are dissolved in DMF (20 mL) and stirred for 12 h at 23° C. The mixture was poured into water and extracted with ethyl acetate (3×, 50 mL). The ethyl acetate layer is washed with saturated sodium bicarbonate, 1 N HCl then dried over sodium sulfate and concentrated to give a tan oil. The oil was purified by silica gel chromatography using 10% methanol in dichloromethane with 0.1% NH4OH as eluant to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-(2-methoxyethyl)benzamide (1) as a tan solid, 250 mg (43%). MS (ESI) 733 (M+); 1H NMR (CDCl3) 2.53 (d, 2H, J=6.8 Hz), 2.89 (d, 2H, J=6.8 Hz), 3.23 (s, 3H), 3.37 (s, 3H), 3.54-3.55 (m, 2H), 3.56-3.62 (m, 2H), 4.21 (s, 3H), 5.29-5.28 (m, 2H), 5.67 (s, 2H), 6.31-6.37 (m, 1H), 6.42-6.55 (m, 1H), 6.75-6.85 (m, 2H), 6.89-6.92 (m, 1H), 7.02-7.08 (m, 1H), 7.15-7.28 (m, 6H), 7.45-7.46 (m, 1H), 7.51-7.59 (m, 1H), 7.67-7.69 (m, 1H), 8.55-8.58 (m, 1H).
Reaction SMILES: BrCCC1C=CC=CC=1.[ClH:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][C:39]4[CH:48]=[C:47]5[C:42]([CH:43]=[CH:44][C:45](=O)O5)=CC=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[ClH:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][C:48]4[CH:47]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:36][CH2:37]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: BrCCc1ccccc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(CCc4ccccc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 2-bromoethylbenzene and starting compound A1 as described for compound 18. M. p. 216-217° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[N:7]([C:16]([O:18]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O.[C:25]1([C:31]2[N:32]=[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[S:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[NH:7][C:16]([N:39]1[CH2:40][CH2:41][N:36]([C:33]2[S:34][CH:35]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:32]=2)[CH2:37][CH2:38]1)=[O:18]
Reactant: Cc1noc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)c1Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)c1Cl

Procedure:
A solution of bis(2,2,2-trichloroethyl) (4-chloro-3-methylisoxazol-5-yl)imidodicarbonate (200 mg, 0.418 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (204 mg, 0.836 mmol), diisopropylethylamine (0.144 ml, 0.836 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (123 mg, 73.2%) as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:16](=[CH:17][CH:18]=1)[C:8]1[N:9]([CH2:12][CH:13]([NH2:15])[CH3:14])[N:10]=[CH:11][C:7]=1[CH2:6]2.[B-](Br)(Br)(Br)[S+](C)C.C1COCC1.C([O-])(O)=O.[Na+]>ClCCCl>[NH2:15][CH:13]([CH3:14])[CH2:12][N:9]1[C:8]2[C:16]3[C:5]([CH2:6][C:7]=2[CH:11]=[N:10]1)=[CH:4][C:3]([OH:2])=[CH:18][CH:17]=3
Reactant: COc1ccc2c(c1)Cc1cnn(CC(C)N)c1-2
Agent: C[S+](C)[B-](Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(N)Cn1ncc2c1-c1ccc(O)cc1C2
Yield: 13.3 %

Procedure:
To a solution of the product from Step D (0.56 g, 0.23 mmol) in 1,2-dichloroethane (10 mL) was added boron tribromide-methylsulfide complex in THF solution (1.0M, 0.5 mL, 0.5 mmol) and the solution heated to reflux for 16 h. The solution was allowed to cool, poured into aqueous NaHCO3, extracted with chloroform (2×20 mL), dried (Na2SO4) and concentrated. The crude product was purified by chromatography (silica, 20% methanol in dichloromethane) to give a solid (0.007 g, 13%): 1H NMR (CDCl3) δ7.39 (m, 2H), 7.00 (s, 1H), 6.79 (dd, J=8.4, 2.4 Hz, 1H), 4.30 (dd, J=13.8, 4.8 Hz, 1H), 4.14 (dd, J=13.8,7.8Hz, 1H), 3.55 (m, 1H), 3.48 (bm, 4H), 1.19 (d, J=6.6 Hz, 3H); MS m/z 230 [M+H]+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=3[CH3:69])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:68][C:64]1[C:63]([CH3:69])=[C:62]([N:59]2[C:55]3[N:56]=[CH:57][N:58]=[C:53]([O:52][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=4)=[O:43])[C:54]=3[CH:61]=[N:60]2)[CH:67]=[CH:66][CH:65]=1
Reactant: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(F)c2C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3-c2cccc(F)c2C)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (1.504 mL, 1.50 mmol) was added dropwise to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AF2) (430 mg, 0.61 mmol) in THF (15 mL) over a period of 1 minute and the resulting solution stirred at ambient temperature for 3 hours. Saturated ammonium chloride (20 mL) was added to the reaction mixture which was then diluted with EtOAc (25 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 60 to 100% EtOAc in isohexane then by chiral HPLC to afford the product (160 mg, 56%). 1H NMR (400 MHz, DMSO) δ 1.99 (3H, d), 2.24 (3H, s), 3.50-3.56 (2H, m), 3.58-3.68 (2H, m), 4.00-4.05 (1H, m), 4.08-4.13 (1H, m), 4.61 (1H, t), 5.91-5.96 (1H, m), 7.30-7.33 (1H, m), 7.40-7.51 (2H, m), 7.57-7.60 (1H, m), 7.85-7.88 (1H, m), 8.17-8.18 (1H, m), 8.54 (1H, s), 8.61 (1H, s), 10.85 (1H, s); m/z (ESI+) (M+H)+=467; HPLC tR=1.98 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[NH2:31])O1>COCCOC.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>[NH2:31][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:25]=1[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: Cc1nc(Cl)cc(NC(=O)OC(C)(C)C)n1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)n1
Yield: 26 %

Procedure:
Method 26 was followed using tert-butyl 6-chloro-2-methylpyrimidin-4-ylcarbamate (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (3.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.) in DME/2M Na2CO3 (3:1, 0.07M) at 80° C. for 30 min. Purification via SiO2 column chromatography eluting with EtOAc afforded tert-butyl 6-(3-aminopyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate in 26% yield. LCMS (m/z): 302.1 (MH+); LC Rt=2.23 min.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[N:24][CH:25]=1.CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Reaction time: 15 h
Yield: 95.8 %

Procedure:
Sodium hydride (60%, oily, 310 mg) was added to a mixture of methyl 4-phenyl-3-pyrrolcarboxylate (1.20 g), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (1.88 g), and N,N-dimethylformamide (50 ml) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-1H-pyrrol-3-carboxylate (2.74 g, yield: 96%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=[CH:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1>C1COCC1.[Pt]>[CH3:1][O:2][CH:3]1[CH:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6][N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1
Reactant: COC1CN(Cc2ccccc2)CCC1=COCc1ccccc1
Agent: [Pt]
Solvent: C1CCOC1
Product: COC1CN(Cc2ccccc2)CCC1COCc1ccccc1
Yield: 59.6 %

Procedure:
A mixture of intermediate (3a) (0.043 mol) in THF (250 ml) was hydrogenated with platinum on activated carbon (5%) (3 g) as a catalyst. After uptake of H2 (1equiv.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by high-performance liquid chromatography over LiChroprep RP-18® (750 g; 8 cm; DAC column; eluent A: (0.5% NH4OAc in H2O)/CH3OH 75/25; eluent B: CH3CN; step gradient). The pure fractions were collected and the solvent was evaporated, yielding 8.34 g (59.6%) of (±)-3-methoxy-4-[(phenylmethoxy)methyl]-1-(phenylmethyl)-piperidine (interm. 3b).
Reaction SMILES: [C:1]1([C:7](C2C=CC=CC=2)=[N:8][NH:9][C:10]2[C:15]3[O:16][C:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:14]=3[CH:13]=[C:12]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:11]=2)[CH:6]=CC=CC=1.COC(OC)CC(OC)OC.Cl>C(O)C>[C:33]1([S:30]([C:12]2[CH:11]=[C:10]([N:9]3[CH:6]=[CH:1][CH:7]=[N:8]3)[C:15]3[O:16][C:17]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]=4[C:14]=3[CH:13]=2)(=[O:31])=[O:32])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(NN=C(c4ccccc4)c4ccccc4)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1ccccc1)c1cc(-n2cccn2)c2oc3c(c2c1)CNCC3
Temperature: 100 °C
Yield: 60.6 %

Procedure:
A mixture of the product of step B (65 mg, 0.10 mmol), 1,1,3,3-tetramethoxypropane (18 μL, 0.11 mmol) and concentrated HCl (0.25 mL) was dissolved in ethanol (5 mL). The reaction flask was purged with argon, sealed and heated at 100° C. for 5 h. The reaction mixture was cooled to ambient temperature, quenched with 10% sodium bicarbonate solution, and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 93:7 dichloromethane/methanol) to give 8-(phenylsulfonyl)-6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (23 mg, 56%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.48 (dd, J=2.8, 0.4 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.03-7.97 (m, 2H), 7.93 (d, J=1.6 Hz, 1H), 7.82-7.77 (m, 1H), 7.58-7.45 (m, 3H), 6.53 (dd, J=2.4, 2.0 Hz, 1H), 4.01 (t, J=2.0 Hz, 2H), 3.27 (t, J=5.6 Hz, 2H), 2.90-2.81 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[N+]([O-])=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:3])[CH3:2].[CH3:18][S-:19].[Na+].[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[S:19][CH3:18])[C:8]([O:10][CH3:11])=[O:9])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc(SC)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
A solution of methyl 3-isopropoxy-4-nitrobenzoate (5.7 g) in N,N'-dimethylimidazolidinone (35 mL) is treated with sodium thiomethoxide (2 g), and the mixture is stirred at room temperature for 4 hours. The mixture is then diluted with water (250 mL) containing sodium chloride (47 g), and is extracted with ethyl acetate (2×100 mL). The combined organic extracts are washed with brine (100 mL), dried over magnesium sulfate and evaporated in vacuo, to give a brown oil. The oil is subjected to flash chromatography, eluting with a 1.9 v/v mixture of diethyl ether and pentane, to give methyl 3-isopropoxy-4-(methylthio)benzoate (4.0 g), in the form of a cream solid, m.p. 41°-43° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:25][CH:21]3[CH2:24][CH2:23][CH2:22]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NC4CCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (90 mg, 0.34 mmol) was reacted with cyclobutanamine (CAS-2516-34-9) (48 mg, 0.68 mmol), HATU (146 mg, 0.38 mmol) and DIPEA (0.3 mL, 1.7 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-cyclobutylbenzamide 19. LC/MS (ESI+): m/z 320 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (d, J=7.4 Hz, 1H), 8.70 (s, 1H), 8.59 (t, J=12.2 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (d, J=33.2 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 4.48 (dq, J=16.3, 8.2 Hz, 1H), 2.37-2.22 (m, 2H), 2.22-1.99 (m, 2H), 1.79-1.60 (m, 2H).
Reaction SMILES: C(OP([C:9]([Cl:12])([Cl:11])Cl)(=O)OCC)C.[CH2:13]([O:15][C:16]([CH:18]1[CH:20]([CH:21]=O)[C:19]1([CH3:24])[CH3:23])=[O:17])[CH3:14].[Mg]>CN(C)C=O>[CH2:13]([O:15][C:16]([CH:18]1[CH:20]([CH:21]=[C:9]([Cl:11])[Cl:12])[C:19]1([CH3:23])[CH3:24])=[O:17])[CH3:14]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)Cl
Agent: [Mg]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 25.5 g (0.1 mole) of trichloromethanephosphonic acid diethyl ester and 17.2 g (0.1 mole) of 3-formyl-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was added dropwise to 9.6 g of activated magnesium filings in 100 ml of dimethylformamide in a manner such that the reaction temperature did not exceed 60° C. When the exothermic reaction had ended, the reaction mixture was allowed to cool to room temperature. It was then filtered. 200 ml of water were added to the filtrate; this solution was extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride extracts were dried over sodium sulphate and filtered. The filtrate was distilled. 3-(2,2-Dichloro-vinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was obtained in a yield of 60% of theory.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][NH:18][C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:17][NH:18][C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:26][CH2:25]2)=[N:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)c1nc(N2CCNCC2)sc1NC
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)sc1NC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (16 μl, 0.18 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of ethyl 5-methylamino-2-piperazin-1-yl-thiazole-4-carboxylate hydrochloride (41 mg, 0.15 mmol) and DIPEA (79 μl, 0.45 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters Xbridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 7 mg of a solid (0.017 mmol, 11%).
Reaction SMILES: [C:1]([C:3]([C:24]#[N:25])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22]O)[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2].C(N(S(F)(F)[F:32])CC)C>C(Cl)Cl>[C:1]([C:3]([C:24]#[N:25])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:32])[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2]
Reactant: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCOCCO)ccc2c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCOCCF)ccc2c1
Yield: 60 %

Procedure:
0.20 g (0.6 mmol) of the fifth compound 5 is obtained to be dissolved in 10 mL of anhydrous methylene chloride. 0.16 mL (1.2 mmol) of (diethylamino)sulfur trifluoride (DAST) is added at 0° C. for reaction at a room temperature for 16 hrs. After the reaction is completed, extraction is processed with water and dichloromethane. An organic phase is collected with water removed by sodium sulfate and is concentrated under reduced pressure to be separated and purified by liquid chromatography. Thus, the final product 6,2-(1,1-dicyanopropen-2-yl)-6-{[2-(2-fluoro-ethoxy)-ethyl]methylamino}naphthalene, is obtained, which has a weight of 0.12 g and a yield of 60.0%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:10]CCCO1.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(#N)C.C(O)C>[ClH:1].[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][C:5]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[O:10])[CH2:22][CH2:23]2)=[N:25]1
Reactant: Fc1ccc(C2(CCCCl)OCCCO2)cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CC#N
Product: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
Title product hydrochloride. A mixture of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxane (4.31 g., 0.0176 mole), 3-(1-piperazinyl)-1,2-benzisothiazole (3.86 g., 0.0176 mole), powdered potassium carbonate (2.43 g., 0.0176 mole) and potassium iodide (0.88 g., 0.0053 mole) in 180 ml. of dry acetonitrile is refluxed for a 20 hr. period. The reaction mixture is filtered, concentrated in vacuo and residual oil dissolved in chloroform and filtered. Concentration of the filtrate affords an oily residue which is taken up in 100 ml. of ethanol containing 10 ml. of 3 N hydrochloric acid and refluxed for 15 min. period. Acetonitrile is added to the cooled mixture and the solid obtained collected, 3.3 g. m.p. 248°-250° C. Crystallization of this material from ethanol affords analytically pure 4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone hydrochloride, m.p. 251°-254° C.