Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:37]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]1.CO.[ClH:40]>O1CCOCC1>[ClH:1].[ClH:40].[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:37]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1cnc2nc1Nc1ccc(OCC3CCNC3)c(c1)CCc1cncc(c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Into the reaction was added tert-butyl 3-({[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)pyrrolidine-1-carboxylate (0.024 g, 0.046 mmol), methanol (0.5 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (0.5 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product (19 mg, 92%). LCMS for C22H24ClN6O (M+H)+: m/z=423.2.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)nc2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)nc2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
To solution of tert-butyl 4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound 51.2, 600 mg, 1.98 mmol, 1.00 equiv) in pyridine (15 mL) under nitrogen at 10-15° C. was carefully added POCl3 (3 g, 19.74 mmol, 9.97 equiv). After stirring overnight under nitrogen in a water/ice bath, the mixture was concentrated and the residue was dissolved in 50 mL of ethyl acetate. The organic phase was washed with 1×50 mL of hydrogen chloride (aq. 1M) followed by 1×50 mL of sodium bicarbonate (aq.sat.). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as the eluent to yield 0.26 g (46%) of the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]([F:19])([F:18])[F:17].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:15]2[C:10]([C:11]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:13]=[CH:14]2)=[N:9]1
Reactant: Cc1ccccc1B(O)O
Reactant: FC(F)(F)c1cccc2c(-c3ccccn3)[nH]nc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1-n1nc2c(C(F)(F)F)cccc2c1-c1ccccn1

Procedure:
A solution of 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole (0.2633 g, 1 mmol), 2-methylphenylboronic acid (0.271 g, 2 mmol, copper(II)acetate (0.181 g, 1 mmol) and pyridine (0.161 mL, 2 mmol) in 20 mL of methylene chloride was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel 60, methylene chloride-ethyl acetate, 3:1) to give the title compound (0.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:9]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10][NH:11][C:12]=2[C:13]([O:15]CC)=O)=[O:7])=[C:4]([NH2:28])[CH:3]=1.CN1CCCC1=O.C([O-])(=O)C.[NH4+]>O>[C:18]([C:9]1[C:8]2[C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[NH:28][C:13](=[O:15])[C:12]=2[NH:11][N:10]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 160 °C
Yield: 5.6 %

Procedure:
A solution of ethyl 4-(4-chloro-2-aminobenzoyl)-3-benzoyl-1H-pyrazole-5-carboxylate (620 mg, 1.56 mmol), 1-methyl-2-pyrrolidinone (4 mL) and ammonium acetate (120 mg, 1.56 mmol) was heated at 146° C. for 16.5 hours. The temperature was increased to 160° C. for 1 hour. The solution was allowed to cool to room temperature and water (60 mL) was added. The insoluble material (468 mg) was filtered, dried, and twice subjected to flash chromatography eluting with hexanes:ethyl acetate (90:10-50:50) to give impure product. The crude solid was triturated with ethanol (15 mL), washed with ethanol (3×10 mL) and dried to give the title compound (30.5 mg, 5.6% yield m.p. 370-373° C. dec.).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[O:32]=[C:33]([NH:42][C@H:43]([C:48]([NH:50][CH:51]([CH2:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1)[CH:52]([P:54]([CH2:58]C)([O:56][CH3:57])=[O:55])[OH:53])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[CH:61]1([CH2:60][C@H:51]([NH:50][C:48](=[O:49])[C@H:43]([CH2:44][CH:45]([CH3:46])[CH3:47])[NH:42][C:33](=[O:32])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:52]([P:54]([CH3:58])(=[O:55])[O:56][CH3:57])[OH:53])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: CCP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COP(C)(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Hydroxybenzotriazole (120 mg, 0.784 mmol), diisopropylethylamine (127 μl, 0.728 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (150 mg, 0.784 mmol) were sequentially added to a solution of the title A compound obtained from the previous reaction and the title B compound from Example 17 (176.7 mg, 0.672 mmol) in 3 ml dimethylformamide at 0°. The reaction mixture was warmed and stirred at room temperature for 72 hours after which it was concentrated, then treated with 20 ml pH=4.01 buffer and extracted with ethyl acetate (3×30 ml). Drying and concentration followed by chromatographic purification of the crude product gave 146 mg 52.7%) pure title compound lsomer B, m.p. 188°-207°, [α]D =-71.7° (c=0.545, CH3OH) which was characterized by MS, IR, 1H NMR, 13C NMR and 31P NMR [56.0 ppm w.r.t H3PO4 as external reference, CDCl3, 36.4 MHz].
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:42][CH2:43][CH2:44][CH3:45])[C:12]2[N:17]=[C:16]([C:18]3[CH:39]=[C:38]([CH3:40])[C:21]([O:22][CH2:23][C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[C:20]([CH3:41])[CH:19]=3)[O:15][C:13]=2[N:14]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:42][CH2:43][CH2:44][CH3:45])[C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:41])[C:21]([O:22][CH2:23][C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([OH:33])=[O:32])=[O:25])=[C:38]([CH3:40])[CH:39]=3)[O:15][C:13]=2[N:14]=1
Reactant: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)O)c(C)c3)nc12
Reaction time: 16 h

Procedure:
76 mg of tert-butyl(S)-1-(2-{4-[5-(trans-2-fluorocyclohexyloxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidine-2-carboxylate were dissolved in 1.6 ml of dichloromethane and 0.8 ml of trifluoroacetic acid. After 16 h at room temperature, the mixture was concentrated under reduced pressure and freeze-dried. This gave 83 mg of the title compound.
Reaction SMILES: [CH:1]1([C@@H:4]2[O:16][CH2:15][C:7]3=[N:8][O:9][C@@H:10]([C:11](OC)=[O:12])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.O1CCCC1>[CH:1]1([C@@H:4]2[O:16][CH2:15][C:7]3=[N:8][O:9][C@@H:10]([CH2:11][OH:12])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: OC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of methyl rel-(3R,3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole-3-carboxylate (C36) (3.30 g, 14.6 mmol) in ethanol (30 mL) and tetrahydrofuran (29 mL) was cooled to 0° C. and treated with sodium borohydride (831 mg, 22.0 mmol). The reaction mixture was allowed to warm to room temperature and stir for 20 minutes at that temperature, then was poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification on silica gel (Eluent: 60% ethyl acetate in heptane) afforded the product as an oil. Yield: 1.95 g, 9.89 mmol, 68%. LCMS m/z 198.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 4.67 (br d, J=13.3 Hz, 1H), 4.24-4.31 (m, 1H), 4.13 (d, J=13.3 Hz, 1H), 3.96-4.04 (m, 1H), 3.72 (ddd, J=12.3, 8.8, 3.5 Hz, 1H), 3.38 (ddd, J=10.9, 10.9, 6.6 Hz, 1H), 2.79-2.87 (m, 1H), 2.25 (dd, J=12.9, 6.6 Hz, 1H), 1.80-1.95 (m, 1H), 1.63-1.74 (m, 1H), 0.88-0.99 (m, 1H), 0.50-0.68 (m, 2H), 0.38-0.46 (m, 1H), 0.21-0.29 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O[Li].O>CC(C)=O.O>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(O)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]O
Solvent: CC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cccc(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A suspension of 2-fluoro-3-hydroxybenzoic acid (12.0 g, 76.9 mmol) and potassium carbonate (23.4 g, 169 mmol) in acetone (154 mL) was stirred at ambient temperature for 1 hour. To the mixture was added dimethyl sulfate (21.8 mL, 231 mmol) and the mixture stirred at ambient temperature for 30 minutes then heated at reflux for 4 hours. The mixture was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (154 mL) and the solution cooled to 0° C. in an ice bath. To this solution was added LiOH—H2O (12.9 g, 307 mmol) followed by water (30 mL) and the resulting mixture stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate and the layers separated. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4), filtered and concentrated under reduced pressure to afford 2-fluoro-3-methoxybenzoic acid (12.31 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[H+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[N+:4]#[N:12]
Reactant: O=N[O-]
Reactant: Nc1cc(F)c(F)c(Cl)c1Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cc(F)c(F)c(Cl)c1Cl

Procedure:
To a suspension of 2,3-dichloro-4,5-difluoroaniline (0.88 g) in 42% fluoroboric acid (10 ml) with stirring vigorously was added sodium nitrite (0.43 g) in water (1 ml) at -15° to 0° C. for 14 minutes. After stirred for 3 hours at the same temperature, the resulting precipitate was collected by filtration, washed with 42% fluoroboric acid and then with ether to give the title compound (0.66 g) as white powdery crystals, mp 211° C.-(decompd.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.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].C(O)C.C1(C)C=CC=CC=1>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccsc2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenyl-pyrrolo[3,2-d]pyrimidine (Example 1(e)) (50 mg, 0.21 mmol), thiophene-3-boronic acid (37 mg, 0.287 mmol), tris(dibenzylidene-acetone)dipalladium(0) (Aldrich Chemical Company) (4.7 mg, 0.0051 mmol, 0.025 eq) and triphenylphosphine (Aldrich Chemical Company) (10.8 mg, 0.041 mmol, 0.2 eq) in a mixed solvent (600 μL of toluene, 300 μL of 1.0 M Na2CO3, and 150 μL of ethanol) was heated at reflux under N2 for 17 h. Upon cooling to the room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with CHCl3 (3×20 mL). The organic phase was dried over Na2SO4, filtered and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel a gradient eluant of EtOAc(0-25%):hexanes(100-75%) to afford 43.3 mg (73%) of an off-white solid. Mp: 232-233° C. 1H NMR (CDCl3; 400 MHz): δ 8.57 (s, 1), 8.04 (dd, 1, J=1.2, 2.9), 7.66 (m, 3), 7.59 (dd, 1, J=.2.9, 5.0), 7.52 (t, 2, J=7.7), 7.46 (t, 1, J=7.7), 6.94 (d, 1, J=2.0), 2.86 (s, 3). MS m/z: 292 (M+1), 290 (M−1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:33])[CH3:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH2:31][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CCN
Product: CCNCC1Cc2cc(Cl)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.079 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and ethylamine (0.14 g, 3.38 mmol). mp 230-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([N:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:10]2[CH2:11][CH:12]([N:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[O:33])=[CH:29][CH:30]=1
Reactant: COC(=O)CN(C(=O)OC)C1CNN=C1c1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)CN(C(=O)OC)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1

Procedure:
By substantially following the procedure given in Example 585f using one third (≤13 mmole) of the solution of 3-(4-chlorophenyl)-4-(N-methoxycarbonyl-N-(carbomethoxymethyl)amino)-4,5-dihydro-1H-pyrazole (Example 487c) and 1.87 g (10 mmole) of 4-trifluoromethylphenyl isocyanate, 2.5 g of the desired compound, mp 198°-200° C. was obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH3:10].[CH2:17]1[O:19][CH2:18]1>O>[N:14]1[CH:15]=[CH:16][C:11]([CH:9]([CH3:10])[CH2:18][CH2:17][OH:19])=[CH:12][CH:13]=1
Reactant: CCc1ccncc1
Reactant: C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Product: CC(CCO)c1ccncc1
Temperature: 25 °C

Procedure:
A solution of lithium diisopropylamide [made from n-BuLi (13.3 cm3) and diisopropylamine (2.8 cm3) in T.H.F. (10 cm3)] was added at -70° to a stirred solution of 4-ethylpyridine (2.0 g) in T.H.F. (10 cm3) under nitrogen. After 10 minutes the red solution was treated with ethylene oxide (1 cm3) giving an immediate suspension. After warming to room temperature, water (10 cm3) was added and the phases were separated. The aqueous phase was extracted with chloroform (2×20 cm3) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. Chromatography on silica (Merck 60.9385) eluting with methanol: ethyl acetate, 3:20, gave 3-(4-pyridyl)-butan-1-ol as an oil.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4]>FC(F)(F)C([O-])=O.[Ru+3].FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:5][CH:2]([CH:3]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:4])[CH3:1])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Agent: Cl[Ru](Cl)Cl
Agent: [Ru+3]
Agent: O=C([O-])C(F)(F)F
Product: CCCCOC(C)C(C)OCCCC

Procedure:
Example 18 is repeated, while using 1 m.mole ruthenium trifluoroacetate instead of 1 m.mole ruthenium trichloride. 18 m.moles butanal and 46 m.moles dibutoxybutane have been formed. No butyric acid is present.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12](=O)OC3C=CC=CC=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1n[nH]c2cc(Br)ccc12)Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CNc1n[nH]c2cc(Br)ccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
To a solution of phenyl 6-bromo-1H-indazol-3-ylcarbamate (0.80 g, 2.42 mmol) in 1,4-dioxane (40 mL) was added lithium aluminum hydride (2 M solution in THF, 2.42 mL, 2.42 mmol) dropwise at room temperature. After stirring at 100° C. for 4 hours, the reaction was quenched by 0.2 mL water, followed by 0.2 mL 15% NaOH and 0.6 mL water. The reaction mixture was then filtered and the solid was washed by ethyl acetate. The combined organic layer was washed by brine, dried with sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography with 50:50 (v/v) ethyl acetate-hexanes to afford the title product (0.29 g).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([CH2:29][C:30]2[C:31]([CH3:38])=[C:32]([CH:36]=O)[NH:33][C:34]=2[CH3:35])[CH2:23]1>>[CH3:28][C@H:26]1[NH:27][C@@H:22]([CH3:21])[CH2:23][N:24]([CH2:29][C:30]2[C:31]([CH3:38])=[C:32](/[CH:36]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:33][C:34]=2[CH3:35])[CH2:25]1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was condensed with 4-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:19])=[CH:5][CH:4]=1.Cl.[NH:23]1[CH2:26][CH:25]([OH:27])[CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:23]4[CH2:26][CH:25]([OH:27])[CH2:24]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:19])=[CH:5][CH:4]=1
Reactant: OC1CNC1
Reactant: COc1ccc(Cn2c(=O)ccc3ncc(Br)cc32)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(O)C4)cc32)cc1
Yield: 91 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-7-bromo-1,5-naphthyridin-2(1H)-one (C-5) (8.1 g, 23.46 mmol, 1.0 eq), azetidin-3-ol hydrochloride (3.08 g, 28.15 mmol, 1.2 eq), Pd2(dba)3 (429 mg, 0.47 mmol, 0.02 eq), Xantphos (407 mg, 0.7 mmol, 0.03 eq) and Cs2CO3 (19.87 g, 61 mmol, 2.6 eq) in 1,4-dioxane (100 mL) was heated at reflux temperature under argon atmosphere overnight then cooled and filtered, the filter cake was washed with ethyl acetate and the combined filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1-5% MeOH-DCM) to afford 1-(4-methoxybenzyl)-7-(3-hydroxyazetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-6) (7.2 g, 91% yield). 1H NMR (300 MHz, DMSO-d6) δ: 7.76 (m, 2H), 7.17 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 8.53 (m, 2H), 5.68 (d, J=6.3 Hz, 1H), 5.34 (s, 2H), 4.56 (m, 1H), 4.13 (m, 2H), 3.66 (s, 3H), 3.59 (m, 2H); ESI-MS m/z: 338.1 [M+H]+.
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCCCCCCCN1.[CH2:23]([O:30][C:31]([CH:33]1[NH:36][C:35](=[O:37])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>C(Cl)Cl>[N+:38]([C:41]1[CH:42]=[CH:43][C:44]([S:47]([N:36]2[CH:33]([C:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:32])[CH2:34][C:35]2=[O:37])(=[O:49])=[O:48])=[CH:45][CH:46]=1)([O-:40])=[O:39]
Reactant: O=C1CC(C(=O)OCc2ccccc2)N1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CC(=O)N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 20.1 %

Procedure:
Diazabicycloundecane (152 mg, 1 mM) was added to a mixture of 205 mg (1 mM) 4-benzyloxycarbonyl azetidin-2-one and 181 mg (1 mM) p-nitrobenzenesulfonyl chloride in 10 ml methylene chloride at room temperature. After stirring 21/2 hours, the orange solution was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel in hexane/ethyl acetate to yield 64 mg (17%) of 1-p-nitrophenylsulfonyl-4-benzyloxycarbonyl azetidin-2-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:28])[CH2:27][O:26]2)=[CH:21][N:20]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][C:25]([C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)([OH:26])[CH3:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C2(C)CO2)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of compound 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (0.5 g, 7.5 mmol, 1 equiv.) and NaH (252 mg, 10.5 mmol, 1.4 equiv) in 30 ml of DMF were heated to 120 C; 1 h. It was cooled to RT and compound 2-methyl-5-(2-methyloxiran-2-yl)pyridine (2.46 g, 16.5 mmol, 2.2 equiv) in 17 ml DMF was added dropwise over 12 min. The temperature was again raised to 120 deg C. and stirred for 3 h. The reaction mixture was cooled to RT and 5 ml of water was added to it, diluted with 700 ml of ethyl acetate and the organic part was washed with water (100 ml×3) and then with brine. It was dried over sodium sulphate and concentrated under vacuum. Column purified over 230-400 silica gel using a gradient of 10-20% methanol in ethyl acetate. Yield: 2.3 g (87%)