Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:4]1[C:9]2=[N:10][CH:11]=[C:12]([C:13]#[N:14])[N:8]2[N:7]=[C:6](S(C)(=O)=O)[N:5]=1)[CH3:2].[NH2:28][C:29]1[C:30]([F:49])=[C:31]([N:37]2[CH2:42][CH2:41][C@@H:40]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C@H:39]([OH:48])[CH2:38]2)[CH:32]=[C:33]([C:35]#[N:36])[CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+].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>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.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:35]([C:33]1[CH:34]=[C:29]([NH:28][C:6]2[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:9]3=[N:10][CH:11]=[C:12]([C:13]#[N:14])[N:8]3[N:7]=2)[C:30]([F:49])=[C:31]([N:37]2[CH2:42][CH2:41][C@@H:40]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C@H:39]([OH:48])[CH2:38]2)[CH:32]=1)#[N:36]
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2F)C[C@H]1O
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(S(C)(=O)=O)nn2c(C#N)cnc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2F)nn2c(C#N)cnc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 7) (50 mg, 0.146 mmol), methyl ((3R,4R)-1-(3-amino-5-cyano-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate (46 mg, 0.149 mmol), DPPF (5.66 mg, 10.21 mmol), Cs2CO3 (81 mg, 0.248 mmol), Xantphos (8.44 mg, 0.015 mmol), Palladium(II)Acetate (9.82 mg, 0.044 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture cooled to 25° C., diluted with EtOAc and washed with brine and dried (Na2SO4). The solvents were removed and the material purified on silica gel 25% EtOAc in DCM to afford methyl ((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate (60 mg)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH:24]=[O:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:33]1>[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][C:28]([CH3:30])([CH3:33])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH:24]=[O:25])=[CH:14][CH:13]=2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C=O)cc12
Reactant: C1CCOC1
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl(4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.27 g, 6.2 mmol) in tetrahydrofuran (30 mL) was added manganese dioxide (8.1 g) and the mixture was stirred at room temperature for 12 h. Manganese dioxide was filtered off and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.52 g, 91.6%) as crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]=[O:13])[CH3:2].[C:14]1([CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:22][CH2:21][CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13])[CH3:2]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CCc1cccc(CC)c1N=C=O
Product: CCc1cccc(CC)c1NC(=O)NCC(c1ccccc1)c1ccccc1

Procedure:
The title compound, mp 200°-201° C., was prepared from 2,6-diethylphenyl isocyanate and 2,2-diphenylethylamine according to the method of Example 1.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6](#[N:10])[CH2:7][CH2:8]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>[C:1]([O:5][CH2:8][CH2:7][C:6]#[N:10])(=[O:4])[C:2]#[CH:3]
Reactant: N#CCCO
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: C#CC(=O)OCCC#N
Yield: 28.5 %

Procedure:
A solution of 98 g of propiolic acid (1.4 moles), 99.5 g of hydracrylonitrile (1.4 moles), 2 g of p-toluenesulfonic acid and 200 ml of chloroform were refluxed, using a Soxhlet extractor filled with 3A molecular sieves to remove the water generated during the esterification. A total reflux time of 94 hours was employed. The reaction was cooled, poured into water and extracted with chloroform. The combined extracts were washed with dilute bicarbonate solution, dried (MgSO4), and concentrated to give 49.2 g (29 percent) of a liquid used without purification.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1N1[C:18](=[O:19])[C:17]2[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[CH:21][C:22](=[O:25])[N:23]([CH3:24])[C:16]=2[N:15]=[CH:14]1)([O-])=O.[NH2:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38]>CN(C=O)C>[OH:38][CH2:37][CH:36]([N:35]1[C:18](=[O:19])[C:17]2[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[CH:21][C:22](=[O:25])[N:23]([CH3:24])[C:16]=2[N:15]=[CH:14]1)[CH2:39][OH:40]
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cnc21
Reactant: NC(CO)CO
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C(CO)CO)cnc21
Temperature: 80 °C

Procedure:
To a mixture of 3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 24A (18 mg, 0.03 mmol, 1 eq) in DMF (0.3 mL) was added 2-aminopropane-1,3-diol (29 mg, 0.3 mmol, 10 eq). The reaction mixture was heated at 80° C. for 5 hours. The solvent was removed under vacuum and the residue was purified by preparatory LC/MS (30-55% CH3CN in H2O) to yield 3-(1,3-dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione Example 24 as an off-white solid (10 mg, 66% yield). 1H NMR (400 MHz, MeOD) δ ppm 3.65 (s, 3 H) 3.87-3.95 (m, 2 H) 4.04 (dd, J=11.87, 7.07 Hz, 2 H) 4.88-4.90 (m, 1 H) 5.74 (s, 1 H) 7.29 (t, J=8.34 Hz, 1 H) 7.57-7.69 (m, 2 H) 8.50 (s, 1 H). [M+H] calc'd for C17H16FIN4O4, 487; found, 487.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: CCCCCc1cnc(O)nc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCCc1cnc(Cl)nc1

Procedure:
In 500 ml of phosphorus oxychloride was added 120.4 g (0.724 mol) of the 2-hydroxy-5-pentylpyrimidine described above, and heated to reflux for 5 hours. Excess amount of phosphorus oxychloride was distilled off under a reduced pressure, and the residue was added into an ice water. The product was extracted with toluene, and the extract was washed with aqueous solution of 2N aqueous solution of sodium hydroxide and water in turn, and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue was purified by distillation to obtain 76.3 g (0.413 mol) of 2-chloro-5-pentylpyrimidine. Yield of this product was 57%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][O:24][CH2:25][CH:18]2[CH2:19][O:20][CH2:21]3)[CH:3]=1>C(N)(C)C>[CH:22]12[N:17]([C:4]3[N:5]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=4)[N:7]=[C:2]([NH:14][CH:11]([CH3:12])[CH3:10])[CH:3]=3)[CH:18]([CH2:25][O:24][CH2:23]1)[CH2:19][O:20][CH2:21]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4COCC3COC4)n2)cc1
Solvent: CC(C)N
Product: CC(C)Nc1cc(N2C3COCC2COC3)nc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 145 °C
Yield: 198.6 %

Procedure:
In a 2-5 mL microwave vial was placed 9-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (130 mg, 0.358 mmol) in isopropylamine (5 mL) to give a yellow suspension. The reaction was heated under microwave irradiation at 145° C. for 60 min. The mixture was concentrated. The residue was dissolved in dichloromethane and washed with saturated NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated to give 137 mg (99%) of a yellow foam. HRMS: 386.1824 [M+H]+. For [M+H]+ mass error=0.1 mDa or 0.21 ppm.
Reaction SMILES: [I-].[CH2:2]([N+:6]1([CH3:15])[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].[OH2:16]>>[OH-:16].[CH2:2]([N+:6]1([CH3:15])[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: O
Agent: CCCC[N+]1(C)CCC2CCCCC21
Agent: [I-]
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 g (0.14 mmol) of 1-methyl-octahydroindole was mixed with 53 g (0.29 mmol) of 1-iodobutane in 300 mL of methanol. The reaction mixture was heated at reflux for 72 hours. Then, an additional 0.5 mol equivalent of 1-iodobutane was added and the reaction mixture was heated for an additional 12 hours. The reaction mixture was cooled and the solvent removed on a rotary evaporator to give an off-white powder which was used without further purification. The quaternization afforded 39.4 g (86% yield) of 1-butyl-1-methyl-octahydroindolium iodide. The obtained 1-butyl-1-methyl-octahydroindolium iodide (18.15 g) was dissolved in 56 g of deionized water. To this solution, 70 g of BIO-RAD AG® 1-X8 ion exchange resin was added and the slurry was gently stirred at room temperature overnight. The solution was filtered and the filtrate analyzed for hydroxide content by titration of a small aliquot with dilute HCl. The exchange afforded 1-butyl-1-methyl-octahydroindolium hydroxide in 87% yield.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:19][O:20][C:21](=[O:26])[C:22]([NH2:25])([CH3:24])[CH3:23]>>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([NH:25][C:22]([CH3:24])([C:21]([O:20][CH3:19])=[O:26])[CH3:23])=[O:18])=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3[nH]c2c1
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(=O)c3ccccc3[nH]c2c1

Procedure:
Example 128 was prepared from compound 1C by a route analogous to that used for the preparation of Example 1, replacing the amine in Step E with 2-Amino-2-methyl-propionic acid methyl ester. HPLC retention time=2.453 min./condition A.
Reaction SMILES: B.CSC.C1CCCCC=1.[F:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:15]=[CH:16][C:17]=1[CH:18]([OH:23])[CH2:19][C:20]([CH3:22])=[CH2:21].[OH-:33].[Na+].OO.[Cl-].[NH4+]>O1CCCC1>[OH:23][CH:18]([C:17]1[CH:16]=[CH:15][C:14]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])=[CH:13][C:12]=1[F:11])[CH2:19][CH:20]([CH3:22])[CH2:21][OH:33]
Reactant: C=C(C)CC(O)c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CSC
Solvent: C1=CCCCC1
Product: CC(CO)CC(O)c1ccc(NC(=O)c2ccccn2)cc1F
Reaction time: 0.17 h

Procedure:
1.20 ml of borane-methyl sulfide complex (1 M dichloromethane solution) was added to a tetrahydrofuran (5 ml) solution of 0.082 ml of cyclohexene with cooling with ice. The reaction liquid was stirred for 10 minutes with cooling with ice, and a tetrahydrofuran (3 ml) solution of 301 mg of N-(3-fluoro-4-(1-hydroxy-3-methyl-3-buten-1-yl)phenyl)pyridine-2-carboxamide was added to it, and the reaction liquid was stirred at room temperature for 1 hour. 0.50 ml of aqueous 5 N sodium hydroxide solution and aqueous 35% hydrogen peroxide solution were added in order to the reaction liquid, and stirred at room temperature for 10 minutes. The reaction liquid was poured into an aqueous saturated ammonium chloride solution, extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=9/1) to obtain the entitled compound.
Reaction SMILES: [OH:1][CH:2]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH:7]([CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][P@:11]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[O:12]CCCC.Cl>>[OH:1][CH:2]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH2:3][NH:4][CH2:5][CH2:6][C@@H:7]([CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][P:11]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:12])[OH:17]
Reactant: CCCCO[P@@](=O)(CCCC(CC)CCNCC(O)COc1ccc(O)cc1)COc1ccccc1
Agent: Cl
Product: CC[C@@H](CCCP(=O)(O)COc1ccccc1)CCNCC(O)COc1ccc(O)cc1

Procedure:
The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl}phenoxymethyl-n-hexyl phosphinic acid, n-butyl ester according a modification of the procedure described in Example 25. Acidification to pH 6 with 1M hydrochloric acid followed by C18 reverse phase chromatography and freeze drying gave the title compound as a solid.
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]1([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.O>[C:12]1([CH:18]([CH3:22])[C:19]([O:21][CH3:1])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)c1ccccc1
Temperature: 90 °C

Procedure:
DBU (2.03 g, 13.3 mmol) was added to a mixture of 2-phenylpropionic acid (2.0 g, 13.3 mmol) in DMC (20 mL) and the resulting mixture was heated to reflux (90° C.) for 5 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2Cl2 (50 mL) and water (40 mL). The organic layer was separated and washed in sequence with 2 M HCl (2×40 mL), saturated aqueous NaHCO3 (40 mL) and water (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl 2-phenylpropionate as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:17][CH3:18])[NH:8][CH:7]=1)=[O:5])C>[OH-].[Na+]>[CH3:18][O:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]2
Reactant: CCOC(=O)c1c[nH]c2cccc(OC)c2c1=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2[nH]cc(C(=O)O)c(=O)c12
Temperature: 25 °C
Yield: 34.1 %

Procedure:
A mixture of 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1 g, 7.1 mmol) in 10% NaOH solution (50 mL) was heated to reflux overnight and then cooled to room temperature. The mixture was extracted with ether. The aqueous phase was separated and acidified with conc. HCl solution to pH 1-2. The resulting precipitate was collected by filtration to give 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-4) (530 mg, 52%). 1H NMR (DMSO) δ: 15.9 (s, 1H), 13.2 (br, 1H), 8.71 (s, 1H), 7.71 (t, J=8.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 3.86 (s, 3H); ESI-MS 219.9 m/z (MH+).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=1.[P:7]([O-:22])([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1P(=O)(O)O>>[NH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[P:7]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:22])[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C1=NCCCC1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Agent: O=P(O)(O)C1CCCCN1
Product: O=P(Oc1ccccc1)(Oc1ccccc1)C1CCCCN1
Temperature: 100 °C
Yield: 41 %

Procedure:
This compound was prepared from the trimer of 2,3,4,5-tetrahydropyridine and diphenyl phosphite using the procedure previously described for the synthesis of the diethyl ester (Solodenko, V. A., Kukhar, V. P., Synthesis of DL-(2-Piperidyl) Phosphonic Acid, Zh. Obsh. Khim. 1987, 57, 2392). A mixture of the trimer (10 mmol, 2.5 g) and diphenyl phosphite (30 mmol, 7.0 g) was heated for 1.5 h at 100° C. under argon. The resulted crude diphenyl piperidine-2-phosphonate was dissolved in 100 mL of dry ether, undisolved material was removed by filtration, and the solution was saturated with gaseous HCl. The precipitated hydrochloride 2 was collected by filtration, washed with ether, dried and recrystallized from acetone to give a white solid in 41% yield: top. 172°-174° C.; 1H-NMR (D2O), δ (ppm) 1.5-2.4 (m, 6H), 3.05 (m, 1H), 3.45 (m, 1H), 4.10 (m, 1H), 6.9-7.4 (m, 10H); MS (FAB) m/e 318 (M-Cl)+. Anal. (C17H21NO3PCl): C, H, N, Cl.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[CH:23]=[C:24]([F:33])[C:25]([O:29][CH:30]([CH3:32])[CH3:31])=[C:26]([F:28])[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:23]=[C:24]([F:33])[C:25]([O:29][CH:30]([CH3:31])[CH3:32])=[C:26]([F:28])[CH:27]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC(C)Oc1c(F)cc(CCl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1c(F)cc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)cc1F
Yield: 76.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.17 g) is alkylated using 5-chloromethyl-1,3-difluoro-2-isopropoxy-benzene (0.15 g; 0.68 mmol) and K2CO3 (0.3 g; 2.16 mmol) at RT for 18 h. After aqueous work-up the crude material (0.27 g) is de-acetylated in hydrochloric acid (30 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(3,5-difluoro-4-isopropoxy-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.20 g) is obtained and used without further purification.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH:7]([C:10]([NH2:12])=O)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[N:1]1[C:9]2[CH2:8][CH:7]([CH2:10][NH2:12])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1Cc2cccnc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1Cc2cccnc2C1
Reaction time: 0.08 h

Procedure:
6,7-Dihydro-5H-[1]pyrindine-6-carboxylic acid amide (0.209 g, 1.28 mmol) is added portionwise to a suspension of LiAlH4 (0.204 g, 5.38 mmol) in THF (10 ml). After 5 minutes at ambient temperature, the reaction is heated to reflux for 1.5 hours and then cooled. Water (0.2 ml) is cautiously added, followed by 15% aqueous sodium hydroxide (0.2 ml), followed by further water (0.6 ml). The resultant granular precipitate is filtered and washed with EtOAc. The combined filtrate and washings are evaporated to afford C-(6,7-dihydro-5H-[1]pyrindin-6-yl)methylamine. δc 35.2 (t), 38.9 (t), 41.0 (d), 47.6 (t), 121.6 (d), 132.6 (d), 136.4 (s), 148.1 (s), 164.8 (s).
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=O)[O:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[S:28])[O:3][CH3:4]
Reactant: COP(C)(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: COP(C)(=S)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (1.5 g, 4.7 mmol) and phosphorus pentasulfide (0.52 g, 1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by preparative thin-layer chromatography (on silica gel, eluting with 20% ethyl acetate/hexane) to give methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2OC(=O)C=Cc2ccccc2)c(O)c(C(C)(C)C)c1
Yield: 86 %

Procedure:
To the same flask as used in Example 6 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 151.18 g (1.0 mole) of cinnamic acid, 500 g of toluene and 118.65 g (1.5 moles) of pyridine. After replacing the air in the container with nitrogen, 286.43 g (1.5 moles) of p-toluenesulfonyl chloride was added little by little with stirring. After completion of the addition, temperature maintenance and after-treatment were carried out in the same manner as in Example 6, and the residue was recrytallized from toluene to obtain 404.8 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monocinnamoate having a melting point of 164° to 169° C. Yield, 86%.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[C:25]([N+:35]([O-])=O)=[N:26][N:27](C3CCCCO3)[CH:28]=2)=[CH:12][C:11]=1[F:38])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:35][C:25]1[C:24]([C@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:18]2[O:17][C:13]2[C:14]([CH3:16])=[CH:15][C:10]([S:7]([NH:6][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][N:40]=3)(=[O:9])=[O:8])=[C:11]([F:38])[CH:12]=2)=[CH:28][NH:27][N:26]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCCC[C@@H]1c1c[nH]nc1N
Yield: 94.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (291 mg, 0.409 mmol) prepared in Example 68a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (172 mg, 88%) as a pale yellow solid.