Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([CH2:24][OH:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([NH:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:24][O:25][S:28]([CH3:27])(=[O:30])=[O:29])=[O:26])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reaction time: 4 h
Yield: 75.6 %

Procedure:
[2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (0.78 g, 2.05 mmol) was treated with methanesulfonyl chloride (0.235 g, 2.05 mmol) and pyridine (0.49 g, 6.15 mmol) in 5 mL of anhydrous dichloromethane at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 4 h. The reaction mixture was diluted with 10 mL of dichloromethane and washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silica gel column chromatography (CH2Cl2:MeOH) gave methanesulfonic acid 2-tert-butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propyl ester (0.71 g).
Reaction SMILES: C(OC(OC(OCC)=O)=O)C.C(OC([N:17]1[C:25]([NH2:26])=[C:24]2[C:19]([CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[CH:23]2)=[N:18]1)=O)C>C(O)C>[NH2:26][C:25]1[C:24]2[C:19](=[CH:20][C:21]([C:27]([F:29])([F:28])[F:30])=[CH:22][CH:23]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)n1nc2cc(C(F)(F)F)ccc2c1N
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCO
Product: Nc1n[nH]c2cc(C(F)(F)F)ccc12

Procedure:
Analogously to Example 1, 0.04 mol of 3-amino-6-trifluoromethylindazole and 50 ml of pyrocarbonic acid diethyl ester in 25 ml of ethanol give 3-amino-6-trifluoromethylindazole-2-carboxylic acid ethyl ester (melting point: 153°-155° C; 77% of theory) in 1 hour at 20° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:20]=[C:19]([CH:21](Br)[CH:22](Br)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:11]2[CH2:12][C:13]3([O:18][C:10]=2[C:9]=1[O:31][CH3:32])[CH2:17][CH2:16][CH2:15][CH2:14]3.O>C1COCC1>[Br:7][C:8]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:11]2[CH2:12][C:13]3([O:18][C:10]=2[C:9]=1[O:31][CH3:32])[CH2:14][CH2:15][CH2:16][CH2:17]3
Reactant: COc1c(Br)cc(C(Br)C(Br)c2ccncc2)c2c1OC1(CCCC1)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)cc(C#Cc2ccncc2)c2c1OC1(CCCC1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
Potassium tert-butoxide (0.15 g) was added to a solution of Compound 142a (0.25 g) obtained in Step A in THF (9 ml) at 0° C., followed by stirring at room temperature for 5 hours. The reaction solution was poured into water and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to give Compound 142b (0.12 g, 68.2%) as pale-yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=2)[O:35]1>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:40]=2)[O:35]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1Cl)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2Cl)O3)nc1

Procedure:
2-(2-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 520 mg of 2-(2-chlorophenyl)chroman-4,6-diol (Example 68(b)). The product was recrystallised from 2-propanol. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.68 (dd, 1H, J 7.6, 1.8 Hz), 7.51-7.40 (m, 3H), 7.27 (d, 1H, J 2.9 Hz), 7.23 (d, 1H, J 9.1 Hz), 7.04 (dd, 1H, J 8.8, 2.9 Hz), 6.92 (d, 1H, J 8.8 Hz), 5.59 (d, 1H, J 10.6 Hz), 5.02 (m, 1H), 2.40 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[C:15](=[O:44])[CH:16]([CH2:19][C:20]3[N:21]=[CH:22][N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=3)[CH2:17][CH2:18][C:7]=12>O>[NH:23]1[CH:24]=[C:20]([CH2:19][CH:16]2[C:15](=[O:44])[N:8]3[C:9]4[C:14]([C:6]([CH3:5])=[C:7]3[CH2:18][CH2:17]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:21]=[CH:22]1
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1c[nH]cn1)CC2
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a mixture of acetic acid (50 ml) and water (15 ml), was added 8,9-dihydro-10-methyl-7-[(1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (4.93 g), and stirred at 60° C. for 2 hours. After being cooled, the precipitates were filtered off. The filtrate was neutralized with aqueous 8N-sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was crystallized from diisopropyl ether-ethyl acetate (5:1, V/V) to give 8,9-dihydro-7-[(1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.84 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]=1.[BH4-].[Na+]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1
Reactant: COC(=O)Cc1ccccc1CC1=NCCc2cc(OC)c(OC)cc21
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)Cc1ccccc1CC1NCCc2cc(OC)c(OC)cc21

Procedure:
The title compound was prepared was described in Example 10 from 2-[(3,4-dihydro-6,7-dimethoxy-1-isoquinolyl)methyl]benzeneacetic acid methyl ester (IXc, Ex. 9) and sodium borohydride, and the oil product was usd in the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:17][I:18])[O:13][CH2:12][C@@H:11]([C:14](O)=[O:15])[CH2:10]1.[BH4-].[Na+].B(F)(F)F>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:17][I:18])[O:13][CH2:12][C@@H:11]([CH2:14][OH:15])[CH2:10]1
Reactant: O=C(O)[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Temperature: 27.5 °C
Reaction time: 2 h

Procedure:
A solution of (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7 (150 g) in tetrahydrofuran (750 ml) was added to a pre-cooled solution of sodium borohydride (45.2 g) in tetrahydrofuran (750 ml) at 0-5° C., followed by BF3-etherate (172.29 g) at 0-5° C. Temperature of the reaction mixture was raised to 25-30° C. and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with 5% aqueous hydrochloric acid. Added ethylacetate to the reaction mixture. Both organic and aqueous layers were separated and the aqueous layers were extracted with ethyl acetate. Both the organic layers were combined, washed with water followed by 10% sodium chloride solution and then distilled off the solvent to get the title compound as a residue. Yield: 140 g; purity by HPLC: 98.5%.
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[C:11]([C:22]([OH:24])=O)=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)([O:8][CH3:9])=[O:7].S(Cl)([Cl:27])=O>>[C:6]([C:10]1[C:11]([C:22]([Cl:27])=[O:24])=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c(C(=O)O)nc2cc(Cl)ccc2c1O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)ccc2c1O
Temperature: 0 °C

Procedure:
The free base of 4-(trifluoromethoxy)phenyl hydrazine was prepared from thehydrochloride salt by treatment of the suspended salt (400 mg, 1.75 mM) in ethyl acetate (50 mL) with 2N sodium hydroxide(50 mL). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to provide the free base of 4-(trifluoromethoxy)phenyl hydrazine (325 mg, 1.69 mK). This material was placed into anhydrous tetrahydrofuran (5 mL) and cooled to 0° C. under a nitrogen atmosphere. Concurrently, 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride was prepared from 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carboxylic acid(121 mg, 0.43 mM) by heating to 60° C. in thionyl chloride (4 mL). After 3 hours the crude acid chloride was isolated by distilling away the excess thionyl chloride. The crude3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride (130 mg, 0.43 mM) was then placed in anhydrous tetrahydrofuran (3 mL) at ambient temperature and added via cannula to the 4-(trifluoromethoxy)phenyl hydrazine solution. After 30 minutes the reaction mixture was poured into 1.0N hydrochloric acid producing a precipitate. The solid was isolated to yield the title compound (185 mg, 95%) as an off-white solid, mp 346°-350° C.; MS 456 (M+H). 1H NMR 12.67 (s, 1H, exchangeable), 10.79 (s, 1H, exchangeable), 8.37 (br s, 1H, exchangeable), 8.13 (d, J=8.61 Hz, 1H), 7.83 (d, J=1.76 Hz, 1H), 7.48 (dd, J=8.61, 1.76 Hz, 1H), 7.21 (d, J=8.50 Hz, 2H), 6.94 (d,J=8.50 Hz, 2H), 3.70 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([C:14]([OH:16])=O)[CH3:13])=[C:6]([CH:10]=1)C(O)=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>>[Br:1][C:2]1[CH:10]=[CH:6][C:5]2[O:11][C:12]([CH3:13])=[C:14]([O:16][C:17](=[O:19])[CH3:18])[C:4]=2[CH:3]=1
Reactant: CC(Oc1ccc(Br)cc1C(=O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Oc1c(C)oc2ccc(Br)cc12
Temperature: 150 °C
Yield: 65 %

Procedure:
A mixture of 5-bromo-2-(1-carboxy-ethoxy)-benzoic acid (31.2 g, 108 mmol), acetic anhydride (216 mL) and anhydrous sodium acetate (21.8 g, 266 mmol) is heated under reflux (150° C.) for 4 h. After cooling to room temperature the reaction mixture is carefully quenched with ice-cold water (500 mL). A white precipitate is formed which is collected by suction filtration, thoroughly washed with water and dried in vacuo at 45° C. to afford the title compound as a white powder (19.0 g, 70.6 mmol, 65%). MS (ES+): 269 (M(C11H979BrO3)+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[OH:13].[C:14](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1ccc(Br)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OC)c1C
Yield: 70.4 %

Procedure:
A solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (610 mg, 2.5 mmol), cesium carbonate (1.22 g, 3.7 mmol) and iodomethane (162 μl, 2.6 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 15 hours. The mixture was diluted with ethyl acetate, then washed with 5% aqueous lithium chloride then brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded an orange residue, which was purified by silica gel column chromatography. Eluting with 15% diethyl ether in hexane, purified fractions were pooled and concentrated to afford 455 mg, 1.76 mmol (71%) of methyl 4-bromo-2-methyl-3-(methyloxy)benzoate as a colorless residue. 1H NMR (400 MHz, CDCl3): 7.52 (d, 1H), 7.43 (d, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.55 (s, 3H). MS (EI) for C10H1BrO3: 260 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCN1C(=O)Cc2ccccc21
Product: CCC(=O)c1ccc2c(c1)CC(=O)N2CC

Procedure:
Prepared from readily available starting materials (N-ethyloxindole and propionyl chloride) in a manner analogous to that set forth in Preparation 18.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:13]([CH2:29][N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH:32]([CH3:37])[CH2:31]1)=[C:12]2[C:38]([O:40]C)=[O:39])(=[O:8])=[O:7])[CH3:5]>CO.O1CCCC1>[CH3:5][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:13]([CH2:29][N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH:32]([CH3:37])[CH2:31]1)=[C:12]2[C:38]([OH:40])=[O:39])(=[O:7])=[O:8])[CH3:3]
Reactant: COC(=O)c1c(CN2CCC(=O)C(C)C2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(=O)(=O)C(C)C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)O)CCC1=O
Temperature: 50 °C
Yield: 78.6 %

Procedure:
Sodium hydroxide (11.02 mL of a 2M solution, 22.04 mmol) was added to a yellow solution of methyl 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.24 g, 2.204 mmol) in methanol (11.02 mL) and tetrahydrofuran (11.02 mL). The mixture was heated to 50° C. for 20 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with water (5 mL), and the solid precipitate was collected by filtration, washed with water (2×1 mL), and dried in a vacuum oven at 40° C. to afford 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.95 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ8.53 (d, J=1.76 Hz, 1H), 8.10-8.18 (m, 2H), 7.96-8.05 (m, 2H), 7.83 (d, J=7.81 Hz, 1H), 7.72 (t, J=7.68 Hz, 1H), 3.71 (s, 2H), 3.49 (dt, J=6.77, 13.41 Hz, 1H), 2.68-2.78 (m, 2H), 2.08-2.32 (m, 3H), 1.92-2.03 (m, 2H), 1.22 (s, 3H), 1.20 (s, 3H), 0.70 (d, J=6.55 Hz, 3H); MS (m/z) 549.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([OH:24])=O)[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:43])([C:39]([F:42])([F:41])[F:40])[CH2:36][CH2:37][NH2:38]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([NH:38][CH2:37][CH2:36][C:35]([F:43])([F:34])[C:39]([F:42])([F:41])[F:40])=[O:24])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)C(F)(F)F
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21)NCCC(F)(F)C(F)(F)F

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and ,3,3,4,4,4-pentafluorobutylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, waxy solid (98%). MS: m/e=590(M+H+).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:16]4([CH3:36])[CH3:35])=[CH:10][CH2:9]1)[CH3:7]>C1COCC1.C(O)C.[OH-].[Na+]>[Si:28]([O:27][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@@H:15]([CH2:14][CH2:13][C:12]3[C:11]4[C@:25]([CH3:26])([CH2:24][CH2:23][C:22]=32)[C@@H:8]([C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:37])=[O:2])[CH2:9][CH:10]=4)[C:16]1([CH3:35])[CH3:36])([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: 50 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid methyl ester (3.6 g) is dissolved in a mixture of 150 ml of THF, 120 ml of ethanol and 18 ml of 1M sodium hydroxide. The mixture is stirred for 20 hours at room temperature and 2hours at 50° C. After aqueous work-up and crystallisation from ethanol/water, 2.48 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid is isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]12[S:19][CH2:18][CH2:17][S:16]1.BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]1[S:19][CH2:18][CH2:17][S:16][C:7]=12
Reactant: Cc1cc(C(=O)O)c(C)c2c1CCCC21SCCS1
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)O)c(C)c2c3c(ccc12)SCCS3
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a mixture of 1.2 g of the title compound of Step C in 150 mL of chloroform was added a solution of 0.76 g of bromine in 30 mL of chloroform dropwise. The mixture was stirred overnight at room temperature. To this reaction mixture was then added 10% aqueous sodium thiosulfate. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. The resulting solid was crystallized from 1-chlorobutane to gave 0.65 g of the title compound of Step D as a yellow solid melting at 205° C. (dec.). 1H NMR ((CD3)2SO): δ 2.58 (s, 3H), 2.91 (s, 3H), 2.98 (m, 2H), 3.49 (m, 2H), 7.47 (d, 1H), 7.49 (s, 1H), 7.73 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-])=O)=[C:8]([CH3:16])[CH:7]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]([CH3:16])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc(Cl)c(Cl)c2)c(C)cc1N
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of 18.00 g (57.6 mmol) of 4-(3,4-dichlorophenoxy)-2,5-dimethylnitrobenzene in 40 ml of dioxane and 40 ml of hydrochloric acid is admixed with 39.0 g (173.0 mmol) of tin(II) chloride dihydrate at room temperature and then refluxed for 2 h. It is cooled to room temperature, neutralized with NaHCO3 and extracted repeatedly with dichloromethane, and the extracts are dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure (18.3 g, 89% purity, 99.5% yield, log P (pH 2.3)=3.51).
Reaction SMILES: [CH3:1][PH:2](=[O:5])[O:3][CH3:4].[C:6]([O:9][CH:10]=[CH2:11])(=[O:8])[CH3:7]>>[C:6]([O:9][CH2:10][CH2:11][P:2]([O:3][CH3:4])([CH3:1])=[O:5])(=[O:8])[CH3:7]
Reactant: CO[PH](C)=O
Reactant: C=COC(C)=O
Product: COP(C)(=O)CCOC(C)=O

Procedure:
Various multistep processes to prepare phosphinothricin are known in the art. For example, some routes utilize phosphorus trichloride to produce a phosphinate precursor, which is subjected to hydroformylation-aminocarbonylation, followed by hydrolysis to produce phosphinothricin. In particular, one process for producing phosphinothricin generally comprises converting phosphorus trichloride to methylphosphonous dichloride or a derivative thereof. The methylphosphonous dichloride or derivative thereof is then reacted with methanol to form methyl methylphosphinate. Methyl methylphosphinate is then reacted with vinylic compounds (e.g., vinyl acetate) to form an intermediate (e.g., 2-(methoxy(methyl)phosphoryl)ethyl acetate). The resulting intermediate is pyrolyzed to prepare a vinylphosphinate precursor. The vinylphosphinate precursor is subjected to hydroformylation-aminocarbonylation, followed by hydrolysis of the hydroformylation-aminocarbonylation product in the presence of hydrochloric acid to produce phosphinothricin.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[CH3:12][O-:13].[Na+]>>[CH3:12][O:13][C:4]1[C:3]([F:11])=[C:2]([F:1])[N:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1c(F)c(F)nc(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To pentafluoropyridine (1.0 g, 5.9 mmol) in petroleum ether (60 mL) at 0° C. was added sodium methoxide (0.32 mg, 5.9 mmol). After stirring for 12 hours at ambient temperature, the reaction was washed with water, dried (MgSO4), and the solvent was removed in vacuo to give 4-methoxy-2,3,5,6-tetrafluoropyridine; NMR (CDCl3) 4.3 ppm.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][C:9]1([CH3:21])[C:13]([CH3:14])=[CH:12][CH2:11][CH:10]1[CH:15]=[CH:16][CH2:17]C(O)C.O>CN(C)C1C=CN=CC=1.CC(OC)(C)C>[CH3:8][C:9]1([CH3:21])[C:13]([CH3:14])=[CH:12][CH2:11][CH:10]1[CH:15]=[CH:16][CH2:17][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6]
Reactant: CC1=CCC(C=CCC(C)O)C1(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: COC(C)(C)C
Product: CC(=O)OC(C)CC=CC1CC=C(C)C1(C)C
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
50 g (0.48 mol) of acetic anhydride was added dropwise to the solution of 78.6 g (0.40 mol) of 5-(2,2,3-trimethylcyclopent-3-enyl)pent-4-en-2-ol and 5.0 g of 4-dimethylaminopyridine in 150 ml of MTBE. The reaction mixture was stirred at 50-55° C. for 1 hour, treated with 0.5 l of water and extracted with 3×150 ml of hexane. The combined organic layers were neutralized with aqueous potassium hydrogen carbonate solution, washed with water, dried (MgSO4) and evaporated in vacuo. The residue (102 g) was distilled at 80-81° C./0.2 Torr to give 89.8 g (95% yield) of acetic acid 5-(2,2,3-trimethyl-cyclopent-3-enyl)pent-4-en-2-yl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17]N(CN(C)C)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[C:13](=[CH2:17])[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CN(C)CN(C)C
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Solvent: O=C(O)C(F)(F)F
Product: C=C1CCc2nc3ccccc3c(N)c2C1=O

Procedure:
In 25 ml of trifluoroacetic acid cooled in ice was dissolved 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. To the solution was added dropwise 6.70 ml (2.09 eq) of bisdimethylaminomethane over 5 minutes and thereafter the mixture was maintained at 90°-100° C. for 5 hours during which the starting material was converted to a mixture of intermediate and exo-methylene products. The reaction mixture was poured into ice/NaOH to make it basic and the precipitate was extracted and several portions of 5:1 dichloromethane/MeOH. The combined extracts were evaporated to a residue. The residue was refluxed in toluene for 5 hours during which the intermediate was converted to the end product. The reaction mixture was evaporated to a residue which was purified by chromatography on silica gel (EtOAc) to yield about 2 g of a solid. This was recrystallized from dichloromethane/EtOAc to yield 1.79 g (34%) of product as a solid, melting point 192°-193° C.