Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]([OH:33])=[C:17]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21])(=[O:14])=[O:13])=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]([OH:33])=[C:17]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: NCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 87 %

Procedure:
Following the general procedure for Boc deprotection outlined in example 36, N-[3-[N″-[2-(tert-butoxycarbonylamino)ethyl]aminosulfonyl]4-chloro-2-hydroxyphenyl]-N′(2-chlorophenyl) urea (57 mg, 0.11 mmol) was stirred in trifluoroacetic acid to form the desired product (51 mg, 87%). LC-MS (m/z) 419.2 (M+).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH:9]1([N:12]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:32]=[C:31]([OH:41])[CH:30]=2)[C:13]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[O:14])[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([N:12]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:32]=[C:31]([O:41][CH3:1])[CH:30]=2)[C:13]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[O:14])[CH2:10][CH2:11]1
Reactant: COCCCOc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (54 mg) and methyl iodide (24 μL) were added to a solution of tert-butyl(2R)-2-({cyclopropyl[3-hydroxy-5-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (a compound obtained in Reference Example 12, 120 mg) in N,N-dimethylformamide (6 ml) and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture under ice-cooling and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give tert-butyl(2R)-2-({cyclopropyl[3-methoxy-5-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (88 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:15]([OH:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[C:7]([F:17])[CH:8]=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].Br[CH2:24][C:25]([O:27]CC)=[O:26].[OH-].[Na+].[ClH:32]>O.CN(C=O)C>[Cl:32][CH:24]([O:16][C:15]1[CH:2]=[CH:3][C:4]2[C:5](=[O:18])[C:6]3[C:11]([O:12][C:13]=2[CH:14]=1)=[CH:10][CH:9]=[CH:8][C:7]=3[F:17])[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Cl
Reactant: O=c1c2cc(Cl)c(O)cc2oc2cccc(F)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C(Cl)Oc1ccc2c(=O)c3c(F)cccc3oc2c1
Reaction time: 3 h

Procedure:
A mixture of 1.3 g of 2-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of postassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-65° C. for 3 hours. After cooling the mixture, 2 g of sodium hydroxide and 100 ml of water were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from DMF gave 1.0 g of 2-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 239°-242° C. This compound gave a mass spectrum having a molecular ion peak at m/e 322.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@@H:11]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C3C=CC=CC=3)[C@@H:22]([O:23]C(=O)C3C=CC=CC=3)[C@H:12]2[O:13]C(=O)C2C=CC=CC=2)[N:10]=1)=O>CO>[C@@H:11]1([N:9]2[N:10]=[C:6]([C:4]([NH2:1])=[O:3])[CH:7]=[N:8]2)[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]1[OH:13]
Reactant: COC(=O)c1cnn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 96 h
Yield: 92 %

Procedure:
Methanol saturated with ammonia at 0° (ca 150 ml) was added to 5.71 g (0.010 mol) of 1 in a pressure bottle and kept at room temperature for 4 days. After removal of the solvent, water (30 ml) was added and the mixture was extracted with ether (six 20 ml portions). The solvent was removed and the compound crystallized from ethanol to give 2.25 g (92%) of 4: m.p. 150°-151°; [α]D25 -59.4° (c 1.00, water); nmr (DMSO-d6) δ 5.97 (d, 1, J1',2' 4.0 Hz, 1'--H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CN1CCCC1=O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(C(F)(F)F)cc3)nccc12
Yield: 97.8 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-1, step-2 using 1-chloro-5-nitroisoquinoline (Intermediate-1, step-1, 500 mg, 2.30 mmol), and 4-(trifluoromethyl)aniline (772 mg, 4.70 mmol) in N-methylpyrrolidinone (3 mL) to afford 750 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.94 (d, J=8.4 Hz, 1H), 8.53 (d, J=7.2 Hz, 1H), 8.26 (d, J=6.3 Hz, 1H), 8.06 (d, J=9.0 Hz, 2H), 8.33 (t, J=7.8 Hz, 1H), 7.66 (m, 3H); MS (m/z): 334.19 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34](Cl)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:38]1([C@@H:44]([CH2:46][OH:47])[NH2:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:45][C@@H:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:46][OH:47])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N[C@H](CO)c1ccccc1
Reactant: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2c(S(=O)(=O)N[C@H](CO)c3ccccc3)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a suspension of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid chloride (prepared in Example 204) (2.05 g) in chloroform (60 ml) were added (S)-2-phenylglycinol (767 mg) and diisopropylethylamine (0.99 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure and thereto were added 1N hydrochloric acid (30 ml) and ethyl acetate (60 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford (S)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-sulfonamide (813 mg).
Reaction SMILES: [N+](C)([O-])=O.C(=O)([O-])[O-].[K+].[K+].BrC1C=C(C(=O)/C=C(\C2C=C(Cl)C=C(Cl)C=2)/C(F)(F)F)C=CC=1C[N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45].O>C1(C)C=CC=CC=1>[C:36]1(=[O:45])[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[NH:35]1
Reactant: O=C(/C=C(\c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(CN2C(=O)c3ccccc3C2=O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: O=C1NC(=O)c2ccccc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 344.8 %

Procedure:
A solution of anthracenylmethyl quininium bromide (200 mg), nitromethane (0.04 ml), potassium carbonate (94 mg) and 2-[[2-bromo-4-[(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]phenyl]methyl]isoindoline-1,3-dione (200 mg) in toluene (2 mL) under argon, was heated for 2 hours at 50° C. then potassium carbonate (64 mg) was added. The reaction was heated for 24 hours at 50° C. then more nitromethane (0.02 mL) was added. The reaction was heated again at 50° C. for 1.5 hours then was allowed to stand at room temperature for 18 hours. Water was then added and the resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 2-[[2-bromo-4-[(3R)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-nitromethyl)butanoyl]phenyl]methyl]isoindoline-1,3-dione (174 mg). Chiral HPLC analysis (Chiralpack IB, Heptane/isopropanol 70/30, flow: 1 mL, retention time 12.10 minutes (major enantiomer), 14.34 minutes (minor enantiomer) indicated that the reaction proceeded with 49% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17]Cl)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][SH:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:29][CH2:28][CH2:27][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)NCCS
Product: CC(C)(C)OC(=O)NCCNc1nc(CSCCNC(=O)OC(C)(C)C)cs1

Procedure:
2-(2-t-butyloxycarbonylaminoethylamino)-4-chloromethyl-1,3-thiazole was reacted with 2-t-butyloxycarbonylaminoethanethiol in a manner similar to that described in Example 42. 1H NMR (CDCl3) δ 1.50 (s, 18H), 2.80 (m, 2H), 3.30-3.60 (m, 6H), 3.72 (s, 2H), 5.10 (br s, 1H), 5.40 (br s, 1H), 6.38 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22]>ClCCl.O>[CH3:18][O:19][C:20]([CH2:21][NH:22][S:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A 47.5 g (0.6 mol) sample of pyridine was added dropwise to a stirred and cooled (ice bath) slurry of 53.0 g (0.3 mol) benzenesulfonyl chloride and 37.7 g (0.3 mol) glycine methyl ester hydrochloride in 500 ml dichloromethane. The reaction mixture was then allowed to warm to 25° C. and was stirred for about 16 hours. The reaction mixture was diluted with 250 ml water, the organic layer was separated, washed with water, washed with 10% aqueous hydrochloric acid solution, washed with water, dried over magnesium sulfate and evaporated to give 36.5 g N-(methoxycarbonylmethyl)benzenesulfonamide, which crystallized as a colorless solid melting at 62°-63° C. A 3.5 g (0.035 mol) sample of triethylamine was added dropwise to a solution of 8 g (0.035 mol) N-methoxycarbonylmethyl)benzenesulfonamide and 6.5 g (0.035 mol) trichloromethylsulfenyl chloride in 150 ml dichloromethane. The reaction mixture was then stirred at about 25° C. for about 1 hour, washed with water, dried over magnesium sulfate and evaporated to give 7.5 g of N-methoxycarbonylmethyl-N-trichloromethylthiobenzenesulfonamide, which crystallized as a colorless solid melting at 61°-62° C. The compound is tabulated in Table I as Compound No. 1.
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:20]=2)[CH2:15][C@@H:14]1[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27](=[O:32])[C:28]([F:29])([F:31])[F:30])=[CH:23][CH:24]=2)[CH2:15][C@@H:14]1[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(O)C(F)(F)F)cc2)C[C@@H]1CCC(=O)OC
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(=O)C(F)(F)F)cc2)C[C@@H]1CCC(=O)OC
Yield: 46.8 %

Procedure:
(2S, 4S)-1-N-Dodecyl-4-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy]pyrrolidine-2-propanoic acid, methyl ester (150 mg, 0.276 mmol) was oxidized as described in the preparation of 4-[N-dodecyl-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (70 mg, 47%) as a pale yellow oil. [a]D=−35.7° (c 0.84, CDCl3) Treatment of the above free amine with anhydrous hydrogen chloride (1.0 M in ether) gave the hydrochloride salt as a pale yellow foam.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(C(C)C)nncc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C)nncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 3-(1-isopropylphthalazin-6-yl)-4-methylbenzoate (37.5 mg, 0.11 mmol) in tetrahydrofuran (0.3 mL) and methanol (0.15 mL) was treated with 1N aq. sodium hydroxide (0.28 mL, 0.28 mmol) and stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and the residue was taken up in water. The pH was adjusted with 10% HCl solution to ˜7. The precipitate formed was collected via filtration and dried under high vacuum to afford the title compound as a maize-colored solid. MS (ES+): 307.2 (M+H)+.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O>C(O)(=O)C>[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:1]
Reactant: COc1cc(Br)c(O)c(CO)c1
Reactant: Br
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c(CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In the course of 30 minutes, at room temperature, 20 g of hydrogen bromide are introduced into a suspension of 50 g of 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in 300 ml of anhydrous acetic acid. The reaction mixture is stirred for 5 hours at room temperature and the resulting solution is concentrated by evaporation. The black-brown oily residue, which crystallises slowly when left to stand at room temperature, is crystallised from ethyl acetate/cyclohexane (5:1) with the addition of a small amount of activated charcoal. 3-Bromo-2-hydroxy-5-methoxy-benzyl bromide is thus obtained [1H-NMR (360 MHz, CDCl3); 3.75 (s, 3H, OCH3), 4.53 (s, 2H, CH2BR), 5.45 (s, 1H, OH), 6.85 (d, 1H), 7.00 (d, 1H) ppm].
Reaction SMILES: O1C2=CC=CC2=CC=C1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:22]([O:25][CH2:26][CH3:27])(=O)[CH3:23]>[Pd].CO>[O:25]1[C:26]2[CH:27]=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:23][CH:22]1[CH:14]1[CH2:15][CH2:10][N:11]([C:16](=[O:21])[C:17]([F:18])([F:20])[F:19])[CH2:12][CH2:13]1
Reactant: O=C(N1CCCCC1c1ccc2cccc-2o1)C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: O=C(N1CCC(C2Cc3ccccc3O2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(4-benzofuran-2-yl-piperidin-1-yl)-2,2,2-trifluoro-ethanone (11.50 g), 10% palladium on carbon (1.15 g), ethyl acetate (135 mL) and methanol (15 mL) is shaken under hydrogen atmosphere (3.5 bar) at room temperature for 24 h. The catalyst is then separated by filtration and the filtrate is concentrated to give an oil that is submitted to the next reaction without further purification. Yield: 11.12 g (crude); LC (method 2): tR=1.34 min.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[C:14]1[C:22]2[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]=2[S:16][C:15]=1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:24][N:20]1[C:21](=[O:23])[C:22]2[C:14]([CH:3]=[CH:2][C:1]([N:10]3[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]3)=[O:4])=[C:15]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[S:16][C:17]=2[N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]1=[O:25]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: C=CC(=O)Cl
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C=CC(=O)N3CCN(C)CC3)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acryloyl chloride (0.65 ml) was added dropwise to a solution of 1-methylpiperazine (0.94 ml) and triethylamine (2 ml) in acetonitrile (10 ml) in a pressure tube at 0° C. and stirred at room temperature for 1 hour. 5-Bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.40 g, Example 1c)), palladium acetate (0.019 g) and tri-o-tolylphosphine (0.051 g) was added to the pressure tube and the reaction was heated at 70° C. for 21 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-5% ethanol in dichloromethane to give a brown solid. The solid was triturated with acetonitrile to give the title compound as a white powder (0.042 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[CH:14]1([N:13]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:5]2[C:3]([OH:4])=[O:2])[CH2:15][CH2:16]1
Reactant: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 168.8 %

Procedure:
To a stirred solution of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (150.0 mg, 0.33 mmol) in anhydrous THF (3.5 mL) and anhydrous methanol (1.0 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.66 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a yellow solid. The yellow solid was redissolved in water (5 mL), and concentrated. Acetic acid (2 drops) was added. A yellow solid precipitated out, and the solid was filtered, rinsed well with water, and dried on high-vacuum pump to give 243.6 mg (77.4%) of the product. 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.54 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.95 (br s, 1H), 7.65-7.52 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 6.67 (t, J=9.6 Hz, 1H), 3.53-3.28 (m, 1H), 1.20-1.07 (m, 2H), 0.85 (m, 2H); LC-MS (method C): [M+H]+=438.0, RT=0.67 min.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8]3=[C:9]([C:14]([O:16][C:17](=[O:18])[C:7]3=[CH:6][CH:5]=1)=O)[CH:10]=[CH:11][CH:12]=2)([O-:3])=[O:2].O.S(O)(O)(=O)=O.[CH2:25]([N:27]([CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH3:26].Cl>N1C=CN=C1>[CH2:25]([N:27]([CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:17](=[O:18])[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:13]4[C:8]=3[C:9](=[CH:10][CH:11]=[CH:12]4)[C:14]2=[O:16])=[CH:30][CH:29]=1)[CH3:26]
Reactant: CCN(CCO)c1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccc([N+](=O)[O-])c3cccc1c23
Agent: Cl
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: O
Product: CCN(CCO)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1

Procedure:
2.0 g (8.22 mmol) of 4-nitronaphthalene-1,8-dicarboxylic anhydride and 2.68 g (9.04 mmol) of N-ethyl-N-(2-hydroxyethyl)-p-phenylenediamine sulfate monohydrate were stirred in 12 g of molten imidazole at 130° C. under an argon atmosphere for 1 hour. After cooling, the mixture was poured into 400 mL of 2 N hydrochloric acid and the precipitate was suction-filtered off, washed with water and dried. The resulting product was used in Step 2 without further purification.
Reaction SMILES: C([O:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)(=O)C.[ClH:29]>C(O)C.O>[ClH:29].[OH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]2)=[CH:12][CH:11]=1
Reactant: O=C(Oc1ccc(CN2CC=CCC2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ccc(CN2CC=CCC2)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 1-(4-benzoyloxybenzyl)-1,2,3,6-tetrahydropyridine (1.0 g.) in ethanol (15 ml.) and water (5 ml.) containing sodium hydroxide (0.245 g.) was stirred for 2.5 hours. Ice-water (35 ml.) was added followed by acetic acid to pH7. The solid which formed was collected by filtration, washed with water, dried and dissolved in acetone (10 ml.). The solution obtained was acidified with concentrated hydrochloric acid to pH3 to give 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.6 g.), m.p. 232°-4° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[OH-].[Na+]>CO.O>[C:20]([O:19][C:17]([N:5]1[CH2:6][C@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12])[CH2:8][C@H:4]1[C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
(2S,4R)-N-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxyproline methyl ester (5.9 g, 16.5 mmol) was dissolved in methanol (45 ml) and water (11 ml). Then, 2.5N aqueous sodium hydroxide (6.6 ml, 16.5 mmol) was added thereto. The mixture was stirred at room temperature for 6 h, and then the organic solvent was distilled off. The aqueous layer was washed with ethyl acetate, then adjusted to pH 2.5 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and concentrated in vacuo to obtain crude (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyproline (5.1 g). ##STR384##