Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])([CH3:10])[CH3:9].[Br:19]NC(=O)CCC(N)=O>S(=O)(=O)(O)O>[Br:19][C:16]1[CH:17]=[CH:18][C:11]([CH:8]([CH3:10])[CH3:9])=[C:12]([CH:15]=1)[CH:13]=[O:14]
Reactant: CC(C)c1ccccc1C=O
Reactant: NC(=O)CCC(=O)NBr
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of trifluoroacetic acid (50 ml) and 2-isopropylbenzaldehyde (2.0 g, 13.5 mmol) was added conc. sulphuric acid (98%) (10 ml) at room temperature, followed by N-bromosuccinamide (NBS, 3.6 g 20.2 mmol) in portions. After 2 hrs, the mixture was poured into ice water and extracted with dichloromethane (3×30 mL). The organic layers were combined and neutralized with saturated aqueous sodium bicarbonate, washed with brine (30 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography to furnish 5-bromo-2-isopropylbenzaldehyde (1.80 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:17])([CH3:16])[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[C:18]1([CH3:30])[CH:23]=[CH:22][C:21]([S:24]([CH2:27][N+:28]#[C-:29])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[N+:28]([C:27]([S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH3:30])=[CH:23][CH:22]=1)(=[O:25])=[O:26])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([CH3:17])[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:17])([CH3:16])[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)#[C-:29]
Reactant: CC(C)(CCCCCBr)COC1CCCCO1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCCCC(C)(C)COC1CCCCO1)(CCCCCC(C)(C)COC1CCCCO1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 220.9 %

Procedure:
Under nitrogen atmosphere, to a solution of 2-(7-bromo-2,2-dimethylheptyloxy)-tetrahydropyran (26.0 g, 39.4 mmol), tetra-n-butylammonium iodide (3.0 g, 8.1 mmol) and p-toluenesulfonyl methyl isocyanide (7.80 g, 39.4 mmol) in anhydrous DMSO (200 mL) was added sodium hydride (3.80 g, 20.5 mmol, 60% dispersion in mineral oil) in portions at 5-10° C. The reaction mixture was stirred at room temperature for 20 h and quenched with ice-water (400 mL). The product was extracted with diethyl ether (3×100 mL). The combined organic layers were washed with water (200 mL) and saturated sodium chloride solution (2×200 mL), dried over MgSO4, and concentrated in vacuo to get crude 2-[8-isocyano-2,2,14,14-tetramethyl-15-(tetrahydropyran-2-yloxy)-8-(toluene-4-sulfonyl)-pentadecyloxy]-tetrahydropyran (28.2 g) as an orange oil, which was used without purification. A solution of this crude product (28.0 g) and 48% sulfuric acid (46 g, from 12 mL of concentrated sulfuric acid and 24 mL of water) in methanol (115 mL) was stirred for 80 min at room temperature. The solution was diluted with ice-water (120 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with saturated Na2CO3 solution (2×150 mL) and saturated NaCl solution (150 mL). The organic solution was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes:ethyl acetate=2:1) to give 8-oxo-2,2,14,14-tetramethylpentadecane-1,15-diol (9.97 g, 80% over two steps) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 3.30 (s, 4 H), 2.39 (t, 4 H, J =7.2 Hz), 2.07 (br. s, 2 H), 1.60 - 1.55 (m, 4 H), 1.28-1.17 (m, 12 H), 0.85 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 212.0, 72.0, 43.0, 38.6, 35.2, 30.3, 24.0, 23.8. HRMS (LSIMS, gly): Calcd. for C19H39O3 (MH+): 315.2899, found: 315.2886. HPLC: 94.7% purity.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:16]([Cl:26])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[Cl:26][C:16]1[CH:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: CC(c1ccc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Reactant: O=COc1ccccc1
Product: CC(c1ccc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 59 %

Procedure:
The title compound is prepared in 59% yield (50 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (70 mg, 0.17 mmol, Intermediate-29, single enantiomer) and phenyl formate (42 mg, 0.35 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[N:50]=[C:49]1[CH2:57][NH2:58]>>[S:48]1[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[N:50]=[C:49]1[CH2:57][NH:58][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:43]
Reactant: NCc1nc2ccccc2s1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nc2ccccc2s1
Yield: 81 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with benzo[d]thiazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 81% yield: 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.44 (m, 1H), 7.41-7.34 (m, 1H), 7.31-7.24 (m, 2H), 7.07-6.98 (m, 2H), 6.63 (t, J=5.5 Hz, 1H), 6.13 (s, 1H), 5.01 (d, J=5.5 Hz, 2H), 4.44 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.53 (s, 3H); MS (ES+) m/z 481.2 (M+1).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](F)=[C:9]([F:31])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:30].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:8]2[C:7]([Cl:6])=[C:16]3[C:11]([C:12](=[O:30])[C:13]([C:27]([OH:29])=[O:28])=[CH:14][N:15]3[C:17]3[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=3)=[CH:10][C:9]=2[F:31])[CH2:37]1
Reactant: NC1CNC1
Reactant: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To 400 mg of N,N-dimethylformamide were added 100 mg of 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 102 mg of the title compound as a colorless powder.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=3[CH2:9][CH2:8][C@@H:7]2[CH3:17])=[O:5])[CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:18][C:12]1[CH:13]=[CH:14][C:15]2[N:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[C@@H:7]([CH3:17])[CH2:8][CH2:9][C:10]=2[C:11]=1[OH:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H]1CCc2c(O)cccc2N1C(=O)C1CC1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (4.0 g, 17.3 mmol) in acetonitrile (600 mL) and dichloromethane (150 mL). The solution was cooled to −10° C., and a solution of N-bromosuccinimide (3.08 g, 17.3 mmol) in acetonitrile (50 mL) was added dropwise over 3 h. The resulting solution stirred for 30 minutes at −10° C., and was then concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 0-20% ethyl acetate/petroleum ether) to afford (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (3.6 g, 68%) as a light yellow solid. MS: (ES, m/z): 310, 312 [M+H]+
Reaction SMILES: C([N:8]1[C@H:12]2[CH2:13][CH2:14][C@@:15]3([CH2:19][C@@H:18]([C:20]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=4[O:31]CC4C=CC=CC=4)[CH2:17][O:16]3)[C@:9]1([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:10][C@H:11]2[S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40])C1C=CC=CC=1>[Pd].C(O)C>[OH:31][C:21]1[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:25][C:20]=1[C@H:18]1[CH2:17][O:16][C@:15]2([CH2:14][CH2:13][C@@H:12]3[NH:8][C@@:9]2([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:10][C@H:11]3[S:39]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:19]1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2OCc2ccccc2)CO1
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2O)CO1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 106.5 %

Procedure:
A mixture of (1R*,2R*,4′S*,5S*,6R*)-8-benzyl-2′,3′,4′,5′-tetrahydro-4′-(2-benzyloxy-5-trifluoromethoxyphenyl)-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan](Description 16; 2.2 g, 2.97 mmol), 5% palladium on charcoal (3 g, 1.4 mmol) and ethanol (55 ml) was stirred under hydrogen atmosphere (1 atm) at +70° C. for 70 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (1.77 g, quant.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CC1CCN(C(=O)OC(C)(C)C)CC1)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CC1CCNCC1)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyl]-piperidine-1-carboxylic acid tert-butyl ester (210 mg; 0.4 mmol; 1 eq.) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in to afford the title compound (131 mg, 77%) as an off-white solid. 1H NMR (CDCl3) δ 7.38-7.24 (m, 4H), 5.04-5.01 (m, 2H), 4.51 (s, 1.3H), 4.48 (s, 0.7H), 3.04-2.96 (m, 2H), 2.91 (s, 2H), 2.85 (s, 1H), 2.70 (s, 1H), 2.61-2.57 (m, 4H), 2.53-2.43 (m, 2H), 1.80-1.57 (m, 4H), 1.19-1.06 (m, 2H). HPLC (max plot) 100%, Rt 2.75 min. UPLC/MS: (MS+) 424.4 ([M+H]+).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+:4].C(O)(=O)/[C:6](=[C:8](\[CH:10]=[O:11])/Br)/Br.[OH2:14]>C(O)C>[CH:10](/[O-:11])=[C:8](\[N+:1]([O-:3])=[O:2])/[CH:6]=[O:14].[OH2:2].[Na+:4]
Reactant: O=N[O-]
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C/C(=C\[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium nitrite (714 g, 10.2 mol) in 700 ml of water at 50° C.±5° C. was added over a period of 3 hours a solution of mucobromic acid (48) (700 g, 2.7 mol) in 700 ml of warm ethanol. The reaction was stirred for 15 minutes, cooled to 0° C., and 700 ml of ethanol was added. The resulting orange precipitate was collected by vacuum filtration and dried in vacuo to yield sodium nitromalondialdehyde monohydrate (305 g, 1.9 mol) which was used in the next step without further purification. Glycine ethyl ester (300 g, 2.9 mol) and nitromalondialdehyde monohydrate (305 g, 1.9 mol) were placed in a 12 l round bottom flask and slurried with a mechanical stirrer in 560 ml of methanol and 280 ml of water. Sodium hydroxide (800 g, 20 mol) dissolved in 1.6 l water was added to the solution at a rate which maintained the temperature at 50° C. The reaction was cooled to 0° C. with an ice bath and neutralized to pH. 0 with 1.7 l HCl (conc.) while maintaining the temperature below 10° C. A black precipitate was removed by filtration through Celite and the product was extracted with 20 liters of ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) as a brown solid which was used without further purification. To a solution of 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) dissolved in 180 ml of methanol was added 8 ml of concentrated sulfuric acid. The solution was refluxed for 15 hours, cooled to 0° C. and 90 ml of water was added. The solution was then allowed to stand at −20° C. for 2 days. The resulting light brown crystals were collected by vacuum filtration to yield pure methyl-4-nitropyrrole-2-carboxylate (49) (10 g, 0.62 mol) in 23% overall yield. 1H NMR (DMSO-d6) δ 14.2 (br s, 1H), 7.74 (d, 1H, J=1.6 Hz), 7.35 (d, 1H, J=1.7 Hz), 3.73 (s, 3H).
Reaction SMILES: CC(C)=O.[OH-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:19]2[CH2:21][CH2:20]2)[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]([CH:19]2[CH2:21][CH2:20]2)[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)[C@@H](c1ccc(Cl)cc1)C1CC1
Yield: 0 %

Procedure:
Horse liver esterase (4.6 g horse liver acetone powder, Sigma Chemical Co.) is suspended in water (200 ml) at room temperature and the pH is adjusted to 7.5 with 1.0 M sodium hydroxide. Methyl (2RS)-(4-chlorophenyl)(cyclopropyl)ethanoate (7.0 g, 31.4 mol) is added and stirring is continued at room temperature with the addition of 1.0 M sodium hydroxide as needed to maintain the pH at 7.1-8.0. After 14 ml of base had been consumed, the pH was brought to 3 with 10% hydrochloric acid, ethyl acetate is added and the mixture is filtered through diatomaceous earth. The organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography affords (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (2.5 g, 37.9%) and recovered ester (4.1 g). The ester was resubjected to the hydrolysis conditions with additional horse liver esterase (1.0 g ) for an extended period during which an additional 4.4 ml of 1.0 M sodium hydroxide is consumed. Acidification, workup and purification as described above affords methyl (2S)-(4-chlorophenyl)(cyclopropyl)ethanoate (3.1 g, 36.2%) The enantiomeric excess of (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (as the methyl ester) and (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid are determined with the chiral NMR shift reagent Eu(hfc)3 to be >96:4 and >98:2 respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1.COC1C=C(C2C=NC=CC=2)C=CC=1>>[CH3:15][C:11]1[CH:10]=[C:9]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(Br)c1
Reactant: Brc1cccnc1
Agent: COc1cccc(-c2cccnc2)c1
Product: Cc1cccc(-c2cccnc2)c1

Procedure:
3-(3-methylphenyl)-pyridine was prepared from 81.5 g (0.52 mol) 3-bromopyridine and 120 g (0.70 mol) 3-bromotoluene as described for the preparation of 3-(3-methoxyphenyl)-pyridine. (Example I7). B.p. 87°/0.05 mmHg. Yield 61.7 g (69%).
Reaction SMILES: [F:1][C:2]([F:28])([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13](O)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:56][CH2:57][C:58]1[CH:59]=[CH:60][C:61]([NH:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[N:62][C:63]=1[CH3:64].CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:2]([F:1])([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:56][CH2:57][C:58]2[C:63]([CH3:64])=[N:62][C:61]([NH:65][C:66]([O:68][C:69]([CH3:71])([CH3:70])[CH3:72])=[O:67])=[CH:60][CH:59]=2)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 2-(3-{[2,2-difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)acetic acid (15 mg, 37 μmol), as prepared according to the procedure of step 10 of Example 4, in DMF (0.3 mL) was added BOP (26 mg, 58 μmol), N-[5-(aminomethyl)-6-methyl(2-pyridyl)](tert-butoxy)carboxamide (12 mg, 51 μmol), and a solution of DIEA (19 mg, 146 μmol) in DMF (0.1 mL) (Sanderson, P. E., et al., WO 97/01338 (1997)). The mixture was stirred overnight, the solvents evaporated, and the resulting mixture was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with 10% KHSO4, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0.3, 0.6, and 1%) to give the title compound (11 mg, 49% yield) as a white solid. 1H-NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.4 Hz, 1H), 8.17-8.14 (m, 1H), 7.72-7.61 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.19 (dd, J=10.0, 8.3 Hz, 1H), 6.81 (dd, J=8.8, 1.7 Hz, 1H), 6.47 (t, J=9.1 Hz, 1H), 4.32 (s, 2H), 4.12-4.03 (m, 2H), 3.67 (d, J=2.0 Hz, 2H), 2.40 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calc'd for C32H32ClF4N4O3 (M+H): 631.2. Found: 631.1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:11][C:12]1[CH:13]=[C:14]2[C:20]3([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:19][N:18]([C:33]3[C:34]4[C@H:41]([CH3:42])[CH2:40][CH2:39][C:35]=4[N:36]=[CH:37][N:38]=3)[C:15]2=[CH:16][CH:17]=1)=O)(C)(C)C.[ClH:49]>C(Cl)Cl.O1CCOCC1.CCOCC>[ClH:49].[ClH:49].[ClH:49].[CH3:42][C@H:41]1[C:34]2[C:33]([N:18]3[C:15]4[C:14](=[CH:13][C:12]([O:11][CH:10]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[CH2:9][NH2:8])=[CH:17][CH:16]=4)[C:20]4([CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[CH2:19]3)=[N:38][CH:37]=[N:36][C:35]=2[CH2:39][CH2:40]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(OC(CNC(=O)OC(C)(C)C)c5ccccc5)ccc43)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(OC(CN)c5ccccc5)ccc43)c21
Reaction time: 8 h
Yield: 5 %

Procedure:
A solution of tert-butyl 5-(2-(tert-butoxycarbonylamino)-1-phenylethoxy)-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.235 g, 0.358 mmol) in DCM (4 mL) was treated with 4N HCl in dioxane (1 mL). The reaction was stirred at about room temperature overnight. The solvents were removed and the crude residue was partitioned between DCM and 1N HCl. The aqueous phase was extracted with DCM (×3), and then basified with 1N NaOH. The free base was extracted with DCM. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase column chromatography (0-60% ACN/H2O) to give the free base, which was taken up in DCM and acidified with 2N HCl in ether. Removal of the solvents under reduced pressure afforded 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yloxy)-2-phenylethanamine trihydrochloride (0.008 g, 5%). LCMS (APCI+) m/z 456.2 [M+H]+; Rt=2.49 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([C@H:7]([OH:10])CO)[C@@H:4]([C@H:11]([OH:14])CO)[O:3]1.I([O-])(=O)(=O)=O.[Na+].[BH4-].[K+]>>[CH3:1][C:2]1([CH3:15])[O:3][C@H:4]([CH2:11][OH:14])[C@@H:5]([CH2:7][OH:10])[O:6]1
Reactant: CC1(C)O[C@H]([C@H](O)CO)[C@@H]([C@H](O)CO)O1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CC1(C)O[C@H](CO)[C@@H](CO)O1
Yield: 92 %

Procedure:
The starting material (1) (3,4-O-isopropylidene-D-mannitol) was reacted with sodium periodate and potassium borohydride as described in J. Chem. Soc., Perkin Trans. I., 1972, 275 (the contents of which are herein incorporated by reference) to yield compound (2) in 92% yield. Compound (2) (5.1 g) was dissolved in pyridine (40 ml) and cooled in ice. To this solution was added methanesulphonyl chloride (18 ml), dropwise with stirring. The mixture was allowed to stand at room temperature for 3 hours, after which time it was added to a solution of sodium bicarbonate. This solution was then extracted with dichloromethane (5×50 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo. The residue obtained was recrystallised from ethanol to give 2,3-O-isopropylidene-1,4-di-O-methanesulphonyl-D-threitol (3), (6.6 g, 66%), m.p. 83°-85° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([NH2:11])=[C:4]([NH2:12])[N:3]=1.[CH:13]([CH:15]=O)=O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]2[C:4](=[N:12][CH:13]=[CH:15][N:11]=2)[N:3]=1
Reactant: O=CC=O
Reactant: CCOc1nc(N)nc(N)c1N
Solvent: CCO
Product: CCOc1nc(N)nc2nccnc12
Yield: 206.4 %

Procedure:
To a solution of 2,5,6-triamino-4-ethoxy-pyrimidine (10.54 g, 62.37 mmoles) in ethanol (160 ml) was added glyoxal (40% solution in water, 2.7 ml, 18.6 mmoles). The reaction mixture was refluxed for 4 hours. Some insoluble material was filtered off. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica, using a CH3OH/CH2Cl2 mixture (5:95) as the eluent), providing the pure title compound (7.34 g, yield: 62%). The spectral data of the product are identical with the literature data (W. Pfleiderer et al. cited supra).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13].Br[CH2:22][C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1>CN(C=O)C.CC(O)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[N:11]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][C:3]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[C:2]([F:1])[CH:7]=3)[S:10][CH:22]=2)=[CH:26][CH:27]=1
Reactant: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nc(Cc3ccc(Cl)cc3)cs2)cc1F
Temperature: 95 °C
Yield: 46.8 %

Procedure:
The mixture of the 2-fluoro-N-thiazol-2-yl-4-thioureido-benzenesulfonamide (32 mg, 0.000048 mol) and 1-bromo-3-(4-chloro-phenyl)-propan-2-one (14 mg, 0.000058 mol) in DMF/AcOH (1:1) was heated at 95° C. for 20 min. The crude product was purified using Gilson preparative HPLC (reverse phase, Phenomenex 250×30 min, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS. The appropriate fractions were combined and dried on a lyophilizer to give the desired product as a light yellow powder (10.8 mg, 47%).