Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH2:54])[S:52][CH:53]=1)[CH3:45].Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH:54][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])[S:52][CH:53]=1)[CH3:45]
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)c2cn(C(C)C)c3cc(Cl)ccc23)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
A solution of triphenylphosphine (182 mg, 0.69 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (124 mg, 0.69 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with (2-amino-thiazol-4-yl)-acetic acid ethyl ester (294 mg, 1.58 mmol) and was stirred at 25° C. for 16 h. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (10 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded {2-[(6-chloro-1-isopropyl-1H-indole-3-carbonyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester (62 mg, 24%) as an orange foam: mp 65-75° C.; (ES)+-HRMS m/e calcd for C19H20ClN3O3S (M+H)+ 406.0987, found 406.0986.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:17][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1F
Yield: 45.3 %

Procedure:
To a warm solution of 4′-amino-3-fluoro-3′-nitro-[1,1′-biphenyl]-4-carbonitrile (Preparation 85, 0.86 g, 3.3 mmol) in ethanol (75 mL) was added saturated aqueous ammonium chloride solution (12 mL, 180 mmol) and iron (2.41 g, 43.2 mmol). The reaction solution was heated to reflux for 1 hour. The reaction mixture was allowed to cool, filtered, and the filtrate was adjusted to pH=9 with saturated aqueous sodium hydrogen carbonate solution and then the mixture was concentrated in vacuo to a residue. The residue was treated with methanol and the resulting suspension was filtered and the filtrate concentrated to dryness. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (0.34 g, 45%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[ClH:3].Cl.[CH2:5]([N:8]([CH2:16][CH2:17][CH3:18])[CH2:9][CH2:10][CH2:11][S:12]C(=N)N)[CH2:6][CH3:7]>O>[ClH:3].[CH2:16]([N:8]([CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][SH:12])[CH2:17][CH3:18]
Reactant: CCCN(CCC)CCCSC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)CCCS
Temperature: 95 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
25M Aqueous sodium hydroxide solution (11 ml) was added dropwise at 0° C. under nitrogen to a stirred solution of S-[3-(dipropylamino)propyl]isothiourea dihydrochloride (40 g) in water (100 ml), then the mixture was stirred at 95° C. for 2 hours and allowed to cool to ambient temperature. The product was extracted into ether (4×70 ml), the extracts were dried over magnesium sulphate, and the solvent was removed in vacuo. The residue was dissolved in ether, and the solution was saturated with hydrogen chloride to give a small amount of white solid which was collected by filtration. The filtrate was concentrated in vacuo, and the residue was combined with the white solid and dissolved in ethanol. The solution was saturated with hydrogen chloride and the solvent was removed in vacuo to leave crude 3-(dipropylamino)propanethiol hydrochloride (18.3 g) as a colourless semisolid which was used without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:37])[CH3:36])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([O:27][C:25]([NH:32][C@@H:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:38][O:39][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnccc1-c1ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1F
Temperature: 80 °C
Yield: 59.6 %

Procedure:
Methyl 4-(4-chloro-2-fluorophenyl)nicotinate (50 mg, 0.188 mmol) in toluene (1 mL) was treated with cesium carbonate (92 mg, 0.282 mmol) and N-Boc-L-Leucinol (121 mg, 0.565 mmol). The mixture was purged with nitrogen gas for 5 min and treated with di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (48.0 mg, 0.113 mmol). After purging the mixture with nitrogen for another 5 min, palladium(II)acetate (42.3 mg, 0.188 mmol) was added and nitrogen bubbled through for another 10 min. The mixture was sealed tightly and heated at 80° C. for 12 h. The mixture was filtered through a bed of diatomaceous earth (Celite®) and washed with ethyl acetate (2×3 mL). The washings were concentrated under reduced pressure. The residue was purified by combi flash (ethyl acetate and petroleum ether) to afford (S)-methyl 4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinate (50 mg, 0.112 mmol, 60% yield). LC/MS (ESI) m/e 447.2 [(M+H)+, calcd for C24H32FN2O5 447.2]; LC/MS retention time (method C): tR=2.17 min.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][OH:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>O1CCCC1>[N+:13]([C:16]1[CH:17]=[C:18]([CH2:22][CH:23]=[O:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: C1CCOC1
Product: O=CCc1cccc([N+](=O)[O-])c1

Procedure:
90 mmol of iodoxybenzoic acid are added to 60 mmol of 2-(3-nitrophenyl)ethanol in 300 ml of tetrahydrofuran. The reaction mixture is heated at reflux for 4 hours, then cooled and filtered. The filtrate is concentrated to yield the expected compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
First, 70 mg of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.25 ml of N,N-dimethylformamide, to which 36 mg of potassium carbonate and 27 mg of propargyl bromide were added, and the mixture was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 76 mg (yield, 96%) of 3-[4-chloro-2-fluoro-5-(propargyloxy)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-156; m.p., 106.9-107.1° C.).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44](O)=[O:45])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C1COCC1>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][C:39]=4[CH3:47])[CH:31]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CO)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (2 g, 2.81 mmol) and THF (18.74 ml) were stirred at 0° C. (ice bath). To this mixture was added borane tetrahydrofuran complex (5.90 ml, 5.90 mmol) in 3 min. The resulting mixture was staged at 0° C. for 15 min. The ice bath was then removed. Reaction mixture was stirred at room temperature for additional 1 hr. TLC indicated completion of reaction. Reaction was quenched by water (ice bath). The crude mixture was worked up with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting dark mixture was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted by a EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated affording the title compound. LCMS (ESI) calc.=697.19; found=680.29 (M-OH−)+. 1H NMR (CDCl3, 400 MHz, 1:1 mixture of atropisomers): δ 7.83 (d, J=4 Hz, 1H), 7.71 (s, 0.5H), 7.67 (s, 1H), 7.66-7.58 (m, 2.5H) 7.43 (d, J=8 Hz, 0.5H), 7.40 (d, J=8 Hz, 0.5H), 7.38-7.32 (m, 1H), 7.28-7.23 (m, 1H), 7.22-7.14 (m, 2H), 7.12 (s, 1H), 7.05 (d, J=5.6 Hz, 0.5H), 7.03 (d, J=5.6 Hz, 0.5H), 5.56 (d, J=8.4 Hz, 0.5H), 5.23 (d, J=8 Hz, 0.5H), 4.97 (d, J=10.8 Hz, 0.5H), 4.93 (d, J=10.8 Hz, 0.5H), 4.68 (s, 2H), 4.15 (d, J=15.6 Hz, 0.5H), 3.95 (d, J=15.6 Hz, 0.5H), 3.85 (s, 1.5H), 3.83 (s, 1.5H), 3.80-3.66 (m, 1H), 2.32 (s, 1.5H), 2.26 (s, 1.5H), 0.52 (d, J=6.8 Hz, 1.5H), 0.38 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[S:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=3)=[CH:18][CH:19]=2)=[N:12][N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NCc1nnc(-c2ccc(O)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)phenol (1 g, 3.5 mmol) in methanol (9 mL) containing NaHCO3 (1.2 g, 13.9 mmol) and di-t-butyldicarbonate (Boc2O; 1.5 g, 7.0 mmol) was stirred for 5 h. The resulting mixture was filtered and the filtrate concentrated. The residue was dissolved in CH2Cl2 (48 mL) and treated with 0.5 M NaOCH3 in methanol (8.3 mL). After stirring at room temperature for 1 h, the volatiles were removed under vacuum to yield tert-butyl ((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate. To a solution of tert-butyl((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (1.01 g, 2.89 mmol), dimethylformamide (16 mL) and potassium carbonate (1.36 g, 9.86 mmol) was added 3-fluorobenzylbromide (0.61 mL, 4.93 mmol), and the mixture was stirred at room temperature overnight. After 24 h, the resulting mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, heptane:EtOAc) to yield tert-butyl((5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate. 1H NMR (400 MHz, CDCl3) δ 7.87-7.92 (m, 2H), 7.33-7.42 (m, 1H), 7.14-7.23 (m, 2H), 7.01-7.08 (m, 3H), 5.13 (s, 2H), 4.68-4.77 (m, 2H), and 1.48 (s, 9H); MS (ES+) 416 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O>[Cl:15][CH2:16][CH2:17][C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CC(C)=O
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCCl)cc1
Yield: 74 %

Procedure:
19.2 g (100 millimoles) of 3-(p-aminobenzoyl)-propionic acid were stirred with 24.8 g (195 millimoles) of 3-chloropropionyl chloride in 200 ml of absolute acetone for 10 hours at room temperature. The mixture was then evaporated down, the residue was stirred with 200 ml of water, and the product was filtered off under suction at 10° C., washed with cold acetone and dried at 100° C. under reduced pressure. 21 g (75%) of 3-[p-(3-chloropropionylamino)-benzoyl]-propionic acid were obtained as yellowish crystals of melting point 181°-182° C. (acetonitrile).
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH2:12].[Br:26][C:27]1[CH:32]=[C:31](Br)[CH:30]=[C:29]([Br:34])[CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:24]1[C:25]2[N:13]([CH2:10][CH2:11][CH2:12][C:31]3[CH:32]=[C:27]([Br:26])[CH:28]=[C:29]([Br:34])[CH:30]=3)[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: C=CCn1c2ccccc2c2ccccc21
Reactant: Brc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(CCCn2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
9-BBN (0.5 M in THF, 38 mL, 19 mmol) was added dropwise into a solution of 9-allylcarbazole (29) (3.0 g, 14.5 mmol) in THF (10 mL) at 0° C. The mixture was stirred at room temperature for 15 minutes and then at 35° C. for 4 hours before transferring into a mixture of 1,3,5-tribromobenzene (19.5 g, 60.3 mmol), Pd(PPh3)4 (0.84 g, 0.72 mmol), K2CO3 (10.0 g, 72.4 mmol), H2O (15 mL) and THF (15 mL). The reaction mixture was stirred at 90° C. overnight, cooled to room temperature, and then extracted with chloroform. The organic extracts were combined, washed with water and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by column chromatography on silica gel with hexane/methlylene chloride 10:1 to 9:1 (v/v) as the eluent to yield 30 as a white crystals (5.4 g, 84%). 1H NMR (400 MHz, CDCl3, 298 K): 8.11-8.10 (d, 2H), 7.49-7.45 (m, 3H), 7.34-7.32 (m, 2H), 7.26-7.20 (m, 4H), 4.37-4.33 (t, 2H), 2.65-2.60 (d, J=7.6 Hz, 2H), 2.25-2.18 (m, 2H).
Reaction SMILES: [C-]#N.[Na+].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([CH:20]=[O:21])[O:19][C:13]=2[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH3:22][OH:23]>[O-2].[O-2].[Mn+4]>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([C:20]([O:23][CH3:22])=[O:21])[O:19][C:13]=2[CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C=O)oc2C1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1nc2c(o1)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h

Procedure:
Sodium cyanide (220 mg) and manganese dioxide (780 mg) were added to a solution of 5-(tert-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (225 mg) in methanol (9.0 ml) at room temperature. After stirring for 30 minutes, the reaction mixture was filtered through Celite with ethyl acetate. The filtrate was washed with water (50 ml) and saturated saline (50 ml) and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2→1:1) to obtain the title compound (120 mg) as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][C:13]1C=CC(S(O)(=O)=O)=CC=1>C(OCC)(OCC)(OCC)C>[CH3:12][C:13]1[O:11][C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(C)(OCC)OCC
Product: Cc1nc2cccc(C(=O)O)c2o1

Procedure:
A solution of 3-amino-2-hydroxy-benzoic acid (9.40 mmol) and PTSA (0.34 mmol) in triethyl orthoacetate (5.77 mL) is heated to reflux for 5 h and concentrated in vacuo. The residue is washed with ether and dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.67 min; [M+H]+=178.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1([Se]Br)C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH:11]=[C:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Agent: Br[Se]c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -15 °C
Reaction time: 1 h

Procedure:
3.65 g (3R,5S)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) is added to toluene (20 ml). Sodium hydride (400 mg) is added to the mixture. The mixture is cooled to −15° C. 22 ml Potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) is then added. The resulting mixture is then stirred for 1 h at −15° C. Phenylselenyl bromide (2.8 g) in toluene (20 ml) is then added to the mixture. The resulting mixture is stirred for 0.5 h at −15° C. The mixture is then poured into water and the phases are separated. The organic phase is concentrated under reduced pressure. Ethyl acetate (50 ml) and aqueous hydrogen peroxide (10 ml, 30%) is then added to the residue at ambient temperature. After 1 h of stirring, the phases are separated. The organic phase is washed with saturated sodium hydrogen carbonate solution, and then saturated sodium hydrogen sulfite solution, before being concentrated under reduced pressure. The residue is crystallised from isopropyl acetate/heptane (20 ml:5 ml) to afford (R)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (4a, R1=Boc). 1H NMR (DMSO): 1.56 (9H), 1.66 (3H), 3.02 (1H), 3.32 (1H), 4.75 (1H), 7.04 (1H), 7.18 (2H), 7.36 (1H), 7.46 (2H), 7.60 (2H), 7.66 (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.Cl.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH2:48])[CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:48][CH2:47][CH2:46][N:43]3[CH2:42][CH2:41][N:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=4)[CH2:45][CH2:44]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCN1CCN(c2ccccn2)CC1
Agent: Cl
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCN1CCN(c2ccccn2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 2-(4-pyridin-2-yl-piperazin-1-yl)-ethylamine tetrahydrochloride (Reference Example 5) according to the method described in Example 1e. MS (EI) 637.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)#[N:25].F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C>CN(C)C=O.C(OCC)(=O)C>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:14][C:11]2[S:12][CH:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)=[O:34])=[CH:28][CH:27]=1)#[N:25]
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2csc(NC(=O)Cc3ccc(C#N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.41 g 4-(4-Methoxyphenyl)-1,3-thiazol-2-amine was dissolved in 2 ml dimethylformamide. 3.0 ml N,N-Diisopropylethylamine, 1.0 g commercially available (4-Cyano-phenyl)-acetic acid and 2.25 g O-((Ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate were added. The reaction mixture was stirred at room temperature overnight. Then 200 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml saturated NaHCO3 solution and then dried over MgSO4. The solvents were removed in vacuo and the residue purified by RP-HPLC to obtain 610 mg 2-(4-Cyano-phenyl)-N-[4-(4-methoxy-phenyl)-thiazol-2-yl]-acetamide as yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][C:16](=[O:23])[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=[O:3])[CH3:2].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].Cl>C1COCC1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][CH:16]([OH:23])[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(=O)C4)[C@H]3CC[C@]12C
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(O)C4)[C@H]3CC[C@]12C
Yield: 104.1 %

Procedure:
A solution of the ketone 9 (1.03 g, 3.28 mmol) in dry THF (20 mL) at 0° C. under nitrogen was treated, via syringe, with lithium tri-tert-butoxyaluminohydride (1.0 M, 1.5 eq, 4.92 mL, 4.92 mmol). After 2 h the solution was poured into 1N HCl (100 mL). The layers were separated and the aqueous layer was extracted with ether (3×50 mL). The organic layers were combined, washed with saturated aqueous NaCl solution (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give a white solid (1.08 g), Rf0.3 (30% EtOAc/hexane), which was used without further purification.