Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[OH:1][C:2]1[CH:7]=[N+:6]([O-:20])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(O)cn1
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
To a suspension of methyl 5-hydroxypyridin-2-carboxylate (5.30 g) in dichloromethane (75 ml), m-chloroperbenzoic acid (>65%, 11.0 g) is added under ice-cooling, and the mixture is stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure. The residue is suspended in ethyl acetate and collected by filtration to give the title compound (4.62 g). Mother liquor is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform to methanol/chloroform=1/5). The resulting solid is suspended in ethyl acetate/diethyl ether and collected by filtration to give the title compound (0.68 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([Si]([C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28])(CC)CC)C>CO.O>[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[C:17]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28])#[CH:14]
Reactant: CC[Si](C#Cc1cccc(C(F)(F)F)c1CC(=O)OC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cccc(C(F)(F)F)c1CC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
K2CO3 (0.210 g, 1.52 mmol) was added to a solution of methyl 2-(2-((triethylsilyl)ethynyl)-6-(trifluoromethyl)phenyl)acetate (A92) (0.175 g, 0.491 mmol) in MeOH (1 mL) and the mixture stirred for 10 minutes at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were concentrated under reduced pressure and the residue dissolved in MeOH (1 mL). K2CO3 (0.204 g, 1.48 mmol) was added and the mixture stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3×20 mL) then the combined organic extracts were concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) to which K2CO3 (0.230 g, 1.66 mmol) was added and the resulting mixture stirred at room temperature for 30 minutes. Water (20 mL) was added and the mixture extracted with DCM (3×20 mL). The combined organic extracts were concentrated under reduced pressure to give the title compound A93 (0.113 g, 95%); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 4.08 (m, 2H), 3.70 (s, 3H), 3.35 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:20])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2cc(Br)cnc21
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Temperature: 90 °C
Yield: 2.9 %

Procedure:
A mixture of 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.05 g, 2.33 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.6 mL, 18.6 mmol), and potassium carbonate (0.97 g, 7.0 mmol) in 10% aqueous dioxane (19 mL) was sparged with Ar. Pd(PPh3)4 (134 mg, 0.12 mmol) was added and the reaction was sealed and heated to 90° C. for 6.5 h. The reaction was allowed to cool to rt and concentrated in vacuo. The remaining residue was dissolved in EtOAc (250 mL), washed sequentially with water (100 mL), aqueous 0.1 M HCl solution (150 mL), and brine (100 mL). The resulting solution was dried (Na2SO4) and concentrated. Purification by reverse phase HPLC yielded 23 mg of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as the TFA salt: LCMS (m/z): 342.9 (MH+), tR=0.74 min
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)[CH:25]=[O:26]>>[C:17]1([CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([N:9]3[CH2:8][C:7]4[CH:6]=[CH:5][CH:4]=[N:3][C:2]=4[NH:1][C:25]3=[O:26])[CH2:15][CH2:14]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ncccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Product: O=C1Nc2ncccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4.2 g (0.0142 mol) of 2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine, 2.4 g (0.0148 mol) of N,N′-carbonyldiimidazole and 50 ml of dimethylformamide was heated to 100° C. for 30 minutes. The still warm mixture was stirred into 300 ml of ice water, the precipitate formed was suction filtered and recrystallised from acetonitrile. After drying in vacuo 4.5 g (98.3% of theory) of colourless crystals of melting point 187° C. were obtained.
Reaction SMILES: C[C@@H:2]1[C@:19]([OH:28])([C:20]([CH2:22][O:23]P([O-])([O-])=O)=[O:21])[C@:18]2([CH3:29])[C@H:4]([C@H:5]3[C@:15](F)([C@@H:16]([OH:30])[CH2:17]2)[C@:14]2([CH3:32])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[Na+].[Na+].C[C@@H]1[C@](O)(C(CO)=O)[C@]2(C)[C@H]([C@H]3[C@](F)([C@@H](O)C2)[C@]2(C)C(=CC(C=C2)=O)CC3)C1>>[CH3:32][C@@:14]12[C@H:15]3[C:16]([CH2:17][C@:18]4([CH3:29])[C@@:19]([OH:28])([C:20]([CH2:22][OH:23])=[O:21])[CH2:2][CH2:3][C@H:4]4[C@@H:5]3[CH2:6][CH2:7][C:8]1=[CH:9][C:10](=[O:11])[CH2:12][CH2:13]2)=[O:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)COP(=O)([O-])[O-]
Agent: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: [Na+]
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO

Procedure:
Eight rabbits of the New Zealand breed were used, weighing approximately 2 kg. In the right eye of each animal, 0.8 ml/week of Bentelan Depot (equivalent to 4 mg betametasone) were instilled for 4 weeks. The left eye was kept as control. The medicament, administered subconjunctivally, brought about an increase of the intraocular tension in the first week, reached its peak in the second week and then remained constant until the fifth week.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C@@H:9]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:23][O:24][CH:25](OC)[O:26][CH3:27]>CO>[CH2:1]([N:8]([CH3:17])[C@@H:9]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:25]([O:26][CH3:27])[O:24][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)OC
Reactant: CN(Cc1ccccc1)[C@H](C=O)C1CCCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(OC)[C@H](C1CCCC1)N(C)Cc1ccccc1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of (S)-2-(benzyl(methyl)amino)-2-cyclopentylacetaldehyde (7.9 g, 34 mmol, 1.0 eq) in MeOH (200 mL) was added concentrated H2SO4 (12.5 g, 127 mmol, 3.7 eq) drop-wise at 0° C. The reaction mixture was stirred for 10 min, then trimethylorthoformate was added (33 g, 311 mmol, 9.0 eq.) at 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then heated to reflux for overnight. After cooled, the solvent was evaporated under reduced pressure, and the obtained residue was poured into sat NaHCO3 (300 mL, aq), extracted with ethyl acetate (300 mL). The organic layer was washed with brine, dried over sodium sulphate and evaporated to give a residue, which was purified by column chromatography on silica to yield the product 6 (8.6 g, 90% for two steps) as a light color oil.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][NH2:20]>CN1C(=O)CCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:2]2=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]2[CH:4]=[N:20]1
Reactant: NNc1ccc(F)cc1F
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.7 %

Procedure:
To a dry 16×100 mm Chem-Glass reaction tube under N2 was added 2-fluoro-4-iodonicotinaldehyde (5 g, 19.92 mmol), (2,4-difluorophenyl)hydrazine (3.01 g, 20.92 mmol) and anhydrous NMP (35 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temp, and then placed in a 180° C. oil bath for 4 h. The reaction mixture was then allowed to stir at room temperature for 72 h. The reaction mixture was diluted with EtOAc (1200 mL) and the organic layer was extracted with water (6×350 mL), brine (1×100 mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by Biotage Silica gel chromatography on a 300 g Thompson Single Step™ silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 10 column volumes to give 4.53 g (44.6%) of Intermediate 13A, as a light yellow solid that contained 28% of the uncyclized hydrazone intermediate ((E)-3-(2-(2,4-difluorophenyl)hydrazono)methyl)-2-fluoro-4-iodopyridine). 1H NMR (500 MHz, CCl3D) δ ppm 8.21 (1 H, d, J=4.58 Hz), 8.14 (1 H, s), 7.59-7.71 (2 H, m), 7.10 (2 H, td, J=7.55, 3.81 Hz). LC/MS (Condition A): T=3.7 min, (M+H)+ 357.90.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:22])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])N=1.CS(O)(=O)=O.N1CCCC1>>[NH2:22][C:8]([N:4]1[CH2:1][CH2:2][CH2:6][CH2:5]1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12]
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Agent: CS(=O)(=O)O
Solvent: C1CCNC1
Product: NC(=NS(=O)(=O)c1ccccc1[N+](=O)[O-])N1CCCC1

Procedure:
The compound of Example 27 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-2-nitrobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 298.32; found mol. wt. (M+H) 299.3; 596.8 (Dimer)
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:27][C@@H:28]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:6]1[C:7]([NH:27][C@@H:28]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]2)=[N:8][C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][C:20]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:25][CH2:26]3)=[CH:13][CH:12]=2)=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cnc(C(N)=O)c(Nc3ccc(N4CCC5(CC4)OCCO5)cc3)n2)C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2nc(Nc3ccc(N4CCC5(CC4)OCCO5)cc3)c(C(N)=O)nc2Br)C1
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a mixture of tert-butyl (3R)-3-[(5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (10 g), chloroform (200 mL) was added N-bromosuccinimide (3.46 g) under ice-cooling, followed by stirring for 1 hour. To the reactant was added silica gel, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-400:10:1) to obtain tert-butyl (3R)-3-[(3-bromo-5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (6.17 g) as a yellow amorphous substance.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][CH2:37][CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: O=CCc1ccccc1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NCCc3ccccc3)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 32 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 27 mg (0.22 mmol) phenylacetaldehyde yielding 44 mg (46%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-((S)-3-methyl-1-phenethylamino-butyl)-thiazol-2-yl]-amine as a yellow solid. MS ISP (m/e): 476.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.34 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.24-7.13 (m, 6H), 7.02 (s, 1H), 7.00 (d, 1H), 6.64 (s, 1H), 3.76 (s, 3H), 3.59 (br t, 1H), 2.72-2.59 (m, 4H), 2.14 (s, 3H), 1.59-1.48 (m, 3H), 0.87 (d, 3H), 0.82 (d, 3H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1>>[C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]([C:27]3[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=3)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)ccc1CS(=O)(=O)c1ccccc1
Product: COC(=O)c1cc(-c2ccnn2C)ccc1CS(=O)(=O)c1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Example 37, starting from methyl 2-(benzenesulphonylmethyl)-5-bromobenzoate (Intermediate 63) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:29][NH2:30]>>[CH3:29][NH:30][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Reactant: CN
Product: CNc1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Temperature: 50 °C

Procedure:
1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (Example 56) (42.7 mg, 0.1 mmol) is dissolved in methylamine (30% in EtOH, 1 mL) in a sealable tube and heated under Ar for 10 min at 50° C. After evaporating the solvent, the product is purified by preparative TLC (2 20×20 cm plates, acetone/CH2Cl2=3:7) to give the title compound as a white solid: M+H=404.1; 1H-NMR (400 MHz, CDCl3): 8.22 (s, 1H, pyridinyl), 7.84 (s/broad, 1H, NH), 7.62 (s, 1H, 3-CF3-phenyl), 7.52 (d, 8.0 Hz, 1H, CF3-phenyl), 7.35 (t, 8.0 Hz, 1H, 3-CF3-phenyl), 7.28 (m, 3H, CF3-phenyl/oxo-phenyl-amine), 6.97 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 5.62 (d/broad, 2H, pyridinyl), 5.44 (s/broad, 1H, NH), 2.89 (s/broad, CH3—N); Rf (acetone/CH2Cl2=3:7): 0.36.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].O>CCOCC>[Br:1][CH2:2][C:3]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCNCC
Solvent: O
Solvent: CCOCC
Product: CCN(CC)C(=O)CBr
Temperature: -15 °C

Procedure:
Under a nitrogen atmosphere, a 1-liter flask is charged with 2-bromoacetylbromide (46.34 g, 230 mmol) and 300 ml ether. The flask is chilled to −15° C., and a solution of diethylamine (33.72 g, 460 mmol) in 200 ml ether is added over 1 hour to the flask. The resulting thick slurry is stirred cold for 1 additional hour, then warmed slowly to room temperature, and stirred overnight. The mixture is added to 250 ml cold water, and the resulting aqueous solution is extracted with ether (3 times, 200 ml ether each time). The combined ether extracts are washed with phosphoric acid (5 wt percent, 200 ml), aqueous potassium carbonate (8 wt percent, 200 ml) and thereafter brine (150 ml). The ether extract is then dried over sodium sulfate and concentrated in vacuo to a light brown residue. The residue is vacuum distilled to yield 2-bromo-N,N-diethylacetamide as a clear, colorless oil (22.99 g, 52% yield). 1H NMR (300 MHz, CDCl3), δ (PPM): 1.08 (t, 3H), 1.20 (t, 3H), 3.33 (q, 4H), 3.79 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)nc1
Reaction time: 7 h
Yield: 40 %

Procedure:
To a solution of 6-Methylnicotinonitrile (11-1) (Lancaster) (15 g, 127 mmol) in carbon tetrachloride (300 ml) was added N-bromosuccinimide (27.12 g, 152.4 mmol). The resulting solution was degassed and purged with nitrogen and AIBN (2,2′-azobisisobutyronitrile) (2.08 g, 12.6 mmol) was added. After 7 hours at 85° C., another batch of AIBN (1.04 g) was added and stirring was continued for another hour. After removal of the solvent the crude product was subjected to flash column chromatography in ethylacetate/hexanes to yield 10 g pure material (40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C@@H:9]([C:15]([N:17]2[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])[N:10]([CH3:14])[C:11](=[O:13])[CH:12]=1>[Pd].CCO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C@@H:9]1[C:15]([N:17]1[C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:20][O:19][C:18]1=[O:29])=[O:16]
Reactant: CN1C(=O)C=C(c2ccccc2F)[C@H]1C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C[C@@H](c2ccccc2F)[C@H]1C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 17 h
Yield: 33.6 %

Procedure:
To a slurry of 20% palladium on carbon (10 g, 0.06 equiv) in EtOH (1 L) was added a solution of diastereomeric mixture of 3-{[(2R)-3-(2-fluorophenyl)-1-methyl-5-oxo(3-pyrrolin-2-yl)carbonyl(4S)-4-benzyl-1,3-oxazolidin-2-one and (4S)-3-{[(2S)-3-(2-fluorophenyl)-1-methyl-5-oxo(3-pyrrolin-2-yl)]carbonyl}-4-benzyl-1,3-oxazolidin-2-one (154 g, 0.36 mol) in EtOH (1 L) and the resulting mixture was vigorously stirred under a H2 atmosphere (1 Atm) for 17 h. The reaction mixture was filtered through a pad of Celite®. NMR analysis of the filtrate showed only partial reduction, and the reaction mixture was treated with 10% palladium on carbon (Degussa type, 30 g, 0.1 equiv) in EtOH (4 L). After stirring under a H2 atmosphere (1 Atm) for 17 h, the reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure onto silica gel (250 g), then filtered through a plug of silica gel eluting with EtOAc. The filtrate was concentrated under reduced pressure onto silica gel (400 g) and purified by flash chromatography (2.5 kg silica gel, gradient from 25% to 60% EtOAc/hex) to afford (4S)-3-{[(2S,3S)-3-(2-fluorophenyl)-1-methyl-5-oxopyrrolidin-2-yl]carbonyl}-4-benzyl-1,3-oxazolidin-2-one (48 g, 30%) as a yellow solid: TLC (50% EtOAc/hex) Rf 0.22; 1H NMR (CDCl3; rotomeric mixture) δ 2.63 (dd, J=4.9, 9.5 Hz, 1H), 2.74-2.85 (m, 4H), 3.07 (dd, J=3.4, 13.2 Hz, 1H), 3.34 (t, J=8.3 Hz, 1H), 3.84-4.09 (m, 3H), 4.27 (dd, J=9.6, 18.8 Hz, 1H), 5.77 (d, J=8.8 Hz, 1H), 6.95-7.26 (m, 10H); HPLC ESMS m/z (rel abundance) 397 (MH+, 75%); and 3-{[(2R,3R)-3-(2-fluorophenyl)-1-methyl-5-oxopyrrolidin-2-yl]carbonyl}(4S)-4-benzyl-1,3-oxazolidin-2-one (48 g, 30%) as a yellow solid: TLC (50% EtOAc/hex) Rf 0.13; 1H NMR (CDCl3; rotomeric mixture) δ 1.63 (dd, J=11.2, 13.4 Hz, 1H), 2.64 (dd, J=2.8, 13.1 Hz, 1H), 2.75-2.93 (m, 5H), 3.95 (dd, J=3.4, 9.2 Hz, 1H), 4.09 (t, J=7.8 Hz, 1H), 4.40-4.50 (m, 2H), 5.77 (d, J=8.6 Hz, 1H), 7.04-7.12 (m, 4H), 7.21-7.32 (m, 5H); HPLC ES-MS m/z (rel abundance) 397 (MH+, 90%); and a mixture of the two diastereomers (17 g, 11%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.CC(C)(C)[CH:17]=[O:18]>CCOCC>[F:8][C:5]1[N:6]=[CH:7][C:2]([CH2:17][OH:18])=[CH:3][C:4]=1[CH3:9]
Reactant: CC(C)(C)C=O
Reactant: Cc1cc(Br)cnc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(CO)cnc1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
5-Bromo-2-fluoro-3-methylpyridine (2.0 g, 0.011 mol) was dissolved with stirring in anhydrous ether (30 mL) and cooled to −70° C. This was treated at <−60° C. with n-butyl lithium (4.8 mL, 2.5M in hexane, 0.012 mol) and the reaction mixture stirred at <−70° C. for one hour. Trimethylacetaldehyde (1.14 g, 0.013 mol) was added and the reaction mixture allowed to warm to −10° C. The reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to dryness. Purification of the residue by chromatography over silica (5-25% ethyl acetate:hexane) gave the desired product (1.6 g, 77%) as a clear oil.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:13])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Li+]>COCCOC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:3][OH:2])[CH3:13])=[O:7])([CH3:11])([CH3:12])[CH3:10]
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Product: C[C@@H](CO)NC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
This compound was prepared in 90% yield from the ester 4a (2.44 g, 12 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. The product was used for the next reaction without further purification. 1H NMR (CDCl3) δ 1.14 (d, J=6.6 Hz, 3H, CHCH3), 1.44 (s, 9H, t-Bu), 2.71 (br s, 1H, CH2OH), 3.45 and 3.55 (AB part of ABX spectrum, 7 lines, JAX =4.7 Hz, JBX =7.4 Hz, JAB =10.1 Hz, 2H, 2H, CH2OH), 3.47-3.95 (m, 1H, CHCH3), 4.68 (br d, 1H, NH). Anal. Calcd. for C8H17NO3 : C, 54.84; H, 9,78; N, 7.99. Found: C, 54.84; H, 9.96; N, 7.96.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=1)[NH2:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:17][C:16]1[CH:18]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[CH:14][C:15]=1[CH3:19]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(Br)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (3.7 g, 0.003 mol) and 4-chlorophenylboronic acid (20.2 g, 0.13 mol) are added to a solution of 5-bromo-2-methylaniline (20 g, 0.1 mol) in 1,2-dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 20° C., a solution of 20% aqueous sodium carbonate (300 ml) is added to the mixture, and the resulting mixture is heated at reflux for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 3-amino-4′-chloro-4-methylbiphenyl (21.0 g).