Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:6]=1[Br:15])(=[O:3])[CH3:2].C(N(C1C=C(C)[C:26](OC)=[C:25]([CH3:32])[C:24]=1Br)C(=O)C)C=C.C(Br)C=C>>[CH3:26][C:25](=[CH2:24])[CH2:32][N:4]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:6]=1[Br:15])[C:1](=[O:3])[CH3:2]
Reactant: C=CCN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Reactant: COc1c(C)cc(NC(C)=O)c(Br)c1C
Solvent: C=CCBr
Product: C=C(C)CN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Yield: 86 %

Procedure:
Treatment of 4-acetamido-3-bromo-2,6-dimethylanisole (2.7 g, 10 mmol) according to a procedure similar to the one used for making compound 8, substituting methallylbromide for allyl bromide, afforded 14 (2.8 g, 86% yield) as a viscous liquid. Spectral data: 1H NMR (250 MHz): δ 1.71 (s, 3H), 1.75 (s, 3H), 2.18 (s, 3H), 2.33 (s, 3H), 3.26 (d, 1H, J=15 Hz), 3.66 (s, 3H), 4.62 (s, 1H), 4.75 (s, 1H), 4.82 (d, 1H, J=15 Hz), 6.82 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C>[CH3:14][C:2]1([CH3:1])[CH2:10][C:9]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1
Reactant: Fc1ccccn1
Reactant: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.8 %

Procedure:
To a solution of 6,6-dimethyl 3-ethyl-4,5,6,7-tetrahydro-1H-indol-4-one (50 mg, 0.26 mmol) in DMF (4 mL) at 0° C., was added NaH (11 mg of a 60% dispersion in mineral oil, 0.29 mmol). The cooling bath was removed and the mixture stirred at room temperature for 20 min. After this time 2-fluoropyridine (26 μl, 0.29 mmol) was added and the residue heated at 90° C. for 6 h. The solvent was evaporated and the residue partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed an silica gel, eluting with hexane:EtOAc (2:1), to give the title pyrrole (18 mg, 26%) as a colourless solid. mp 125-127° C. 1H NMR (360 MHz, CDCl3) δ 1.10 (6H,s), 1.23 (3H,t,J=7.4 Hz), 2.38 (2H,s), 2.83 (2H,d of q, J=7.4 and 1.0 Hz), 2.92 (2H,s), 6.88 (1H,s), 7.25-7.27 (1H,m), 7.30 (1H,d,J=8.0 Hz), 7.82 (1H,d of t, J=7.7 and 1.9 Hz), 8.51-8.57 (1H,m). MS (ES+) 269 (M+1).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][NH:28][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NCc1ccccn1
Product: CN(C(=O)Oc1ccc(C(=O)NCc2ccccn2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 2-aminomethylpyridine. The crude product was used without further purification (57%, oil). HPLC-MS: m/z=362.2 (M+1); Rt: 2.43 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 29) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a yellow foam (63 mg, 26%).
Reaction SMILES: I[C:2]1[C:3]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[N:22][C:4]=2[N:5]2[C:10]=1[CH:9]=[CH:8][N:7]=[C:6]2[NH:11][S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[SnH3]C1N=CC=CN=1.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Li+].[Cl-]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[CH3:27][O:26][C:25]1[C:3]2[CH:2]=[C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:11][S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:14])=[O:13])[N:5]3[C:4]=2[N:22]=[CH:23][CH:24]=1
Reactant: COc1ccnc2c1c(I)c1ccnc(NS(=O)(=O)c3ccc(C)cc3)n12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccnc2c1cc1ccnc(NS(=O)(=O)c3ccc(C)cc3)n12
Yield: 29.9 %

Procedure:
A solution of 24b (295 mg, 0.60 mmol), 27 (258 mg, 0.9 mmol), Pd2(dba)3.CHCl3 (120 mg, 0.12 mmol), PPh3 (60 mg, 0.24 mmol), LiCl (74 mg, 1.8 mmol) and CuI (23 mg, 0.12 mmol) in dioxane (25 mL) was refluxed for one hour. The solvent was evaporated and the crude dissolved in CH2Cl2. The organic solution was extracted three times with 4N HCl solution. The aqueous solutions were basified together with solid NaHCO3 and extracted with CH2Cl2. The organic solution was evaporated and the mixture was purified by flash column chromatography. Elution with CH2Cl2/MeOH (99/1) gave 23b (66 mg, 28%) and with CH2Cl2/MeOH (9/1) gave 25 (209 mg, 71%) as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][N:8]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[CH2:10][CH2:9]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:7][N:8]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[CH2:10][CH2:9]1)[CH3:6]
Reactant: NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of ethyl chloroformate (3.6 g) in 25 ml dichloromethane was slowly added to a solution of 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine (9 g) in 100 ml dichloromethane containing sodium bicarbonate (7 g). After one hour, the reaction mixture was filtered and concentrated to 11 g solid. A 3 g sample was recrystallized from ether to yield 2.2 g white crystals, mp 156°-157°.
Reaction SMILES: O.[C:2]([OH:12])(=[O:11])[C:3]1[NH:10][C:8](=[O:9])[NH:7][C:5](=[O:6])[CH:4]=1.N12CCCN=C1CCC[CH2:15][CH2:14]2.C(I)C.O>CN(C)C=O>[C:2]([O:12][CH2:14][CH3:15])(=[O:11])[C:3]1[NH:10][C:8](=[O:9])[NH:7][C:5](=[O:6])[CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Solvent: CCI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 87400.6 %

Procedure:
Orotic acid monohydrate (53.19 g, 0.306 mmol) was added to a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (46.51 g, 0.306 mmol) in dimethylformamide (85 ml). After stirring for 5 min., ethyl iodide (57.14 g, 0.366 mmol) was added to the solution and the mixture was heated at 60° C. for 5 hrs. Water (1 L) was added, and the resulting precipitate was collected by filtration, washed with water, and dried to give ethyl orotate (49.25 g, 88%).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([O:21][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[N:30]=4)[CH:27]=3)[CH:37]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in 1-methylpyrrolidin-2-one (7.0 mL) was added N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with toluene and diisopropyl ether to give the title compound (256 mg, 84%) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:17]([NH2:18])=[CH:16][C:10]2[N:11]=[C:12]([NH2:15])[N:13]=[N:14][C:9]=2[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:15][C:12]1[N:13]=[N:14][C:9]2[CH:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[C:17]([NH:18][C:35]([NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[CH:16][C:10]=2[N:11]=1
Reactant: Cc1ccccc1-c1cc2nnc(N)nc2cc1N
Reactant: CC(C)(C)N=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cc2nnc(N)nc2cc1NC(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
To a solution of 7-o-tolyl-benzo[1,2,4]triazine-3,6-diamine (compound 16 on scheme (CCLXIX)) (0.12 mmol, 30 mg) in 5 mL anhydrous 1,4-dioxane was added potassium bis(trimethylsilyl)amide (53 mg, 0.26 mmol) and the mixture was stirred at room temperature under argon for 1.5 h. To the red solution was added tert-butylisocyanate (28.5 μl, 0.36 mmol) and stirring was continued for 2 h at room temperature. The product was poured into saturated aqueous NaHCO3 solution (40 mL) and was extracted with EtOAc (100 mL). The combined organic phases were dried (Na2SO4) and the solvent was evaporated to give 1-(3-amino-7-o-tolyl-benzo[1,2,4]triazin-6-yl)-3-tert-butyl-urea (28 mg, 67%). The title product was prepared as a red solid (27.8 mg, 48%) from the above intermediate and 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide following the above-described coupling procedure and was purified by reverse phase preparative HPLC. 1H NMR DMSO-d6: δ 1.37 (s, 9H), 1.87 (m, 2H); 2.01 (m, 2H), 2.16 (s, 3H), 3.04 (m, 4H), 3.24 (td, J=6.1 Hz, J=6.1 Hz, 2H), 3.56 (m, 2H), 7.21 (s, 1H), 7.33-7.40 (m, 4H), 7.50 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.88 (t, J=6.1 Hz, 1H), 7.99 (s, 1H), 8.34 (s, 1H), 8.83 (s, 1H), 9.53 (br s, 1H), 10.21 (s, 1H). MS (ESI+) m/z=603.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:46][N:47]([C:49]([NH2:51])=[O:50])[NH2:48])[CH:43]=[CH:44][CH:45]=1>C(OCC)(=O)C.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:48][N:47]([CH2:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[CH:41]=2)[C:49]([NH2:51])=[O:50])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: COc1cccc(CN(N)C(N)=O)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2cccc(OC)c2)C(N)=O)cc1
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl]butyric acid (4.86 g, 16.5 mmol) was dissolved in ethyl acetate (40 mL). Oxalyl chloride (2.43 g, 19.14 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (100 mg, 1.37 mmol). Completion of acid chloride formation was verified by HPLC. This solution was then added dropwise to a suspension of 1-(3-methoxyphenylmethyl)hydrazine carboxamide methanesulfonate (4.80 g, 16.5 mmol) and pyridine (1.30 g, 16.5 mmol) in ethyl acetate (55 mL) at 0-5° C. After stirring at 0-5° C. for 6 h, an additional charge of pyridine was added (1.30 g, 16.5 mmol) and the solution was stirred at 0-5° C. for 1 h at which time the reaction was complete. The solution was warmed to rt and washed twice with 1N HCl (80 mL) and twice with 5% aq. NaHCO3 (80 mL). The organic layer was dried (MgSO4), filtered and concentrated to a waxy solid. The solids were recrystallized from a mixture of toluene (17 mL) and n-heptane (7 mL) at 60° C., cooled to 0-5° C. and filtered. The solids were dried in vacuo at 40° C. overnight, affording the title compound as a white solid (5.05 g, 65%): 1H NMR (DMSO-d6, 60° C.) δ 9.60 (s, 1H), 7.19 (t, 1H, J=8 Hz), 7.00 (d, 2H), 6.80 (m, 3H), 6.71 (d, 2 H, J=8 Hz), 5.92 (s, 2H), 4.52 (s, 2H), 4.15 (q, J=7 Hz), 3.71 (s, 3H), 2.45 (t, 2H, J=7 Hz ), 2.07 (t, 2H, J=7 Hz ), 1.73 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.17 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 171.9, 159.9, 159.3, 153.7, 140.5, 135.9, 129.9, 129.7, 120.9, 119.4, 114.1, 113.1, 79.2, 61.6, 55.5, 50.9, 34.3, 33.4, 27.2, 25.7, 14.6; IR (KBr mull): 3450, 3320, 3275, 3202, 2997, 2940, 1730, 1646, 1511 cm−1; Anal. Calcd. for C25H33N3O6: C, 63.68; H, 7.05; N, 8.91. Found: 63.49; H, 7.02; N, 8.99.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH2:16][C:15]([NH:14][CH:7]([CH3:6])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:26])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(C)CCCC(C)NC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)CCCC(C)NC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 56.1 %

Procedure:
Thiosemicarbazide (1.32 g, 14.5 mmol) was added to a solution of N-(1,5-dimethyl-hexyl)-4-oxo-4-phenyl-butyramide (2.54 g, 87.9 mmol), prepared in the previous step, in 30 ml of methanol plus 2.4 ml of 1 N HCl plus 2.4 ml of water and the reaction stirred at room temperature for 48 hours. The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2.95 g of an off-white solid foam. Purification of this foam by chromatography on silica gel (230-400 mesh) using 3:1 hexane-ethyl acetate and then 3:1 ethyl acetate-methylene chloride as the eluents gave the title compound (2.63 g, 82%) as a white foam, mp 58-65° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O>[O:16]([C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccnc(Br)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1ccnc(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
At 190° C., (2-bromopyridin-4-yl)methanol (550 mg), phenol (330 mg) and potassium carbonate (450 mg) were stirred for 30 minutes. To the reaction solution was added 330 mg of phenol, and the mixture was stirred at the same temperature for further 30 minutes. To the reaction solution were added 700 mg of phenol and 450 mg of potassium carbonate, and the mixture was stirred at the same temperature for further 1 hour. The reaction solution was cooled, then diluted with water, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-100:0)) to afford the title compound as a brown oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[C:25]([Cl:27])[N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:37]1[CH:44]=[CH:43][C:40]([O:41][CH3:42])=[CH:39][CH:38]=1)[C:29]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([C:28]([O:21][CH2:20][C@H:19]2[O:22][C@@H:15]([N:14]3[C:23]4[N:24]=[C:25]([Cl:27])[N:26]=[C:10]([NH:9][C:1](=[O:8])[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:11]=4[N:12]=[CH:13]3)[CH2:16][C@@H:17]2[OH:18])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:29]2[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)nc(Cl)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
Compound 123 was prepared from compound 122 as per the procedure of example 107 using compound 122 (2.5 g, 6.43 mmol), DMTCl (2.37 g, 7 mmol), dry TEA (0.71 g, 7 mmol) and dry pyridine (100 ml). The crude product was purified by flash chromatography using methylene chloride→ethyl acetate containing 18 TEA as the eluent to give 3 g (68%) of pure 123 as a foam.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:14](=[O:15])[O:13][CH2:12][CH2:11][N:10]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.COC(=O)C(N)C1C=CC(F)=CC=1.FC(F)(F)C(O)=O>C(OC(C)C)(=O)C>[CH2:16]([N:10]1[CH:11]=[CH:12][O:13][C:14](=[O:15])[C@@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Agent: COC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (−)-3-bromocamphor-8-sulphonic acid ((−)-3BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 17.24g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79%(R), 21%(S). The liquors were stirred at 65° C. for 3 days, then cooled to 0-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64%(R), 36%(S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20 h. The mixture was cooled to 0-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 2.2g, ee 99.2% (S) isomer. Total weight of (−)-3BCS salt: 20.28g, 97% yield. A sample (0.5g) of the (−)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one) as the free base: yield 8.7 g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH2:25][C:26]([NH:1][C:2]2[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ncccc1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ncccc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry CH2Cl2 (20 mL) was added to methyl 3-aminopicolinate (116) (0.421 g, 2.77 mmol). The solution was purged with nitrogen. Triethyl amine (1.16 mL, d=0.726, 8.31 mmol) was added to the solution via syringe. Phenylacetyl chloride (117) (0.805 mL, d=1.169, 6.09 mmol) was added to the solution via syringe. The mixture was stirred overnight at room temperature under nitrogen. The mixture was then stirred at 40° C. for 6 h. More triethyl amine (0.50 mL, 3.6 mmol) was added and, an hour later, more phenylacetyl chloride (0.400 mL, 3.02 mmol) was added. The mixture was stirred an additional hour and allowed to cool to room temperature. The reaction was quenched with water (20 mL), and the aqueous layer removed. The organic layer washed with water (3×15 mL), and dried with MgSO4. Silica gel was added and the slurry rota-evaporated to dryness. The resulting silica was chromatographed on silica (40 g, Davisil, grade 643, mesh 200-450) and eluded with EtOAc-hexanes (2:1, 400 mL). The appropriate fractions were collected (Rf =0.35). The solvent was rota-evaporated to yield the title compound (118) as a yellow oil, which, upon drying, precipitated out as a yellow solid (0.4463 g, 59.6%); Rf =0.35. 1H NMR (CDCl3) δ3.78 (s, 2, benzyllic), 3.97 (s, 3, CH3O--), 7.38 (m, 6, phenyl & H-5), 8.39, (dd, J1 =0.6, J2 =3.9, 1, H-4), 9.10 (dd, J1 =8.4, J2 =8.3, 1, H-6), 10.96 (s, 1, NH); MS (m./z) 270 (M+, 35), 211 (35), 179 (85), 153 (40), 147 (65), 119 (40), 94, (40), 91 (100).