Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C@@:14]1([CH3:41])[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C@@H:17]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:16]([C@@H:34]([CH2:38][CH3:39])[CH:35]([OH:37])[CH3:36])[C:15]1=[O:40])[CH:12]=[CH2:13].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C@@:14]1([CH3:41])[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C@@H:17]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:16]([C@@H:34]([CH2:38][CH3:39])[C:35](=[O:37])[CH3:36])[C:15]1=[O:40])[CH:12]=[CH2:13]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)O)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Reaction time: 0.03 h

Procedure:
To a solution of oxalyl dichloride (78 μL, 0.87 mmol) in DCM (1.5 mL) at −60° C. was added a solution of DMSO (93 μL, 1.30 mmol) in DCM (1.5 mL) under N2. After being stirred for 2 min, a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one prepared in example 151, Step C (200 mg, 0.434 mmol) in DCM (1.5 mL) was added and the resulting solution was stirred for 15 min. at −60° C. Then, triethylamine (305 μL, 2.17 mmol) was added to the reaction solution. After being stirred at rt for 20 min, the reaction was quenched (water), extracted (2×EtOAc), and washed (2×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by combi flash (SiO2, 24 g, 20% and 30% EtOAc/Hexanes) provided the title compound as a colorless foam.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:31])[N:17]([CH2:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[CH:6]=[C:5]([CH3:15])[N:4]3[C:16](=[O:31])[N:17]([CH2:19][C:20]4[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=4)[N:18]=[C:3]3[C:2]=2[C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[CH:13][CH:12]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
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: Cc1ccccc1
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 161.8 %

Procedure:
To a suspension of 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (53 mg, 0.103 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84 mg, 0.414 mmol), and 2.0 M aqueous sodium carbonate (1 mL, 2 mmol) in toluene (2 mL) was added (Ph3P)4Pd (36 mg, 0.03 mmol), and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (30-70%) in hexanes to obtain 85 mg of the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 32 mg (62%) of the title compound as a light yellow powder. HPLC/MS: retention time=3.00 min, [M+H]+=510.4.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3](O)[CH2:2]2.N12CCC(CC1)CC2O.[CH2:19]1[S:23](=[O:25])(=[O:24])[O:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[N+:1]12([CH2:21][CH2:20][CH2:19][S:23]([O-:25])(=[O:24])=[O:22])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=S1(=O)CCCO1
Reactant: OC1CN2CCC1CC2
Agent: OC1CC2CCN1CC2
Solvent: ClC(Cl)Cl
Product: O=S(=O)([O-])CCC[N+]12CCC(CC1)CC2
Temperature: 0 °C
Yield: 97.8 %

Procedure:
1.91 grams of 3-quinuclidinol was added to a 100 mL round bottom flask containing a stir bar. 50 mL of chloroform was added to the flask and mixture stirred to dissolve the quinuclidinol. The solution was cooled to near 0° C. in an ice bath. 1.83 grams of propane sultone was dissolved in 8 mL of chloroform in a test tube and then added dropwise to the solution of 3-quinuclidinol with stirring. During the addition of the propane sultone a white solid began to precipitate from solution. Following the addition the ice bath was removed and the solution allowed to warm to room temperature. The mixture was allowed to stir overnight then diluted with 50 ml of acetone and the solid collected on a fine porosity fritted glass funnel. The white precipitate was washed with 30 mL of acetone and the solid dried in a drying chamber containing Drierite® to obtain 3.42 g of a white solid. The structure was confirmed by positive mode electrospray mass spectrometry (M+Na)=286.2 and 1H NMR.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].O.NN>CO.[Fe](Cl)(Cl)Cl>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN(C)C)CC2
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CCN(C)C)CC2
Temperature: 64 °C
Reaction time: 12 h
Yield: 19 %

Procedure:
To N,N-dimethyl-3[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-3-oxo-1-propanamine (1.52 g, 5.4 mmol) in MeOH (50 mL) was added iron (III) chloride (0.220 g, 1.35 mmol, Aldrich) and activated carbon (2.0 g, Aldrich). The reaction mixture was stirred at 64° C. for 20 min before the dropwise addition of hydrazine hydrate (1.2 mL, 37.5 mmol, Aldrich) over 5 min. The reaction was kept stirring at 64° C. for additional 12 h. Filtration removed the solids and the filtrate was concentrated and purified via chromatography on SiO2 (0-10% 2 M NH3 in MeOH/DCM) to afford 1-[3-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (0.270 g, 19% Yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.72 (s, 1 H), 6.63 (s, 1 H), 3.95-4.15 (m, 2 H), 3.81 (s, 3 H), 3.76 (s, 2 H), 3.10 (t, J=8.43 Hz, 2 H), 2.83-2.96 (m, 2 H), 2.70 (t, J=7.15 Hz, 2 H), 2.41 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[C:25]([O:35][CH2:36][CH3:37])(=[O:34])[CH:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[OH:27].C(N(CC)CC)C>CC(C)=O.O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:27][CH:26]([C:25]([O:35][CH2:36][CH3:37])=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:11]
Reactant: CCOC(=O)CC(O)C(=O)OCC
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CC(OC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC
Yield: 66.7 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.8 g, 0.01 mole) in acetone (10 ml) was successively added diethyl DL malate (1.9 g, 0.01 mole) in acetone (10 ml) and triethylamine (1.01 g, 0.01 mole) in acetone (5 ml). A white precipitate quickly formed. The reaction was heated to reflux for 24 hours. Upon cooling, the reaction was poured in water (75 ml) and extracted twice with methylene chloride (25 ml @). The combined organic extracts were successively washed with 5% sodium hydroxide and brine solutions. The dried solution was stripped of solvent to give 3.56 g of an amber oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: CCOC(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with ethyl chloroformate (247 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [CH2:1]([N:7]1[C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH2:1]([N:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1cncc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCn1cncc1CO
Temperature: 0 °C
Yield: 95.7 %

Procedure:
A solution of the product of step (i) (420 mg, 2 mmol) in THF (15 ml) was added to a suspension of lithium aluminium hydride (380 mg, 10 mmol) in THF (15 ml) with stirring at 0° C. under argon. After 1 hour a saturated aqueous solution of sodium carbonate (1 ml) was added dropwise and the mixture was stirred for a further 15 minutes before being filtered through a pad of diatomaceous earth, washing well with ethyl acetate. The filtrate was evaporated to give 1-hexyl-5-hydroxymethylimidazole (349 mg, 96% yield) as a solid;
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (290 mg, 56%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([N:19](S(C)(=O)=O)[S:20]([CH3:23])(=[O:22])=[O:21])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([O:15][CH3:16])[C:8]([O:17][CH3:18])=[N:7]2.Cl>>[Cl:3][C:4]1[C:5]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([O:15][CH3:16])[C:8]([O:17][CH3:18])=[N:7]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N(S(C)(=O)=O)S(C)(=O)=O)c2nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Aqueous sodium hydroxide (1M, 145 ml, 145 mmol) was added to a suspension of 6,7-dichloro-5-di(methanesulphonyl)amino-2,3-dimethoxy-quinoxaline (12.28 g, 28.6 mmol) and the mixture was stirred at room temperature for 16 hours. The resulting orange solution was treated with 2M hydrochloric acid (to pH 3) and the solid which precipitated was filtered off, washed with water and ether, and dried under reduced pressure at 80° C. to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (8.46 g, 84%) as a white solid, mp 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)[C:9]2[C:10]([C:17]([OH:19])=O)=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH:14]4[CH2:15][CH2:16]4)[CH:13]=3)[C:17](=[O:19])[N:20]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2cn(C3CC3)nc2C(=O)O)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C4CC4)cc3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-1H-pyrazole-3-carboxylic acid (Step 39.2). tR: 3.88 min (HPLC 1); tR: 0.88 min (LC-MS 2); ESI-MS: 395 [M+H]+ (LC-MS 2); Rf=0.33 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.04 (m, 2H) 1.08-1.14 (m, 2H) 1.90 (s, 3H) 3.34 (s, 3H) 3.83-3.91 (m, 1H) 6.11 (s, 1H) 7.18-7.23 (m, 2H) 7.30-7.38 (m, 3H) 7.68-7.71 (m, 1H) 7.88 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:9](=[O:12])[C:10]#[CH:11])=[N:6][CH:7]=1>CN(CCN(C)C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:11]=[CH:10][C:9](=[O:12])[C:8]=2[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[CH:7]=1
Reactant: C#CC(=O)C(c1ccc(Br)cn1)c1c(F)cccc1F
Agent: CN(C)CCN(C)C
Product: O=c1ccn2cc(Br)ccc2c1-c1c(F)cccc1F

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-1-(2,6-difluorophenyl)but-3-yn-2-one (2 g) in TMEDA was heated to 90° C. for 1 h. LCMS analysis revealed the reaction was complete and the reaction was concentrated. The crude material was purified by silica gel chromatography (CH2Cl2/acetone) to yield the title compound.
Reaction SMILES: S(Cl)(C)(=O)=O.[F:6][C:7]([F:24])([F:23])[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][N:16]=2)=[CH:11][CH:10]=1.CCN(CC)CC.[Li+].[Br-:33]>C1COCC1.CC(C)=O>[Br:33][CH2:21][C:18]1[CH:17]=[N:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:7]([F:24])([F:23])[F:6])=[CH:10][CH:11]=2)=[N:20][CH:19]=1
Reactant: [Br-]
Reactant: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-c2ncc(CBr)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Mesyl chloride (0.55 mL, 7.0 mmol) was added to a solution of alcohol 91 (0.951 g, 3.52 mmol) and Et3N (1.5 mL, 10.8 mmol) in THF (40 mL) at 0° C. and the mixture was stirred at 0° C. for 1 h. The mixture was partitioned between EtOAc and water, and the organic layer was dried and evaporated to give an oil, which was dissolved in acetone (100 mL). LiBr (6.10 g, 70.2 mmol) was added and the mixture was refluxed under N2 for 1 h, then filtered and evaporated. The residue was partitioned between EtOAc and water, and the organic layer was dried and evaporated. Column chromatography on silica gel (eluting with CH2Cl2) gave 5-(bromomethyl)-2-[4-(trifluoromethoxy)phenyl]pyrimidine (92) (1.097 g, 94%) as a white solid: mp 80-81° C.; 1H NMR (CDCl3) δ 8.82 (s, 2H), 8.50 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 4.48 (s, 2H). APCI MS m/z 333, 335 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][C:12]([C:14](=[O:16])[NH2:15])=[C:11]([C:17]2[CH:38]=[CH:37][C:20]3[C:21]4[N:25]([CH2:26][CH2:27][O:28][C:19]=3[CH:18]=2)[CH:24]=[C:23]([C:29]2[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=2)[N:22]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].C([N+](CC=C)(CC=C)CC=C)C=C.C([N+](CC=C)(CC=C)CC=C)C=C>C(O)(C(F)(F)F)=O.CO.C(Cl)Cl>[CH:34]([N:30]1[C:29]([C:23]2[N:22]=[C:21]3[N:25]([CH2:26][CH2:27][O:28][C:19]4[CH:18]=[C:17]([C:11]5[CH2:10][CH2:9][NH:8][CH2:13][C:12]=5[C:14]([NH2:15])=[O:16])[CH:38]=[CH:37][C:20]=43)[CH:24]=2)=[N:33][CH:32]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: C=CC[N+](CC=C)(CC=C)CC=C
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CNCC3)cc1OCC2
Yield: 82 %

Procedure:
5-Carbamoyl-4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was stirred in TFA (1 mL) and DCM (2 mL) for 2 h. The reaction mixture was concentrated in vacuo and the residue triturated with diethyl ether to give a solid. The solid was then treated with tetra allylammonium carbonate (polymer bound) (1.84 g, 4.68 mmol) in methanol and DCM for 30 min. The resin was filtered off and the filtrate concentrated in vacuo to give 4-[2-(2-Isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid amide (0.40 g, 82%). 1H NMR 300 MHz (CDCl3) δ: 8.52-8.46 (1 H, m), 7.88 (1 H, s), 7.71-7.69 (1 H, m), 7.08 (1 H, dd, J=8.30, 1.82 Hz), 6.98 (1 H, d, J=1.79 Hz), 6.01-6.00 (1 H, m), 4.52-4.47 (4 H, m), 3.75 (2 H, s), 3.15 (2 H, t, J=5.82 Hz), 2.51 (2 H, m), 1.60 (6 H, d, J=6.62 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=3)[N:26]=2)=[CH:21][C:20]1=[O:39])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=4)[N:26]=3)=[CH:21][C:20]2=[O:39])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: Cc1nccc(Nc2nccc(-c3ccn([C@H](CO[Si](C)(C)C(C)(C)C)c4ccc(Cl)c(F)c4)c(=O)c3)n2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccc(Nc2nccc(-c3ccn([C@H](CO)c4ccc(Cl)c(F)c4)c(=O)c3)n2)n1
Reaction time: 1 h
Yield: 18.4 %

Procedure:
(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.034 g, 0.060 mmol) was placed in THF (5 mL) at room temperature. Tetra-n-butylammonium fluoride (“TBAF”) (0.18 mL, 0.18 mmol) was added to the mixture. The mixture was stirred for 1 hour, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (0-5.5% MeOH in DCM) to give the product (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.005 g, 18% yield). m/z (APCI-pos) M+1=453.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=[O:18])[C:15]([OH:17])=O)=[CH:11][S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C.[CH3:25][C:26]([O:28][CH2:29][C:30]1[CH2:39][S:38][C@@H:33]2[C@H:34]([NH2:37])[C:35](=[O:36])[N:32]2[C:31]=1[C:40]([OH:42])=[O:41])=[O:27]>C(Cl)Cl.CN(C)CCCO.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=[O:18])[C:15]([NH:37][CH:34]2[C:35](=[O:36])[N:32]3[C:31]([C:40]([OH:42])=[O:41])=[C:30]([CH2:29][O:28][C:26](=[O:27])[CH3:25])[CH2:39][S:38][C@H:33]23)=[O:17])=[CH:11][S:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)O)cs1
Agent: CCOC(=O)Cl
Agent: CN(C)CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=NC(=O)OC(C)(C)C)[nH]3)[C@H]2SC1
Reaction time: 2 h

Procedure:
2.7 g of 2-(2-tert.-butoxycarbonylimino-4-thiazolin-4-yl)-glyoxylic acid containing one molar equivalent of crystal alcohol are activated with a total of 2 ml of chloroformic acid ethyl ester (added in 3 portions) in 40 ml of methylene chloride at -30° C. in the presence of 2.8 ml of triethylamine and 2 drops of 3-dimethylaminopropanol, and the mixture is then combined with a solution of 3.6 g of 7-aminocephalosporanic acid in a mixture of 40 ml of methylene chloride and 3.6 ml of triethylamine. The resulting mixture is then allowed to come to 20° C., after 2 hours the methylene chloride is stripped off, the aqueous solution which remains is washed with ethyl acetate, then acidified (pH 1.5) and extracted with ethyl acetate and the dried organic phase is evaporated in vacuo. The residue is washed with methylene chloride and dried.
Reaction SMILES: [O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].[C:13]1(=[O:20])[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1.[CH2:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O.CCCCCC.[N+]([O-])([O-])=O.[Ag+]>[CH2:25]([CH:24]([C:18]1[C:13](=[O:20])[CH:14]=[CH:15][C:16](=[O:19])[CH:17]=1)[CH2:23][CH2:22][CH2:21][OH:27])[CH3:26]
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCCCCCO
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CCCCCC
Solvent: O
Product: CCC(CCCO)C1=CC(=O)C=CC1=O
Temperature: 60 °C

Procedure:
While stirring at 60° C., a solution of sodium peroxodisulfate (0.01 mol) in water (10 ml) was added to a heterogeneous mixture of silver nitrate (0.2 g) in water (40 ml) and 1,4-benzoquinone (0.01 mol) and 1-hexanol (0.04 mol) in hexane (5 ml). Extraction with diethyl ether followed by vaporization in vacuo yielded a residue which was purified using column chromatography on silica gel (eluting with hexane/diethylether).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:23](=[O:25])[NH2:24])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C(C)(C)C)=[CH:14][CH:13]=1)(C)(C)C>Cl.CCOCC>[NH2:7][C@H:8]([CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[C:23]([NH2:24])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(OC(C)(C)C)cc1)C(N)=O
Agent: Cl
Solvent: CCOCC
Product: NC(=O)[C@H](N)CCCc1ccc(O)cc1

Procedure:
A solution of [(R)-4-(4-tert-Butoxy-phenyl)-1-carbamoyl-butyl]-carbamic acid tert-butyl ester (167 g, 458 mmol) in 1 M HCl in Et2O (4000 ml) is stirred at room temperature for 3 days. After this time, a white solid forms which is collected by filtration and washed with Et2O to yield (R)-2-Amino-5-(4-hydroxy-phenyl)-pentanoic acid amide; [M+H]+ 209
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([Cl:18])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Yield: 96.7 %

Procedure:
3-Chloro-4-[(1-methylethyl)oxy]benzoic acid (D3; 4 g, 18. mmol), dichloromethane (DCM) (30 ml), oxalyl chloride (1.88 ml, 21.4 mmol) and DMF (1.4 μl, 0.019 mmol) were stirred under a blanket of nitrogen for 18 h. The solvent was removed in vacuo to give a yellow oil which crystallised on standing. The solid was dissolved in DCM and the solvent was removed in vacuo to give the title compound as a yellow solid (4.2 g).