Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:21][CH:20]([O:22]CC4C=CC=CC=4)[CH2:19]3)[C:16]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)[C:16]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1C1CC(OCc2ccccc2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1C1CC(O)C1
Temperature: 0 °C
Yield: 123.7 %

Procedure:
A mixture of 4-amino-6-{(S)-1-[1-(3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamino}pyrimidine-5-carbonitrile (0.05 g, 0.11 mmol) in DCM (3 mL) was cooled to 0° C. To this mixture was added boron tribromide (0.22 mL, 0.22 mmol) dropwise and the resultant mixture stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2 mL) and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 404 as an off-white glassy solid (50 mg, 99%). 1H NMR (DMSO-d6): δ 7.97-8.09 (3H, m), 7.74 (1H, dd, J=7.75, 4.8 Hz), 7.50 (2H, br s), 7.26-7.36 (1H, m), 5.67 (1H, qn, J=6.7 Hz), 4.70 (1H, qn, J=8.5 Hz), 3.96 (1H, m), 2.72-2.91 (2H, m), 2.55-2.72 (2H, m), 1.6 (3H, d, 7.2 Hz). LCMS (Method K): RT 2.36 min [M+H]+ 368
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Cl)=O.C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][Cl:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2F)=NC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CCl)n1-2

Procedure:
In the manner given in Preparation 10, 7-fluoro-5(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine is reacted with chloroacetyl chloride and after 1.5 hours with sodium acetate. The mixture is then refluxed to give 8-fluoro-1-(chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 13 8-Chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH:1]1([N:5]([CH3:13])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10])[CH2:4][CH2:3][CH2:2]1.O[Li].O.[ClH:17]>C1COCC1.O>[ClH:17].[CH:1]1([N:5]([CH3:13])[CH2:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)/C=C/CN(C)C1CCC1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C/C=C/C(=O)O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (E)-methyl 4-(cyclobutyl(methyl)amino)but-2-enoate (20) (1.47 g, 8 mmol) in THF/H2O (8 mL/2 mL) was added LiOH.H2O (730 mg, 16 mmol). The reaction mixture was stirred at RT overnight, then acidified with 1N HCl to pH=1 and concentrated in vacuum to afford (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride salt (21) (2.31 g, 97%, mixed with LiCl) as a white solid which was used in the next step without purification. LC-MS (ESI): m/z (M+1) 170.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[N:10]O)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[N:7]2[N:10]=[C:9]([C:12]3[O:13][CH:14]=[CH:15][C:16]=3[CH3:17])[CH:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccoc1C(Cc1cccc(Cl)n1)=NO
Agent: Cl[Fe]Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1ccoc1-c1cc2cccc(Cl)n2n1
Temperature: 15 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone oxime (24.5 g, 97.7 mmol) in 1,2-dimethoxyethane (200 mL) at 0° C. was added trifluoroacetic anhydride (14.5 mL, 103 mmol), while keeping the temperature below 10° C. After the addition was complete, the reaction was warmed to 15° C. The solution was then cooled to 0–5° C. and a solution of triethylamine (28.6 mL, 205 mmol) in 1,2-dimethoxyethane (30 mL) was added over 0.5 hours. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. To this mixture was added iron(II) chloride (0.62 g, 4.9 mmol) and the reaction was heated at 75° C. for 15 hours. The reaction was concentrated, then ethyl acetate and water were added. The organic phase was separated, washed with water, dried (magnesium sulfate), filtered and concentrated. Purification by silica gel chromatography (9:1 hexanes:ethyl acetate) gave 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine (14.6 g, 640%) as yellow oil. 1H NMR (CDCl3): δ 7.52 (d, 1H), 7.48 (d, 1H), 7.10 (t, 1H), 6.92 (d, 1H), 6.86 (s, 1H), 6.42 (d, 1H), 2.49 (s, 3H). MS m/233 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:6](OCC)=[O:7])C.[Li+].[BH4-].Cl>C1COCC1.C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH:5]([CH2:4][OH:3])[CH2:6][OH:7])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)malonic acid diethyl ester (14.6 g, 0.043 mol) in anhydrous THF (100 mL) and anhydrous toluene (100 mL), LiBH4 (2.1 g. 0.96 mol) was added portion wise. The resulting mixture was heated at 60° C. for 17 h, then stirred at ambient temperature for 24 h. The reaction mixture was slowly added to aqueous HCl (0.1 M, 350 mL) and then extracted with EtOAc. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc: MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford the title compound as a colourless oil (6.91 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 3.90-3.75 (m, 4H); 2.75-2.58 (m, 4H); 1.77-1.61 (m, 4H); 1.52 (m, 1H); 1.45 (s, 9H) and 1.26-1.13 (m, 1H).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1[CH2:37][CH:38]=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1[CH2:37]/[CH:38]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To an ice-cooled solution of ethyl diethylphosphonoacetate (1.1 ml, 5.54 mmol) in tetrahydrofuran (10 ml) was added sodium hydride (60%, in oil suspension, 220 mg, 5.5 mmol) under a nitrogen atmosphere, and the mixture was stirred for 30 min at the same temperature. To the ice-cooled reaction mixture was added a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(formylmethyl)pyrrolidine (1.72 g, 5.01 mmol) in tetrahydrofuran (3 ml), and the mixture was stirred for 1 h. The reaction mixture was poured into a mixture of ice water (200 ml) and 1N aqueous potassium hydrogensulfate (20 ml), and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was subjected to silica gel column chromatography (heptane-ethyl acetate) to give (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(E)-3-ethoxycarbonylallyl]pyrrolidine (1.98 mg, yield: 96%).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][C:27](Cl)=[O:28].O>ClCCl>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][C:27]([N:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1)=[O:28]
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: COC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A solution of 2.86 g (20 mmol) of methyl isonipecotate and 2.53 g (2.5 mmol) of triethylamine in 10 mL of dry dichloromethane was cooled to 0° C., and a solution of 4.02 g (22 mmol) of 2,5-dimethylphenylacetyl chloride in 5 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 16 h and then poured into 20 mL of water. The organic layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and hexanes to give 4.95 g (87.5% yield) of the title compound as white crystals.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9]N(C)C(=O)C.C(O)CCC.OP(O)(O)=O>C1(C)C=CC=CC=1>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][CH:9]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)N(C)C
Agent: O=P(O)(O)O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dried product (5.57 g) obtained from step 1 was charged along with 3.1 grams 1,2-phenylenediamine, 120 mL N,N-dimethyl acetamide, 30 mL n-butanol, 10 grams o-phosphoric acid (85%), and 40 mL toluene in a four neck 250 mL reaction kettle equipped with an overhead stirrer, thermocouple, gas inlets adapter and condenser. The mixture was stirred at 250 rpm at room temperature for 15 minutes and heated to 150° C. under argon atmosphere to remove all the toluene. The reaction was continued for 6 hours and the product was cooled to room temperature.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][C@H:33]([CH3:36])[C:34]#[N:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([C@H:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:36])#[N:35]
Reactant: C[C@@H](N)C#N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 40 mg, 0.093 mmol) and (R)-2-aminopropanenitrile (Int-X, 13.00 mg, 0.185 mmol) were dissolved in DMF (1 mL). 4-Methylmorpholine (37.5 mg, 0.371 mmol) and HATU (45.8 mg, 0.121 mmol) were added. After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 35 min, 20 mL/min, 220 nM, product retention=28.5 min) to provide single enantiomer N-((R)-1-cyanoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (27 mg, 0.055 mmol, 59.6% yield): [M+H]+=484.0; 1H NMR (400 MHz, methanol-d4) δ ppm 8.93 (1 H, d, J=7.70 Hz), 8.13-8.24 (2 H, m), 7.50-7.80 (7 H, m), 5.17 (1 H, s), 4.86-4.91 (1 H, m), 1.56 (3 H, d, J=7.04 Hz); HPLC peak RT=9.9 min (Method A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([O:27]C)=[O:26])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=[O:26])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3cccs3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylate (0.85 g, 1.8 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide solution (4 ml). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid (0.79 g, 96.3%) as crystals.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12]([Cu])#[N:13].[C-]#N.[Na+].O>CN(C=O)C.CCOC(C)=O>[C:12]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)#[N:13]
Reactant: N#C[Cu]
Reactant: Ic1cccc2ncccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
A mixture of 5-iodoquinoline (0.56 g; 2.2 mmol) and CuCN (0.51 g; 5.7 mmol) in anhydrous DMF (3 ml) was refluxed for 40 min under N2. After cooling to room temperature, the mixture was diluted to 20 ml with EtOAc and NaCN (0.75 g; 15.3 mmol) was added followed by H2O (10 ml). The resulting mixture was vigorously stirred for 10 min and organic phase was separated, washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (0.33 g; 97%) as colourless solid. 1H-NMR (CDCl3) 7.59-7.63 (m, 1H); 7.78 (m, 1H); 7.98 (dd, 1H, J=3, 6 Hz); 8.36 (d, 1H, J=9 Hz); 8.54 (m, 1H): 9.05 (dd, 1H, J=3, 6 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:41])([CH3:40])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:28]([F:39])[CH:27]=1)[CH2:19][C:20](O)=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.Cl.[NH2:52][OH:53].C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]([CH3:40])([CH3:41])[C@H:3]([NH:15][C:16](=[O:17])[C@H:18]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:28]([F:39])[CH:27]=1)[CH2:19][C:20]([NH:52][OH:53])=[O:21])[C:4]([NH:6][C@@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:5]
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)O)C(C)(C)C)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)NO)C(C)(C)C)c1ccccc1
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 36.6 %

Procedure:
N-[(Dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethaninium hexafluorophosphate N-oxide (740 mg, 1.95 mmol) was added to a stirred solution of (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-fluoro-4-phenoxyphenyl)hexanoic acid (Preparation 5) (731 mg, 1.30 mmol) and diisopropylethylamine (220 μL, 1.30 mmol) in anhydrous dimethylformamide (10 mL) at 0° C. under nitrogen. After 25 min, hydroxylamine hydrochloride (271 mg, 3.90 mmol) was added followed by diisopropylethylamine (880 μL, 5.20 mmol). The resulting mixture was stirred at 20° C. for 16 h, poured into ethyl acetate (150 mL) and washed with pH 7 phosphate buffer solution (3×50 mL), saturated aqueous sodium chloride (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/diisopropyl ether to give the title compound as a colourless solid (275 mg, 24%). Further purification of a sample (130 mg) by preparative hplc (Phenomenex C18 Magellan column, 150×20 mm, 5μ packing, 20 mL/min acetonitrile:aqueous phosphate buffer (8.3 mM, pH 7.2)=1:1, retention time 13.5 min), then trituration with diisopropyl ether, filtration and drying in vacuo at 50° C. gave 50 mg of a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([CH2:12][C:13]([OH:15])=O)=[N:3]1.[CH2:17]([O:19][C:20]([C@H:22]1[C@@H:27]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C@H:26]2[CH2:37][C@@H:23]1[CH2:24][CH2:25]2)=[O:21])[CH3:18].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:17]([O:19][C:20]([C@H:22]1[C@@H:27]([N:28]([C:13](=[O:15])[CH2:12][C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:16])[N:3]=2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C@H:26]2[CH2:37][C@@H:23]1[CH2:24][CH2:25]2)=[O:21])[CH3:18]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1,1-Dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (0.2 g, 0.833 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). (1S,2R,3S,4R)-3-(4-Fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 21, 0.244 g, 0.833 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.168 g, 0.875 mmol). Then N-methylmorpholine (0.177 g, 1.75 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 16 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as an orange oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C26H28FN3O5S 513.58. found 514.4 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:22]([OH:24])=O)=[C:10]([CH2:12][C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:3]1=[O:29].[OH:30][C@@H:31]1[CH2:35][O:34][NH:33][CH2:32]1>>[OH:30][CH:31]1[CH2:35][O:34][N:33]([C:22]([C:9]2[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:29])[N:4]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]=3[S:11][C:10]=2[CH2:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:24])[CH2:32]1
Reactant: O[C@H]1CNOC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3c[nH]c4ncccc34)sc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cc3c[nH]c4ncccc34)sc21

Procedure:
The title compound (55 mg) was prepared from the product of step b, (150 mg) by the method of example 1, step g), and (S)-4-hydroxyisoxazolidine, example 1 part b). MS (APCI) 484 [M+H]+. δ 1HDMSO 0.82-0.85 (6H,m), 2.03-2.13 (1H,m), 3.20-3.21 (3H,m), 3.53-3.68 (3H,m), 3.75-3.90 (2H,m), 4.00-4.18 (3H,m), 4.60-4.80 (1H,m), 5.50-5.55 (1H,m), 6.99-7.02 (1H,m), 7.41-7.44 (1H,m), 7.90-7.97 (1H,m), 8.18-8.20 (1H,m), 11.53 (1H,s,br)
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH2:5]([Cl:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCCCCCCCCO
Reactant: ClP(Cl)Cl
Product: CC(C)CCCCCCCCCCl
Reaction time: 3 h
Yield: 256.7 %

Procedure:
To a 1-gallon glass-line pressure reactor was charged 715 grams of phosphorus trichloride (PCl3, 5.2 moles). To the reactor was charged 2790 grams of isododecyl alcohol (Exxal 12, 15.0 moles) via an addition pump over a period of one hour while maintaining the reaction temperature below 100° C. After addition, the mixture was stirred at 130°-135° C. for 3 hours and cooled. The top organic layer was collected, yielding 2733 grams (94.5%) of isododecyl chloride.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:25][CH:26]=2)=[O:12])[C:4](=[O:28])[CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1Br
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1Br
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 113 mg (0.25 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 70 mg (0.30 mmol, 1.2 eq.) of 2-bromo-5-chlorophenylboronic acid, 103 mg (0.74 mmol, 3.0 eq.) of potassium carbonate and 20 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. A further 10 mg (0.01 mmol, 0.05 eq.) of [1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct and 29 mg (0.12 mmol, 0.5 eq.) of 2-bromo-5-chlorophenylboronic acid were added and the reaction mixture was stirred at 110° C. for a further night and then filtered through Celite. The residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, dried under reduced pressure and purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 72 mg (purity 73%, 38% of theory)