Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:7]([O-:10])(=[O:9])=[O:8])[CH2:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:11][C:12]1[C:13]2[C:14]3[C:15](=[N:27][N:28]([CH2:30][C:31]4[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=2)[CH:16]=[C:17]([CH2:22][C:23]([NH:25][CH3:26])=[O:24])[C:18]=3[CH2:19][S:20][N:21]=1>CC(C)=O>[CH2:1]([S:7]([OH:10])(=[O:9])=[O:8])[CH2:2][S:3]([OH:6])(=[O:5])=[O:4].[NH2:11][C:12]1[C:13]2[C:14]3[C:15](=[N:27][N:28]([CH2:30][C:31]4[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=2)[CH:16]=[C:17]([CH2:22][C:23]([NH:25][CH3:26])=[O:24])[C:18]=3[CH2:19][S:20][N:21]=1
Reactant: O=S(=O)([O-])CCS(=O)(=O)[O-]
Agent: CNC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3Cl)nc3c-2c1CSN=C3N
Solvent: CC(C)=O
Product: O=S(=O)(O)CCS(=O)(=O)O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
An acetone solution (50 ml) of ethane-1,2-disulfonate (70 mg, 0.368 mmol) was added at 5° C. to an acetone solution (50 ml) of 2-{4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide (164 mg, 0.368 mmol). The resulting mixture was stirred at 5° C. for 20 minutes. Thereafter, the reaction solution was left at rest at 5° C. for 18 hours, and it was then stirred at room temperature for 7 hours. Thereafter, the precipitated solid was collected by filtration, and it was then dried under reduced pressure at room temperature for approximately 1 day, so as to obtain the title compound (119 mg, 0.187 mmol).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=2[O:2]1.P(O)([O-])([O-])=O.[Na+].[Na+].P(=O)(O)(O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>O>[CH3:12][C@H:11]([OH:13])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: CC(=O)Cc1ccc2c(c1)OCO2
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Solvent: O
Product: C[C@H](O)Cc1ccc2c(c1)OCO2
Temperature: 22.5 °C
Reaction time: 0.62 h
Yield: 97 %

Procedure:
1 equiv. of 3,4-methylenedioxyphenyl acetone, 0.45 equiv. disodium phosphate, 0.03 equiv. phosphoric acid, 12.5 volumes AD-7 resin and 5.8 volumes of water were mixed together and stirred for 15-60 minutes at 20-25° C. 2.27 equiv. of glucose were added and Z. rouxii ATCC 14462 is added in an amount of 1.5 grams wet cell paste per gram of ketone (this is 0.375 grams/gram on a dry basis). This mixture was diluted with water to 25 volumes and then gently stirred at 33-35° C. for 8-16 hours. The mixture was filtered on a 100 mesh (~150 micron) stainless steel screen, and the resin which was retained by the screen was washed with 25 volumes of water split into 4 separate portions. The product, which was adsorbed to the resin, was then desorbed from the resin with 25 volumes of acetone. The acetone/product solution was then stripped to dryness under vacuum to yield the title intermediate as a yellow, medium viscosity oil. The in-situ yield was 97-100%, while the isolated yield was 85-90%. The potency was 80-95% and the EE is 100%.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14](=[O:19])[NH:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>>[O:19]=[C:14]1[NH:13][CH:12]([CH2:11][CH2:10][CH2:9][CH:3]([NH:2][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(N)CCCC1CCCCC(=O)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Product: CCOC(=O)C(CCCC1CCCCC(=O)N1)NC(=O)OCc1ccccc1

Procedure:
The product of EXAMPLE 246 is treated with benzyl chloroformate under standard conditions to yield title product.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(OCCCOCC1C=CC=CC=1)CCCCCC.C(OCC(O)COCC1C=CC=CC=1)CCCCCC.C=O.[ClH:69]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:69][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1
Reactant: Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: C=O
Agent: CCCCCCCOCC(O)COCc1ccccc1
Agent: CCCCCCCOCCCOCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ncc2[nH]cnc2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-6-chloropurine (Aldrich Chemical Co.) 11.2 g, 0.066 mol) hexamethyldisilazane (160 ml), and ammonium sulfate (1.09 g) is refluxed for 2.5 hours and then cooled, concentrated and pumped to dryness. The residue is dissolved in dry toluene (210 ml) and is treated with Hg(CN)2. The mixture is heated to 80° C. and a solution of 2-(chloromethoxy)-1-(heptyloxy-3-(phenylmethoxy) propane (prepared from 1-(heptyloxy)-3-(phenylmethoxy)-2-propanol (19 g, 0.068 mol), paraformaldehyde (4 g) and dry HCl (g) in CH2Cl2 (160 ml) as described in the first part of Example 7, in toluene (210 ml) is added to the solution and heated to 80°-85° C. for 2.5 hours. The mixture is cooled, concentrated, and diluted with CH2Cl2 (1.0 L) and is allowed to stand overnight. The CH2Cl2 solution is filtered, washed with 30% KI, 10% potassium carbonate solution and water. The organic layer is dried and concentrated. The residue is chromatographed over silica gel column using a high pressure liquid chromatographic instrument (Waters Prep 500). The column is eluted with ethyl acetate and hexane (1:1) to give the condensation product (i.e., chloropurine derivative) (6.45 g) which is hydrolysed as follows.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[F:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:23]=1[N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]1[CH2:20][CH2:19][CH2:18][C:17](=[O:32])[C:16]2=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:23]=1[N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:32])[C:16]2=1
Reactant: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1cccc2c1c1cccc(F)c1n2Cc1ccc(F)cc1
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 71 %

Procedure:
Pyridinium bromide perbromide (0.0.860 g, 0.27 mmol) is added to a solution of 8-fluoro-9-(4-fluorobenzyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one in THF (0.5 mL) and DMF (0.5 mL) and the mixture is heated to 75° C. After stirring for 4.5 h, THF is removed under reduced pressure and the residue is partitioned between ethyl acetate and dilute brine. The combined organic layers are washed with dilute sodium sulfate/brine and the aqueous layer is backwashed with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. A mixture of the resulting residue, lithium bromide (0.0428 g, 0.49 mmol), lithium carbonate (0.0311 g, 0.42 mmol) and DMF (1 mL) is heated at 120° C. for two hours. The mixture is partitioned between ethyl acetate and brine. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (20 mL) using ethyl acetate/heptane (5/95 and 10/90) to give 0.0460 g (71%) of the title compound; MS (ESI−) for C19H13F2NO m/z 308.1 (M−H)−; IR (drift) 1580, 1508, 1461, 1434, 1329, 1274, 1242, 1235, 1221, 1157, 1129, 907, 788, 755, 732 cm−1; 1H NMR (CDCl3) δ5.37 5.64, 6.60, 6.94, 7.14, 7.28, 8.10. Anal. Calcd for C19H13F2NO: C, 73.78; H, 4.24; N, 4.53. Found: C, 72.52; H, 4.18; N, 4.37.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](O)[C:25]#[CH:26].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:9][CH:10]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:11]([O:13][CH2:26][C:25]#[CH:24])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCOC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
2-(benzoylamino)-3-(indol-3-yl)propanoic acid (1.9 g) was dissolved in 75 ml of dry methylene chloride (from phosphorous pentoxide). The solution was cooled to 0° C. in an ice bath and 0.72 ml of propargyl alcohol was added along with 1.39 g of DCC followed by 0.07 g DMAP. The reaction mixture was warmed to room temperature and maintained there for 16 hours. The solution was filtered into a separatory funnel, washed with 5% acetic acid (2×), water (1×) and 5% solution bicarbonate (1×). The separated methylene chloride layer was then dried over magnesium sulfate and evaporated to dryness. The residue was redissolved in ethyl acetate, filtered and the filtrate evaporated to dryness. The orangish residue was dried in vacuo to give propargyl 2-(benzoylamino)-3-(indol-3-yl)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15]O.O.[BrH:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15][Br:18]
Reactant: Br
Reactant: OCc1c(Cl)cccc1Oc1ccccc1
Solvent: O
Product: Clc1cccc(Oc2ccccc2)c1CBr
Yield: 100 %

Procedure:
17.5 g (70.94 mmol) of (2-chloro-6-phenoxy-phenyl)-methanol are heated under reflux for 3 hours in 150 ml of 8% hydrobromic acid. The mixture is cooled, water is added and the mixture is extracted 3× with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and concentrated. 21.21 g (>100%) of crude (2-chloro-6-phenoxy-phenyl)-bromomethane are obtained in the form of a yellow oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.70; 1H-NMR (CDCl3, 200 MHz): 4.78 (s, 2H); 6.70-7.41 (m, 8H).
Reaction SMILES: C(OC(=O)COC1C=CC(S([Br:16])(=O)=O)=CC=1Cl)C.C([C:21]1[CH:31]=[C:30]([S:32][CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[O:36][C:35]=2[CH3:49])[CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([OH:27])=[O:26])C>>[Br:16][C:21]1[CH:31]=[C:30]([S:32][CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:48])[F:47])=[CH:41][CH:40]=3)[O:36][C:35]=2[CH3:49])[CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Br)cc1Cl
Reactant: CCc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CSc1ccc(OCC(=O)O)c(Br)c1

Procedure:
The title compound was prepared from ethyl[4-(bromosulfonyl)-2-chlorophenoxy]acetate (intermediate 114) by a method analogous to that used for the preparation of {2-ethyl4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetic acid (example 145).
Reaction SMILES: P(Cl)(Cl)Cl.[ClH:5].Cl[C:7]([C:17]#[N:18])([CH2:13][CH2:14][CH:15]=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CN(C=O)C>[Cl:5][C:17]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=[CH:15][N:18]=1
Reactant: CCOC(=O)C(Cl)(C#N)CCC=O
Reactant: Cl
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To 35 mL of DMF were added dropwise 6.85 g of PCl3 (50 mmol). Anhydrous HCl was introduced for 5 minutes while keeping the temperature around 70° C. Ethyl 2-chloro-2-cyano-5-oxopentanoate (7.83 g, 38.5 mmol) in 10 mL of DMF was added at 55° C. The resulting mixture was stirred for 2 h at 90° C., cooled to room temperature, quenched with water, extracted with CH2Cl2, dried over MgSO4, concentrated and distilled to give 4.4 g of the title compound (62%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].C1(C=O)CC1>C1COCC1>[CH3:15][N:3]([O:2][CH3:1])[C:4](=[O:14])/[CH:5]=[CH:16]/[CH:17]1[CH2:19][CH2:18]1
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Reactant: [Li]CCCC
Agent: O=CC1CC1
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of N-methoxy-N-methyl diethylphosphonoacetarnide (34.56 g, 144.5 mmol) in THF (200 mls) at -78° C., was added n-butyllithium (57.8 mls of a 2.5M solution in hexanes, 144.5 mmol) dropwise. Upon completion of addition, the mixture was stirred for 30 mins at -78° C. A solution of cyclopropanecarboxaldehyde (6.75 g, 96.3 mmol) in THF (50 mls) was then added dropwise. Upon completion of addition, the cooling bath was withdrawn and the reaction allowed to warm to r.t. It was then diluted with aqueous sat'd NH4Cl (200 mls) and the THF was stripped off in vacuo. The aqueous residue was extracted with ethylacetate (3×200 mls). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 3:2) to afford 14.09 g (94%) of trans-N-methyl-N-methoxy-3-cyclopropylpropenarnide as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:34])[CH3:37]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CCOC(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OCC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A181) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([O:11]C)=[O:10].CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(OCc2ccccc2F)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a clean, dry 100 mL round bottom flask is added methyl 3-(2-fluorobenzyloxy)-5-nitrobenzoate (0.49 g, 1.6 mmole, 1 eq), methanol (5 mL) and 1M sodium hydroxide in water (20 mL). The reaction mixture was stirred at room temperature for 18 h and then quenched with 1M HCl and ethyl acetate. The product was extracted into the organic layer, dried over magnesium sulfate, filtered and evaporated. A white solid was obtained (0.4 g, 85% yield). Calc'd for C14H10NFO5; m/z (M+H+)=292; found 292.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].CO>ClCCl>[C:22]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@@H:10]1[CH3:14])(=[O:24])[CH3:23]
Reactant: C[C@H]1CN(Cc2ccccc2)CCN1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (S)-1-benzyl-3-methylpiperazine (588 mg) and triethylamine (0.47 ml) in dichloromethane (5 ml) was added acetic anhydride (0.32 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 4 hours. Methanol was added to this solution and evaporated. The residue was taken up in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography eluting with a mixture of ethyl acetate and n-hexane (2:1) to give (S)-1-acetyl-4-benzyl-2-methylpiperazine (660 mg).
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]([OH:5])=O.[NH2:32][C@@H:33]([CH:36]([CH3:38])[CH3:37])[C:34]#[N:35].C(O)=O.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:5])[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:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH:36]([CH3:38])[CH3:37])#[N:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)[C@H](N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC(C)[C@@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 7.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 45 mg, 0.104 mmol), (S)-2-amino-3-methylbutanenitrile (Int-XIII), formic acid salt (15.04 mg, 0.104 mmol), 4-methylmorpholine (42.2 mg, 0.417 mmol), and HATU (51.6 mg, 0.136 mmol) were dissolved in DMF (1 mL). After stirring 1 h, this was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give single enantiomer N—((S)-1-cyano-2-methylpropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.8 mg, 0.007 mmol, 7.1% yield, and its purity was 100%): LCMS=512.1 [M+H]+; 1H NMR (500 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.32 Hz), 7.48-7.72 (7 H, m), 5.19 (1 H, s), 4.63 (1 H, d, J=7.49 Hz), 2.01-2.15 (1 H, m, J=13.80, 6.83, 6.83, 6.66 Hz), 1.07 (3 H, d, J=6.66 Hz), 0.95 (3 H, d, J=6.94 Hz); HPLC peak RT=3.0 min (Method E).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][C:23](=O)[O:24]C2C=CC=CC=2)[N:16]=1.Cl>O1CCOCC1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][C:23]([NH:12][S:9]([C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][O:2][CH3:1])(=[O:11])=[O:10])=[O:24])[N:16]=1
Reactant: COc1cc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: COCc1ccsc1S(N)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: COCc1ccsc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.41 g of 3-(methoxymethyl)thiophene-2-sulfonamide and 0.52 g of phenyl N-(4-methoxy-6-methylpyrimidin-2-yl)carbamate in 25 mL of 1,4-dioxane is added 0.3 mL of 1,8-diazabicyclo[5.4]undec-7-ene. After being stirred for two hours at ambient temperature and pressure, the reaction mixture is poured onto 25-50 g of ice and the resultant mixture is acidified to pH 3 by the addition of hydrochloric acid. The desired solid product can be isolated by filtration. Alternatively, it can be extracted into methylene chloride which is then dried over magnesium sulfate, filtered and evaporated to dryness to yield the desired product in sufficiently pure form for the purposes of this invention.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:40])[CH:36]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH:40][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:36]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)nc12

Procedure:
6-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.250 g, 0.763 mmol) and 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.284 g, 1.14 mmol) in a manner analogous to Example 311a and 311b to give product. MP=86-90° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.59 (s, 1H), 8.78 (d, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.45 (m, 2H), 7.38 (d, 1H), 7.05 (m, 2H), 4.40 (m, 2H), 3.85 (s, 3H), 3.52 (m, 2H), 2.75 (m, 2H), 1.42 (s, 9H): MS=540 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[CH2:28][CH2:29][CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:30][CH2:29][CH2:28][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]3=[O:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CCCN1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1CCCCC1=O
Reaction time: 0.5 h

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (0.79 g, 2.9 mmol) and 3-(2-oxo-1-piperidinyl)propanal (0.56 g, 3.6 mmol) under nitrogen in glacial acetic acid (10 mL) was treated with sodium triacetoxyborohydride (1.21 g, 5.7 mmol) at 0° C. for 30 min. After stirring for an additional 30 min., an additional 0.23 g of 3-(2-oxo-1-piperidinyl)propanal and 0.36 g sodium triacetoxyborohydride were added. After stirring another 1 h, an additional 0.145 g of 3-(2-oxo-1-piperidinyl)propanal and 0.3 g sodium triacetoxyborohydride were added and stirred at 0° C. for another ½ hour. The reaction was evaporated in vacuo and the residue was dissolved in CH2Cl2, washed with 2N Na2CO3, and back extracted the aqueous 2× with CH2Cl2. The organics were combined, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was dissolved in CH2Cl2 and chromatographed on silica gel eluting with 10-100% acetone in hexanes to provide, after combining pure fractions and concentrating them in vacuo, the product as a clear viscous oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.31 (m, 3 H), 1.63-1.77 (m, 6 H), 2.19 (t, J=5.90 Hz, 2 H), 3.12-3.25 (m, 4 H), 3.24-3.39 (m, 2 H), 3.94 (s, 2 H), 4.26 (q, J=7.11 Hz, 2 H), 7.08-7.16 (m, 3 H), 7.31 (ddd, J=12.00, 5.33, 3.02 Hz, 2 H), 7.61 (t, J=5.69 Hz, 1 H), 7.76 (d, J=1.82 Hz, 1 H); ES+ MS: 414 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]([CH2:16][CH3:17])[CH3:15])[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[CH3:15][N:14]([CH2:16][CH3:17])[C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: CCN(C)c1nc(Cl)nc2c(SC)ncnc12
Solvent: CS(C)=O
Product: CCN(C)c1nc(N2CCNCC2)nc2c(SC)ncnc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-(N-methyl-ethylamino)-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.