Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:27])([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH3:20])[CH:15]=3)[C:10]([C:28]([OH:30])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(=O)C(O)=O.[CH2:61]1[C:64]2([CH2:67][NH:66][CH2:65]2)[CH2:63][O:62]1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)([OH:27])[CH3:20])[CH:15]=3)[C:10]([C:28]([N:66]3[CH2:67][C:64]4([CH2:61][O:62][CH2:63]4)[CH2:65]3)=[O:30])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1NCC12COC2
Reactant: CC(O)(C#Cc1ccc2c(C(=O)O)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2c(C(=O)N3CC4(COC4)C3)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]indazole-3-carboxylic acid (100 mg, 0.25 mmol) in DMF (2 ml) was added HATU (189.46 mg, 0.5 mmol) followed by 2-oxa-6-azaspiro[3.3]heptane oxalate (94.26 mg, 0.5 mmol) and triethylamine (0.1 ml, 0.75 mmol). The reaction mixture was stirred at RT for 16 hr. Water (2 ml) was added to the reaction mixture and the product extracted into EtOAc (2×5 ml). The combined organics were washed with water (3 mL) and brine (3 mL) and concentrated in vacuo. The crude product was purified twice by flash chromatography (Biotage, 2-12% methanol in DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 1.93 (3H, s), 4.31 (2H, s), 4.74 (4H, q, J=6.9 Hz), 4.87 (2H, s), 6.26 (1H, s), 7.02-7.32 (3H, m), 7.41 (1H, dd, J=8.4, 1.2 Hz), 7.51 (1H, t, J=4.9 Hz), 8.23 (1H, d, J=8.0 Hz), 8.39 (1H, d, J=5.5 Hz), 8.75-9.10 (3H, m); LC-MS: m/z=+483.10 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[O:47]1[C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=[N:48]1.C(N(CC)CC)C>O1CCCC1>[O:47]1[C:51]([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])=[CH:50][CH:49]=[N:48]1
Reactant: O=C(Cl)c1ccno1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added isoxazole-5-carbonyl chloride (0.066 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 698 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH3:16][CH:17]1[O:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][CH:21]1[O:22][CH:17]([CH3:16])[CH2:18][N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:20]1
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: CC1CNCC(C)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCCCN1CC(C)OC(C)C1

Procedure:
This intermediate (12.0 g.) was prepared using the procedure described in Example 4a except using 12 g. (0.045 mole) of methyl 11-bromoundecylate, 5.5 ml. (0.045 mole) of 2,6-dimethylmorpholine, 6.12 ml. of triethylamine, and 15 ml. of toluene and was isolated as a yellow, viscous liquid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[K+]>C1COCC1.C(OCC)C>[CH2:15]([O:13][C@H:10]([CH2:11][O:12][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(benzyloxy)propane-1,2-diol (1 eq) in THF (0.3 M) was added n-tetrabutylammonium bromide (0.2 eq), 1-bromododecane (4 eq) and potassium hydroxide (5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl ether, washed with water, 1 N hydrochloric acid, water, and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give the product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[C:12]([N:14](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:11]3[N:31]=[CH:32][C:33]([C:34]4[CH:35]=[N:36][C:37]5[C:42]([CH:43]=4)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[C:10]3[N:9]=2)[CH2:3][CH2:2]1.CCO.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>[Cl-].[Na+].O.O.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[C:12]([NH2:14])[N:11]3[N:31]=[CH:32][C:33]([C:34]4[CH:35]=[N:36][C:37]5[C:42]([CH:43]=4)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[C:10]3[N:9]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cc(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
To crude 5-(morpholinomethyl)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)-ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 g) in a 20 mL vial was added EtOH (4 mL) and then 4M HCl/dioxane (1.5 mL, 6.0 mmol). The vial was capped and heated at 85° C. for 16 hours. On cooling, saturated NaHCO3 solution (˜0.5 mL) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was then transferred to a separatory funnel using CH2Cl2 (20 mL) and H2O (20 mL) and saturated NaHCO3 solution (20 mL) and brine (20 mL) were added. Organics were extracted with CH2Cl2 (4×30 mL), dried (Na2SO4) and concentrated in vacuo to give crude 5-(morpholinomethyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as a brown solid (0.04 g). LCMS: 0.78 mins, m/z=361.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)O)=[CH:4][CH:3]=1.C([Cl:27])(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[Cl:27])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1cccc(F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccc(F)cc2)c2cccc(F)c2)cc1
Reaction time: 12 h

Procedure:
Bis(4-fluorophenyl)-3-fluorophenylmethanol (999 mg, 3.18 mmol) was added to a 20% solution of acetyl chloride in dichloromethane (10 mL) at rt. The resulting purple solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (20 mL) was added to the residue and then evaporated affording crude bis(4-fluorophenyl)-3-fluorophenylchloromethane which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O>[F:9][C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C@H:11]2[CH3:10])=[N:7][C:6]=1[CH3:8]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1nc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)ccc1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a mixture of 500 mg of 6-bromo-3-fluoro-2-methylpyridine, 580 mg of tert-butyl (3R)-3-methylpiperazine-1-carboxylate, 506 mg of sodium tert-butoxide, and 61 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7.5 mL of toluene was added 48 mg of tris(dibenzylidenacetone)dipalladium (0), followed by stirring at 110° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 780 mg of tert-butyl (3R)-4-(5-fluoro-6-methylpyridin-2-yl)-3-methylpiperazine-1-carboxylate.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])(=[O:13])=[O:12])[CH2:8][C@H:7]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:5])C.CO.O.[OH-].[Li+]>O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([CH:9]1[CH2:10][C@@H:6]([C:4]([OH:5])=[O:3])[C@H:7]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH2:8]1)(=[O:13])=[O:12]
Reactant: CCOC(=O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
To a solution of (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 132 mg) in tetrandrofuran (2.4 mL), methanol (0.6 mL) and water (1.2 mL) was added lithium hydroxide monohydrate (14 mg). The mixture was stirred at 80° C. for 2.5 h then concentrated in vacuo. The residue was dissolved in water and the pH was adjusted to 1 with hydrochloric acid (2N). The precipitate was filtered, washed with water and dried in vacuo to afford the title compound (103 mg, 83%) as a white solid. MS (EI): 446.1 (M+NH4)+.
Reaction SMILES: [C:1]([C:3]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[OH:5])#[N:2].[N+](=[CH2:24])=[N-]>C1COCC1>[C:1]([C:3]([C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[O:5][CH3:24])#[N:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)C(=O)C(C#N)=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(=C(C#N)C(=O)C(C)(C)C)c1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To a solution of 1.0 g of 2-cyano-4,4-dimethyl-1-hydroxy-3-oxo-(2-nitro-4-chlorophenyl)-1-pentene dissolved in 3 ml of dry THF was cautiously added an ethereal solution of diazomethane. The excess starting material was removed by washing the reaction mixture with cold 3% K2CO3, separating the phases, drying the organic phase over MgSO4, filtering, and concentrating under reduced pressure. The crude product was crystallized from hot hexane/THF to yield 250 mg of the product, m.p. 130°-1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].S(=O)(=O)(O)O>O>[C:10]([O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
At room temperature, 3,4-dichlorophenol (298.5 g, 1.83 mol) was dissolved in 191 ml (207 g, 2.02 mol) of acetic anhydride in a 1 liter flask equipped with mechanical stirrer and condenser. Sulfuric acid (3 ml) was added, resulting in a strong exotherm. After 2 hours the mixture was poured into 2 liters of ice and water and extracted 3×1 liter diethyl ether. The organic layers were combined, washed 1×1 liter water, 2×1 liter saturated sodium bicarbonate and 1×1 liter saturated brine, dried over magnesium sulfate and stripped to yield title product as an orange oil, 375 g, tlc Rf 0.5 (1:1 diethyl ether:hexane).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:9][C:10]=1[CH3:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[CH3:11][C:10]1[S:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][C:6]=1[CH2:5][CH2:4][NH2:1]
Reactant: Cc1sc(-c2ccccc2)nc1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Azidoethyl)-5-methyl-2-phenylthiazole (104 mg, 426 μmol) was combined with triphenylphosphine (123 mg, 468 μmol) and water (1 drop, 4 μL, 222 μmol) at RT. The reaction mixture was stirred at RT overnight and the solvent was removed in vacuo to give a light brown residue. The product was obtained after purification by flash chromatography (using silica gel and a 1M ammonia in methanol/dichloromethane gradient) as colorless semisolid (72.3 mg, 331 μmol, 77.8%).
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[C:27]([C:29]1[CH:38]=[C:37]2[C:32]([C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]2=[O:39])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:40][C:33]1([CH3:41])[C:32]2[CH:31]=[CH:30][C:29]([C:27]#[C:28][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:38][C:37]=2[C:36](=[O:39])[CH2:35][CH2:34]1
Reactant: C#Cc1ccc2c(c1)C(=O)CCC2(C)C
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L) was converted into the title compound using 6 g (21.7 mmol) of ethyl 4-iodobenzoate, 5 g (7.2 mmol) of his (triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14](/[CH:18]=[N:19]/[OH:20])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:21]=[C:22]([CH2:27][C:28]([O:30]C)=[O:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>C1COCC1.CO>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:21][C:22]([CH2:27][C:28]([OH:30])=[O:29])([C:23]([OH:25])=[O:24])[O:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O/N=C/c1cccc(OCc2ccccc2)c1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1(C(=O)O)CC(c2cccc(OCc3ccccc3)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 1081 g) was added dropwise to a solution of (E)-1-(3-(benzyloxy)phenyl)-N-hydroxymethanimine (150 g) and dimethyl 2-methylenesuccinate (104 g) in THF (1500 mL) at 5 C (internal temperature: 30 C or lower) over 1 hour, and then, the obtained mixture was stirred at 5 C for 1 hour. To the reaction mixture, methanol (750 mL) was added, and then, a 2 M aqueous sodium hydroxide solution (750 mL) was added dropwise at 5 C (internal temperature: 20 C or lower) over 40 minutes. The obtained mixture was gradually warmed to room temperature and stirred overnight at room temperature. The reaction mixture was concentrated into half the volume under reduced pressure, and then, water (5000 mL) and ethyl acetate (1500 mL) were added to the residue. The aqueous layer was washed with ethyl acetate (1500 mL), then 6 M hydrochloric acid (250 mL) was added thereto, and the obtained mixture was subjected to extraction with ethyl acetate (1500 mL×2). The extract was washed with brine (1500 mL) and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether (10 mL) and hexane (1000 mL) to obtain the title compound (217 g).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[N:31][CH:32]=2)[CH:12]=[CH:11][C:10]=1[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[CH3:50]>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[N:31][CH:32]=2)[CH:12]=[CH:11][C:10]=1[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[CH3:50]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)NCCC(=O)O)nc2)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (5.6 mL, 16.7 mmol) was added to a THF (20 mL) and MeOH (10 mL) solution of ethyl 3-(5-(2-(((2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (3.5 g, 5.6 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[NH2:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(F)(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate 1) (0.5 g, 2.126 mmol) in dry ethanol (5 ml), 2M NaOH (5.32 ml, 10.63 mmol) was added. The yellow solution was stirred at RT. After 5 minutes, the reaction mixture was poured into water (15 ml) and the pH adjusted to pH 6 by addition of 1M HCl. The yellow precipitate formed was filtered under vacuum and dried to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.65 (1H, s), 8.3 (1H, s), 7.86 (2H, br s)
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:36](=[O:37])[N:5]2[C:6]([C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])=[C:7]([CH2:10][S:11][C:12]3[N:17]4[N:18]=[C:19]([CH2:21][O:22][CH3:23])[N:20]=[C:16]4[N:15]=[C:14]([CH3:24])[CH:13]=3)[CH2:8][S:9][C@H:4]12.[NH2:38][C:39]1[S:40][CH:41]=[C:42](/[C:44](=[N:58]/[O:59][CH3:60])/[C:45](OSC2SC3C=CC=CC=3N=2)=[O:46])[N:43]=1>C(Cl)Cl.C(O)C>[ClH:1].[NH2:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[N:58][O:59][CH3:60])[C:45]([NH:2][CH:3]2[C:36](=[O:37])[N:5]3[C:6]([C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[O:26])=[C:7]([CH2:10][S:11][C:12]4[N:17]5[N:18]=[C:19]([CH2:21][O:22][CH3:23])[N:20]=[C:16]5[N:15]=[C:14]([CH3:24])[CH:13]=4)[CH2:8][S:9][C@H:4]23)=[O:46])[N:43]=1
Reactant: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(N)[C@H]4SC3)n2n1
Reactant: CO/N=C(\C(=O)OSc1nc2ccccc2s1)c1csc(N)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(NC(=O)C(=NOC)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
In 100 ml of methylene chloride was dissolved 11.8 g of pivaloyloxymethyl 7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.hydrochloride, and 5.82 g of benzthiazolylthio 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetate was added to the solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 100 ml of a 5% sodium acetate aqueous solution and further washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. 100 ml of isopropanol containing 1.5 ml of conc. hydrochloric acid was added to the residue, and the mixture was thoroughly stirred and further stirred by adding 150 ml of ether. Then, precipitates were collected by filtration, washed with water and dried to obtain powder. This was dissolved in 50 ml of ethanol and filtered and the filtrate was added dropwise into 300 ml of ether. Precipitates were collected by filtration, washed with ether and dried to obtain 7.91 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:26]([OH:28])[CH3:27])[C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[OH:28][C@H:26]([CH3:27])[C@@H:13]([NH:12][C:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[O:15][C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:16]=1
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a solution of N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.56 g, 1.42 mmol) in THF (120 mL) was added PS-BEMP (1.94 g, 4.27 mmol, ˜2.2 mmol/g) and p-TsCl (275 mg, 1.44 mmol) at room temperature. The mixture was stirred at room temperature for 18 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (229 mg, 43%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.98 (m, 2H), 7.85 (d, J=5.5 Hz, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.51˜7.57 (m, 3H), 6.87 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 5.14 (dd, J=6.5, 8.8 Hz, 1H), 4.66 (d, J=6.0 Hz, 1H), 4.58 (m, 1H), 1.49 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([Cl:8])[C:3]=1[Cl:9]
Reactant: O=[N+]([O-])O
Reactant: Clc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
A mixture of 9.0 kg of 1,2,3-trichlorobenzene in 13.32 L of concentrated sulfuric acid is acid by drops to a solution of 4.13 L of 70% nitric acid and 4.13 L of concentrated sulfuric acid at 25-30° C. The slurry is stirred for 1.5-2 hours, then poured over 35 kg of ice and filtered. The filter cake is washed (15 L water) and then dissolved in 58 L of ethyl acetate. The organic phase is washed with water, aqueous sodium bicarbonate solution, and aqueous sodium chloride solution. The solution is dried over magnesium sulfate and concentrated to give the title product.