Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]=[C:27]3[S:21][C:22](=[S:23])[NH:24][C:25]3=[O:26])[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)(C)c1ccc(COc2cccc(C=O)c2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(COc2cccc(C=C3SC(=S)NC3=O)c2)cc1

Procedure:
The 3-[4-(t-butyl)benzyloxy]benzaldehyde (2 g, 7.5 mmol) was coupled to rhodanine (1.19 g, 9 mmol) by reacting the two in the presence of sodium acetate (2.42 g, 29 mmol) and acetic acid. The mixutre was heated to reflux and then refluxed overnight.
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([C:12]([CH2:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][CH:14]([C:12](=[O:13])[C:11]1[CH:22]=[CH:23][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:15][C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17]
Reactant: CC(C)OC(=O)CCC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)CC(Br)C(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
6.24 g of isopropyl 3-(4-phenoxybenzoyl)propionate were dissolved in 50 ml of chloroform. After a catalytic amount of anhydrous aluminum chloride was added, a solution of 3.62 g of bromine in 20 ml of chloroform was added dropwise over 30 minutes. The reaction mixture was washed with water, then dried over magnesium sulfate. The chloroform was removed by evaporation under reduced pressure to give oily isopropyl 3-bromo-3-(4-phenoxybenzoyl)propionate, which was dissolved, without purification, in 50 ml of dimethylformamide. 3.02 g of potassium acetate were added under ice-cooling, and the mixture was stirred for 30 minutes. Diethyl ether was added to the reaction mixture, which was then washed with water and dried over magnesium sulfate. The diethyl ether was distilled off under reduced pressure and the residue was recrystallized from a mixture of hexane and diethyl ether to give 5.83 g of isopropyl 3-(4-phenoxybenzoyl)acrylate.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH3:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.CNC1CCCCC1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([C:3]([OH:2])=[O:4])=[CH:6]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Cc1ccc(I)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccc(-n2cc(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
Indole-3-carboxylic acid methyl ester (2.50 g), 4-methyl-iodobenzene (3.72 g), copper (I) iodide (136 mg), N,N′-dimethyl-1,2-cyclohexanediamine (0.5 ml) and potassium carbonate (4.06 g) were stirred at 120° C. for 48 hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in ethanol (10 ml), sodium hydroxide (1.17 g) was added and stirred at room temperature overnight. The reaction solution was concentrated with an evaporator, the aqueous layer was acidified by the addition of 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the titled compound (184 mg) as a dark brown solid.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>C(O)C>[Cl:12][C:11]1[C:2]([NH:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: COC(CN)OC
Solvent: CCO
Product: COC(CNc1nc2ccccc2nc1Cl)OC

Procedure:
A mixture of 5.0 g of 2,3-dichloroquinoxaline and 5.5 ml of aminoacetaldehyde dimethyl acetal in 75 ml of ethanol is refluxed for 4 h. After concentrating under vacuum, the resulting mixture is added with water and extracted with ethyl acetate. The organic extracts are then washed with saturated NaCl, dried and evaporated. The residue is finally chromatographed on SiO2 (eluent: CH2Cl2), thereby obtaining 5.0 g of 2-chloro-3-(2,2-dimethoxyethylamino)quinoxaline (IR (KBr): 3347, 2936, 1580, 1523, 1129 cm-1). 4.5 g of this product are then treated with 20 ml of 48% HBr and the mixture is refluxed for 4 h. After cooling down, the mixture is neutralized with aqueous NaOH and the resulting precipitate is filtered under vacuum and dried to obtain 3.2 g of imidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.)
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[C:13]([O:15]CC3C=CC=CC=3)[CH:12]=[CH:11][C:10]=2[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[NH:23][C:24](=[O:29])[C:25]([F:26])([F:27])[F:28]
Reactant: [H][H]
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1O)C(F)(F)F

Procedure:
A mixture of 1.5 grams (0.0036 mole) of, N-[2,4-bis(phenylmethoxy)phenyl]-2,2,2-trifluoroacetamide and 0.2 gram (catalyst) of 10% palladium on carbon in 125 mL of ethanol was treated with hydrogen gas in a Parr Hydrogenator, yielding 0.80 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]([NH2:12])=[S:11].CC([O-])=O.[Na+]>CCO>[C:4]([C:3]1[N:9]=[C:10]([NH2:12])[S:11][CH:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)CBr
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-3,3-dimethyl-butan-2-one (300 mg, 1.7 mmol) was dissolved in 10 mL of EtOH. To this solution was added thiourea (1.7 mmol, 129 mg) followed by NaOAc (3.4 mmol, 279 mg). This mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure and used without any further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:27](O)=[O:28])[CH:3]=1.F[P-](F)(F)(F)(F)F.[N:37]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.N1(O)C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:27]([NH2:37])=[O:28])[CH:3]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccccc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
To a solution of 4-methyl-5-[(phenylsulfonyl)(2,3,6-trifluorophenyl)methyl]pyridine-2-carboxylic acid (300 mg, 0.71 mmol) in N,N-dimethylformamide (6 ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (556 mg, 1.07 mmol), benzotriazol-1-ol (144 mg, 1.07 mmol), ammonium chloride (76 mg, 1.42 mmol), and N-ethyldiisopropylamine (0.5 ml, 2.85 mmol) were added in an Argon atmosphere at room temperature. After stirring for 3 hours at room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate, and then was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, subsequently the filtrate was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, and then was collected by filtration, to obtain the title compound (227 mg, 0.54 mmol, 76%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.OC1C2N=NNC=2C=CC=1.[NH2:37][C@@H:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C@H:39]1[F:51]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:37][C@@H:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:40][C@H:39]2[F:51])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Agent: CCOC(=O)Cl
Agent: Oc1cccc2[nH]nnc12
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution of 0.41 g (2.02 mmol) of 4-amino-5-chloro-2-methoxybenzoic acid in 10 mL of dry DMF was added 0.29 g (2.89 mmol) of triethylamine at room temperature under N2-atmosphere. After stirring for 10 min at rt, a solution of 0.22 g (2.02 mmol) of ethyl chloroformate in 2 mL of DMF was added dropwise at rt and stirring was continued for 30 min, while the temperature was maintained at rt (cooling with waterbath at rt). Then 0.27 g (2.02 mmol) of hydroxybenzotriazole was added as a solid in one portion at rt and the solution was stirred for 30 min. Subsequently, a solution of 0.42 g (1.93 mmol) of amine 5 in 3 mL of DMF was added dropwise at rt and the reaction mixture was stirred overnight at rt. Afterwards, the mixture was poured in 20 mL of brine and extracted with EtOAc (3×25 mL). The combined organic fraction was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1:1:0.1) to yield 0.72 g (93%) of pure trans-tert-butyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-fluoropiperidine-1-carboxylate 6 as a solid. 1H NMR (CDCl3): δ 1.47 (9H, s); 2.17-2.28 (1H, m); 2.96-3.19 (2H, m); 3.74 (1H, dm, J=13.7 Hz); 3.90 (3H, s); 3.92-4.40 (3H, m); 4.45 (1H, ddt, J=4.4 Hz, 8.3 Hz, J=48.4 Hz); 6.30 (1H, s); 7.82 (1H, d, J=7.2 Hz); 8.08 (1H, s). 19F NMR (CDCl3): δ −189.0 (d, J=44.7 Hz). 13C NMR (CDCl3): δ 28.4 (3×), 29.1 (br), 41.5 (br), 45.6 (br), 50.1 (br), 56.4, 80.4, 88.2 (d, J=182.3 Hz), 97.9, 111.8, 112.1, 133.2, 147.1, 154.7, 157.6; 164.5. IR (ATR, cm−1): ν=3478, 3378, 1683, 1619, 1593, 1420, 1247, 1146. MS (ES+) m/z (%): 346/48 (M+H+, 100); 402/404 (M+H+, 60).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:25][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccccc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccccc3)c2c1

Procedure:
A mixed solution of 6.8 g of the above-mentioned 2-tert-butyl-9-phenylanthracene, 4.3 g of N-bromosuccinimide and 60 ml of dimethylformamide was stirred under nitrogen gas stream at room temperature for 2 hours. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-phenylanthracene.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:16][CH:15]=[CH:14]2)=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccnc(F)c1N
Solvent: CC(=O)O
Product: Cc1ccnc(F)c1-n1cccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
2-Fluoro-4-methylpyridin-3-amine (1.0 g, 7.93 mmol) and 2,5-dimethoxytetrahydrofuran (1.08 mL, 1.05 equiv.) were suspended in 3 mL of acetic acid and refluxed for 2 hours. The reaction was cooled down to room temperature. The solvents were removed and the residue was purified by silica gel chromatography (EtOAc/hexanes=1:8, Rf=0.3) to afford 1.0 g (72%) oil. 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J=0.8, 5.1 Hz, 1H), 7.17 (d, J=5.1 Hz, 1H), 6.74 (td, J=2.1, 0.9 Hz, 2H), 6.40 (t, J=2.1 Hz, 2H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.2, 157.8, 149.6, 149.5, 145.5, 145.4, 123.80, 123.76, 122.1, 109.8, 17.29, 17.25. HRMS (m/z) calcd for C10H10FN2 (M+H) 177.0828. found 177.0827. Richards, et al. (2008) Bioorg. & Med. Chem. Lett. 18:4325-27.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[C:13]3[CH:21]=[C:22]([CH3:24])[CH2:23][C:12]=23)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([Cu])#N.Cl[Si:34]([CH:37]1[C:45]2[C:40](=[C:41]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=3)[CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH:56]([CH3:58])[CH3:57])([CH3:36])[CH3:35]>CCOCC.CCCCCC.O>[C:52]([C:49]1[CH:50]=[CH:51][C:46]([C:41]2[CH:42]=[CH:43][CH:44]=[C:45]3[C:40]=2[CH:39]=[C:38]([CH:56]([CH3:58])[CH3:57])[CH:37]3[Si:34]([CH:21]2[C:13]3=[CH:14][C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=4)=[C:12]3[CH:23]=[C:22]2[CH3:24])([CH3:36])[CH3:35])=[CH:47][CH:48]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: CC1=Cc2cc3c(c(-c4ccc(C(C)(C)C)cc4)c2C1)CCCC3
Reactant: CC(C)C1=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc2C1[Si](C)(C)Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CC1=Cc2c(cc3c(c2-c2ccc(C(C)(C)C)cc2)CCCC3)C1[Si](C)(C)C1C(C(C)C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Solution of 9-(4-tert-butylphenyl)-2-methyl-5,6,7,8-tetrahydro-1H-cyclopenta[b]naphthalene (4d, 2.97 g, 9.38 mmol) in Et2O (50 ml) was cooled to −60° C., and n-BuLi (1.6 M in hexane, 6.04 ml, 9.67 mmol) was added. The resulting mixture was allowed to warm to room temperature, stirred for 3 h, cooled to −60° C., and CuCN (50 mg, 0.55 mmol) was added. After 15 min, solution of chloro-(4-(4-tert-butylphenyl)-2-isopropyl-1H-inden-1-yl)-dimethylsilane (9.67 mmol) in Et2O (24 ml) was added, and resulting mixture was allowed to warm to room temperature and stirred for 16 h. Water (5 ml) and hexane (200 ml) were added, organic phase was separated, dried over MgSO4, passed through silica gel and evaporated. The product was dried in vacuo and used without purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.C([O:14][C:15]([NH:17][NH2:18])=[S:16])C>C(#N)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[CH2:2][S:16][C:15](=[O:14])[NH:17][N:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=S)NN
Solvent: CC#N
Product: O=C1NN=C(c2ccc(Cl)cc2)CS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-1-(4-chloro-phenyl)-ethanone (90.71 mmoles) and hydrazine-carbothioic acid O-ethyl ester (90.71 mmoles) in acetonitrile (84 ml) is stirred at ambient temperature for 3 hours. The solid formed is filtered off, washed with acetonitrile and ethyl ether and then dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][C@H:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)ccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1C
Temperature: 0 °C

Procedure:
To an ice-cooled suspension of (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine-2,5-dione (1.35 g) in tetrahydrofuran (22 ml) was added lithium aluminum hydride (0.378 g) at 5° C. or below under a nitrogen atmosphere. The mixture was stirred under reflux for 3 hours. After cooling the mixture to 5° C. or below, 2N sodium hydroxide was added to the mixture. After stirring the mixture for 30 minutes, insoluble matters were collected by filtration and washed with tetrahydrofuran. The filtrate and the washings were combined and the solvent was evaporated under reduced pressure to give (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine in the form of an oily substance. A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.80 ml) in dichloromethane (1 ml) was added dropwise to an ice-cooled solution of (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)-piperazine obtained by the above process and triethylamine (0.84 ml) in dichloromethane (10 ml) at 5° C. or below over 5 minutes. After stirring at the same temperature for 30 minutes, the reaction mixture was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (4:1). Fractions containing the desired compound were collected and the solvent was evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbenzyl)-piperazine (1.92 g) in the form of an oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][S:32]([CH3:31])(=[O:34])=[O:33])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1)CNS(C)(=O)=O
Reaction time: 5 h

Procedure:
To a solution of Example 74 (70.0 mg, 0.212 mmol) in DMF (1 mL) was added triethylamine (0.089 mL, 0.64 mmol) and methanesulfonyl chloride (0.018 mL, 0.23 mmol). After 5 hours, more methanesulfonyl chloride (0.010 mL) was added. The reaction mixture was stirred overnight and treated with water slowly. The precipitate was filtered, washed with water, and oven dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 0.92 (s, 6H), 2.81 (d, J=7.14 Hz, 2H), 2.87 (s, 3H), 3.15 (d, J=6.35 Hz, 2H), 6.79-7.02 (m, 4H), 7.22 (dd, J=7.93, 4.76 Hz, 1H), 8.15 (d, J=2.38 Hz, 1H), 8.28-8.37 (m, 2H), 12.16 (s, 1H). MS (ESI+) m/z 408.0 (M+H)+.
Reaction SMILES: [CH:1]([F:7])([F:6])[C:2]([F:5])([F:4])[F:3].C(F)(F)(F)[C:9](Cl)([F:11])[F:10]>>[CH:1]([F:7])([F:6])[C:2]([F:5])([F:4])[F:3].[CH2:9]([F:11])[F:10]
Reactant: FC(F)(F)C(F)(F)Cl
Agent: FC(F)C(F)(F)F
Product: FCF

Procedure:
HFC-125 that is substantially free of CFC-115 can be produced in a process comprising contacting an HFC-125 precursor and an HFC-32 precursor with HF optionally over a catalyst to produce a mixture comprising HFC-125 and HFC-32, removing impurities other than CFC-115 from the mixture by distillation or other processes, separating the CFC-115 from the mixture comprising HFC-125 and HFC-32 by azeotropically distilling the low-boiling azeotrope of CFC-115 and HFC-32 overhead in a distillation column, and, recovering a mixture of HFC-125 with HFC-32 substantially free of CFC-115 from the bottom of the distillation column.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[CH:7]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C1(C)C=CC=CC=1>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]2([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]2)/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:6]2[CH:7]=[C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])[N:4]=[N:5]2)=[O:30])[N:17]=1
Reactant: N=C(N)n1cccn1
Reactant: NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N=C(N)NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2oxoethylidene)amino)oxy)cyclopropane-carboxylic acid (559 mg, 1.06 mmol) and Pyrazole-1-carboxamidine hydrochloride (310 mg, 2.12 mmol) in DMF (12 mL) was added DIPEA (1.48 mL, 8.45 mmol). After 16 h of stirring at rt, the solution was diluted with toluene (20 mL), causing a dense oil to separate out. The top layer was decanted and the remaining oil was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (240 mg, 39%) as a white powder. LCMS: Rt=0.28 min, m/z=572.0 (M+H) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 8.09 (s, 1H), 7.18 (s, 1H), 5.52 (d, J=5.4 Hz, 1H), 4.97 (dd, J=14.1, 5.5 Hz, 1H), 4.91 (q, J=5.5 Hz, 1H), 4.84-4.76 (m, 1H assumed; partially obscured by solvent residual peak), 4.55 (s, 2H), 1.49-1.36 (m, 2H), 1.34-1.23 (m, 2H). E-isomer was also obtained. LCMS: Rt=0.32 min, m/z=572.0 (M+H) Method 2m_acidic. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J=9.6 Hz, 1H), 8.11 (s, 1H), 7.41 (s, 1H), 7.13 (s, 2H), 6.50 (s, 1H), 5.18 (dd, J=9.6, 5.3 Hz, 1H), 4.97 (d, J=13.5 Hz, 1H), 4.76-4.58 (m, 1H), 4.52 (dd, J=16.11, 7.70 Hz, 1H), 4.26-4.05 (m, 2H), 1.86-2.08 (m, 1H), 1.34-1.07 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:29]([O:34][CH3:35])(=[O:33])[C@@H:30]1[O:32][CH2:31]1.CCOCC.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1>[OH:32][C@@H:30]([C:29]([O:34][CH3:35])=[O:33])[CH2:31][N:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[S:15]([CH3:18])(=[O:16])=[O:17]
Reactant: COC(=O)[C@H]1CO1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@H](O)CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O
Temperature: 70 °C
Yield: 82.1 %

Procedure:
To a mixture of N-[4-(4-trifluoromethylphenoxy)phenyl]methanesulfonamide (16.55 g, 50 mmol) from Step A, K2CO3 (17.3 g, 125 mmol), and benzyltriethylammonium chloride (1.135 g, 5 mmol) in dried 1,4-dioxane (75 mL) was added methyl(R)-glycidate (15.3 g, 150 mmol). The mixture was sealed and was heated to 70° C. for 24 h. The mixture was then poured into Et2O/H2O (200 mL/200 mL). The organic layer was washed with brine (200 mL), dried (Na2SO4), and filtered. After removal of solvent, the crude product was recrystallized from Et2O/hexane to give 17.8 g of the product (83%) as a pale brown solid. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.0 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.29 (d, J=6.0 Hz, 1H), 4.03-3.97 (m, 2H), 3.72 (s, 3H), 3.06 (s, 1H, OH), 3.05 (s, 3H); MS (EI) 456 (M++Na, 100), 434 (M++1). Anal. Calcd for C18H18F3NO6S: C, 49.88; H, 4.19; N, 3.23. Found: C, 50.00; H, 4.02; N, 3.22.