Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1.O>N1C=CC=CC=1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:63]([CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:69])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: O=C1CCC(=O)O1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)CCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reaction time: 3 h

Procedure:
After 3 hours at room temperature, a solution of 500 mg (0.59 mmole) of taxol, 900 mg (7.6 mmole) of succinic anhydride in 12 mL of pyridine is evaporated to dryness in vacuo. The residue is treated with 20 mL of water, stirred for 20 min. and filtered. The precipitate is dissolved in acetone, water slowly added, and the fine crystals collected. This yields 490 mg (86%) of title compound which showed: mp 178°-80° C., [a] -42.1° (c=1.1 EtOH); Anal. (C H NO H 0) C,H,N.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[N:47]=[C:46]([NH:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:45]([F:53])=[CH:44][N:43]=1>C(Cl)(Cl)Cl>[C:49]([NH:48][C:46]1[C:45]([F:53])=[CH:44][N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[N:47]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)Nc1nc(N)ncc1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ncc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 3 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 210 mg of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 340 mg of 2-amino-4-(t-butylamino)-5-fluoropyrimidine. The solution was concentrated under reduced pressure. To the residue were added 550 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 1 hour and 10 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel, 16 g; eluent: chloroform:methanol, 200:1), and the corresponding fractions were collected and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 98 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:32])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:33](Cl)(=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1.[O:46]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]1.C(N(CC)CC)C>ClCCl>[F:26][C:23]([F:24])([F:25])[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([N:8]([CH3:32])[C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:52][CH:49]4[CH2:50][CH2:51][O:46][CH2:47][CH2:48]4)=[O:34])=[CH:3][CH:4]=3)[CH2:14][CH2:13]2)=[CH:17][CH:18]=1)([OH:31])[C:27]([F:30])([F:28])[F:29]
Reactant: CN(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(c1ccc(NC(=O)NC2CCOCC2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A solution of 2-(4-((4-((4-aminophenyl)(methyl)amino)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.303 mmol, 140 mg) and 4-nitrophenyl carbonochloridate (0.303 mmol, 61.2 mg) in dichloromethane (1 mL) was stirred at room temperature for 30 minutes. Tetrahydro-2H-pyran-4-amine (0.607 mmol, 61.4 mg) was added followed by triethylamine (0.910 mmol, 0.127 mL, 92 mg) and the reaction stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane/saturated sodium bicarbonate solution and filtered through a hydrophobic frit. The organic layer was concentrated and the residue was purified by silica column chromatography (eluent: dichloromethane to 4% methanol in dichloromethane) to give the title compound (74.2 mg). MS (ESI) m/z 589.2 [M+H]+
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.Cl.C1C[O:38]CC1>>[OH:38][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Agent: Cl
Product: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)Nc3ccc(O)nc3)nc3c2CCC3)n[nH]1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of N-(6-fluoro-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (500 mg, 1.111 mmol) in THF (10 mL) was added HCl (1 mL) and reaction mixture was stirred at 60° C. for 16 h. The progress of reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum to obtain crude product which was purified by reverse HPLC to afford N-(6-hydroxy-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (249 mg). 1H NMR (400 MHz, CD3OD) δ (ppm): 1.17-1.30 (m, 6H), 2.17-2.37 (m, 4H), 2.38-2.50 (m, 1H), 2.79-2.95 (m, 3H), 3.00-3.10 (m, 2H), 3.22-3.38 (m, 2H), 3.58-3.70 (m, 1H), 3.80 (brs, 1H), 4.81 (dd, 1H), 6.22 (s, 1H), 6.68 (d, 1H), 7.60 (d, 1H), 7.98 (s, 1H). Separation by chiral HPLC provides enantiomers 63a and 63b.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30]>>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Product: O=C(O)CCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
This compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Example 4.1 step 1) and ethyl 6-bromohexanoate analogously to 7-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid (Example 1 step 1 and step 2. Step 1 was carried out using microwave radiation).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([O-:25])[CH3:24].[Na+].C(O)C>O>[CH2:23]([O:25][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:24]
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cccc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 200 °C
Yield: 39 %

Procedure:
A solution of (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (63 mg, 0.2 mmol) and 21% sodium ethanolate solution in ethanol (112 uL, 0.3 mmol) was heated to 200° C. for 30 minutes in a microwave oven. The same amount of sodium ethanolate solution was added and the reaction was again heated to 200° C. for 30 minutes in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound as a light brown solid (25 mg, 39%). MS ISP (m/e): 325.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.45 (t, 1H), 7.34 (s, 1H), 7.15 (d, 1H), 6.92 (d, 1H), 6.87 (s, 1H), 6.50 (s, 1H), 6.37 (d, 1H), 6.24 (d, 1H), 4.35 (q, 2H), 3.83 (s, 3H), 2.30 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:9].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[C:15]1([N:13]2[CH:14]=[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:9])[CH:11]=[N:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1ccccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccccc1C(=O)c1cnn(-c2ccccc2)c1
Yield: 67 %

Procedure:
Prepared from (2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (264 mg, 1.0 mmol) and ethyl bromoacetate according to GP2 to give 235 mg (67%) of the title compound as white solid: 1H NMR (CDCl3): δ 1.26 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.67 (s, 2H), 6.84 (d, J=8.3 Hz, 1H), 7.10 (ts, J=7.4, 0.8 Hz, 1 Hz), 7.29-7.36 (m, 1H), 7.41-7.53 (m, 4H), 7.72-7.78 (m, 2H), 8.18 (s, 1H), 8.58 (s, 1H); 13C NMR (CDCl3): δ 14.3, 61.7, 65.4, 112.2, 118.8, 119.3, 119.7, 120.0, 122.1, 125.8, 127.6, 129.7, 129.9, 130.1, 130.6, 131.8, 132.1, 136.3, 139.7, 142.8, 155.0, 168.9, 188.7.
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][N:11]1[CH2:15][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:12]1=[O:24])C1C=CC=CC=1.[NH3:26]>CO>[CH2:17]([O:16][C:14]1[CH2:15][N:11]([CH2:10][C:9]([NH2:26])=[O:8])[C:12](=[O:24])[CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N
Reactant: O=C(CN1CC(OCc2ccccc2)=CC1=O)OCc1ccccc1
Solvent: CO
Product: NC(=O)CN1CC(OCc2ccccc2)=CC1=O

Procedure:
25.0 g of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester was dissolved in 500 ml of methanol and stirred at 40° C with passing of gaseous NH3 for 5 hours. Then the reaction solution was evaporated and the residue was mixed with 50 ml of acetone. The precipitated crystals were filtered by suction and dried. 15.2 g of TLC pure product with a melting point of 174.5 to 175.5° C. was obtained. For the product:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>N1C=CC=CC=1.ClCCl>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a stirred suspension of 3-bromophenol (50 g, 0.29 mol) in pyridine (200 mL) and dichloromethane (100 mL) was added dropwise acetyl chloride (25 mL, 0.35 mol) at 0° C. and the mixture was stirred 18 h at room temperature. LC-MS showed that the reaction was complete. Pyridine and dichloromethane was evaporated in vacuo. Water (600 mL) was added and acidified with hydrochloric acid at pH 2. The reaction mixture was extracted with ethyl acetate (500 mL×3) and the organic phase was dried over anhydrous sodium sulfate, filtrated, concentrated and purified by column chromatography (PE:EA=60:1) to afford compound E-1 as a colorless liquid (46 g, 74%).
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[OH-].[Na+].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:11]([N:3]1[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CSCN1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 108.2 %

Procedure:
1 liter of acetone was added to a solution of 266.2 g of (4R)-thiazolidine-4-carboxylic acid in 1 liter of a 2N aqueous solution of sodium hydroxide. The solution was cooled at a temperature between 2° and 5° C., and then a solution of 280 g of benzoyl chloride in 0.8 liter of acetone was added dropwise, while maintaining the pH value of the reaction mixture at 7.5-8.0 by the addition of 1 liter of a 2N aqueous solution of sodium hydroxide. When the addition was complete, the reaction mixture was stirred at a temperature between 0° and 5° C. for 1 hour, after which it was concentrated by evaporation under reduced pressure to a volume of about 2.5 liters. The concentrate was washed with 2 liters of ethyl acetate, the aqueous phase was adjusted to a pH value of 2.0 by the addition of concentrated hydrochloric acid, maintaining the temperature at between 0° and 5° C., and the mixture was extracted twice, each time with 2 liters of ethyl acetate. The ethyl acetate phase was washed with a 10% w/v aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 511.2 g of (4R)-3-benzoylthiazolidine-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[C:3]=1[Cl:10].[CH3:11][O-:12].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[CH:5]=[C:4]([Cl:9])[C:3]=1[Cl:10]
Reactant: C[O-]
Reactant: Fc1cc(Cl)c(Cl)c(Br)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(Cl)c(Br)c1

Procedure:
1-Bromo-2,3-dichloro-5-fluorobenzene (5.1453 g, 21.10 mmol) was dissolved in THF (25 mL) at room temperature and cooled to 0° C. Then, 5.1 g of sodium hydride (60%, 128 mmol) was added and 2.0 mL of methanol was added slowly. Additional THF (5 mL) was added. The mixture was stirred at room temperature for 10 minutes, then heated at 75° C. for four hours and cooled to room temperature. The mixture was poured into ice with some aq. sat. NH4Cl solution and extracted with EtOAc (3×100 mL). The organic solution was washed with brine, dried over Na2SO4, concentrated to dryness. The residue was purified with flash column chromatography on silica gel using hexane as solvent to afford the product (4.6727 g) as a white solid in 87% yield. 1H-NMR (CDCl3): δ 7.109 (d, J=3.0 Hz, 1H), 6.988 (d, J=3.0 Hz, 1H), 3.786 (s, 3H). The product was also synthesized from 1-bromo-2,3-dichloro-5-fluorobenzene and sodium methoxide in THF. The final product was purified by recrystallization from hexane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][CH:29]=O>ClCCl.CCCCCC.O>[Br:21][C:20]([Br:24])=[CH:29][CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25]
Reactant: O=CCCC(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: FC(F)(F)CCC=C(Br)Br

Procedure:
To a −78° C. solution of oxalyl chloride (4.13 mL, 47.4 mmol) in 60 mL of dichloromethane was added dimethylsulfoxide (4.76 mL, 67.1 mmol). After 10 minutes, 4,4,4-trifluorobutanol was added dropwise (5.059 g, 39.49 mmol), followed by dropwise addition of triethylamine (11.01 mL, 78.9 mmol). The solution was alowed to warm to room temperature over 30 minutes, and was quenched by the addition of saturated NH4Cl solution. The organic layer was separated and washed with brine to provide a solution of 4,4,4-trifluoro-1-butanal. To a second solution containing triphenylphosphine (31.1 g, 118 mmol) and carbontetrabromide (19.65 g, 59.2 mmol) in 50 mL of dichloromethane a 0° C. was added dropwise the aldehyde solution described above. Five minutes after complete addition, the reaction was diluted with 250 mL of hexane and 500 mL of water. The Organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material was triturated repeatedly with diethyl ether to remove triphenylphosphine oxide, giving the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].S([CH2:34][N+:35]#[C-:36])(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.CO.COCCOC>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]2[C:16]([C:13]3[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=3)=[CH:36][N:35]=[CH:34]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-n2cncc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 55.7 %

Procedure:
4-Methoxyaniline (2.46 g, 20 mmol) and pyridine-4-carboxaldehyde (1.9 mL, 10 mmol) in toluene (110 mL) in a flask attached to a Dean-Stark trap and reflux condensor was heated at reflux. After 40 hours, the reaction was complete by infrared spectral analysis and mass spectral analysis. The toluene was removed via distillation through the Dean-Stark sidearm, the residue was dissolved in methanol (100 mL) and ca. ½ of the crude imine (ca. 10 mmol, 50 mL of methanol solution) was diluted with methanol (20 mL) and 1,2-dimethoxyethane (20 mL). The solution was then treated with potassium carbonate (2.76 g, 20 mmol) and tosylmethylisocyanide (TOSMIC, 2.93 g, 15 mmol) and was heated at reflux for 3 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was dissolved in methylene chloride and was washed with brine. The brine layer was extracted with methylene chloride and the combined organic layers were dried (MgSO4), were filtered, and were concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate-hexanes-methanol (80:20:0 to 76:19:5) to afford 1.4 g (56% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 160.039, 150.161, 141.009, 137.240, 130.839, 129.179, 127.287, 121.597, 115.106, 55.801; MS (AP/CI) 252.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][CH:29]=3)[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:37]=[O:38]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[CH:37]=[O:38])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(-c3cnc4ccnn4c3C3CCCCC3)cc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice cold solution of 300 mg (0.78 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine in 2 mL of dimethylformamide (DMF) and 1 mL of dichloromethane (DCM) was added 0.085 mL (0.9 mmol) of phosphorus oxychloride (POCl3) and the resulting mixture was allowed to warm up to rt and stirred at rt for 4 h when analysis by thin layer chromatography (TLC) indicated complete conversion of starting material to product. The reaction mixture poured into ice-water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 335 mg of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (436) as a beige solid as indicated by 1H NMR; LC-MS—calcd for C26H25N3O2 [M++H]+: 412.19, found: 412.1.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([F:21])=[C:6]([F:22])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:24]O>CO.O.CCOC(C)=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:8]1[C:9]2[C:10](=[O:11])[O:12][N:24]=[C:1]([CH3:2])[C:4]=2[CH:5]=[C:6]([F:22])[C:7]=1[F:21]
Reactant: CC(=O)c1cc(F)c(F)c(Nc2ccccc2Cl)c1C(=O)O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(=O)c2c(Nc3ccccc3Cl)c(F)c(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of 6-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (50 mg, 0.15 mmol) and hydroxylamine hydrochloride (11 mg, 0.15 mmol) in MeOH-H2O (1 mL/0.5 mL) was added TEA (0.022 mL, 0.15 mmol) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2) to afford the desired product (26.8 mg, 54%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:30](=[O:31])[N:14]2[C:15]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[CH:16][C:17](=[O:19])[S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.[N+](C)([O-])=O>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:30](=[O:31])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[CH:16][C:17](=[O:19])[S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=CC(=O)S[C@H]12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=CC(=O)S[C@H]12
Reaction time: 0.42 h
Yield: 80.2 %

Procedure:
To a solution of benzyl 7β-(2-phenoxyacetamido)-2-oxo-3-cephem-4-carboxylate (369 mg) in methylene chloride (15 ml) were added successively anisole (1.37 ml) and a solution of aluminum chloride (560 mg) in nitromethane (5 ml) under ice-cooling. The mixture was stirred for 25 minutes at the same temperature and poured into a mixture of methylene chloride and dil. hydrochloric acid. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. After addition of diisopropyl ether to the residue, the precipitates were collected by filtration and then washed with a small amount of diethyl ether to give 7β-(2-phenoxyacetamido)-2-oxo-3-cephem-4-carboxylic acid (235 mg). mp 158° to 160° C. (dec.).