Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)C(C)C.C(O)(=O)CC.[CH3:12][CH:13]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14](=[O:22])[CH2:15][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18].C(Cl)C1C=CC=CC=1>>[CH3:12][C:13]([CH3:1])([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:14](=[O:22])[CH2:15][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18]
Reactant: COP(=O)(CC(=O)C(C)Cc1ccccc1)OC
Reactant: CC(C)C(=O)O
Solvent: CCC(=O)O
Solvent: ClCc1ccccc1
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC

Procedure:
Further, following the procedure of Preparation 1, but using in place of the isobutyric acid of Preparation 1, part A, propionic acid, there is prepared dimethyl 3-methyl-2-oxo-4-phenylbutylphosphonate. Following the procedure of Preparation 1, but using the substituted benzyl chlorides described above in place of benzyl chloride and propionic acid in place of isobutyric acid there are prepared the various dimethyl 3-methyl-2-oxo-4-(substituted phenyl)-butylphosphonates wherein the phenyl substitution is as described above.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[K].Cl[C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1.Cl>O>[CH2:1]([O:3][NH:12][C:10]1[CH:11]=[CH:6][C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCO
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Product: CCONc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 96 %

Procedure:
To ethanol (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol, ca. 2.24 equiv) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (57.74 g, 240 mmol, 1.0 equiv, [CAS RN 35375-74-7]) was added in one portion and the resulting dark red mixture was stirred at 55-60° C. for 4 d. The warm reaction mixture was slowly poured into water (ca. 2000 mL), the pH adjusted with a solution of 1 M HCl to 2, the yellow precipitate filtered off, washed with water and dried in air at 60° C. to give 57.81 g (96%) of the title compound as a yellow solid which was used without further purification. MS (ISN): 249.0 [M−H]−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:17])[C:8]([C:14](=[O:16])[CH3:15])=[CH:9][C:10]=1[C:11](=[O:13])[CH3:12])(=O)[CH3:2].[H-].[Na+].C(I)C.Cl>CN1CCCC1=O.C(O)C>[C:11]([C:10]1[CH:9]=[C:8]([C:14](=[O:16])[CH3:15])[C:7]([OH:17])=[CH:6][C:5]=1[NH:4][CH2:1][CH3:2])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1cc(O)c(C(C)=O)cc1C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: CCI
Product: CCNc1cc(O)c(C(C)=O)cc1C(C)=O
Reaction time: 2 h
Yield: 63 %

Procedure:
3-Acetamido-4,6-diacetylphenol (0.01 mole) in N-methylpyrrolidone (NMP) (20 ml) was added to a cooled (<5° C.), stirred suspension of sodium hydride (0.022 mole) in NMP (5 ml). After 15 minutes the mixture was treated with ethyliodide (0.019 mole). After two hours at <5° C., the mixture was acidified with ethanol/conc. HCl (1:1, 20 ml) and heated to reflux for 21/2 hours. The mixture was allowed to cool and the crystalline subtitle compound isolated by filtration. Yield 63%, mp 103°-104° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1.O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (3 g, 13.24 mmol) in dichloromethane (27.6 mL) was added dropwise to a mixture of methyl 4-aminobenzoate (2.0 g, 13.24 mmol), pyridine (3.21 mL, 39.72 mmol) and dichloromethane (41.4 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 2 hours. To the reaction, water (30 mL) was added. The solid was isolated by filtration, washed with water (2×30 mL) and hexane (2×30 mL) to yield methyl 4-[[2-fluoro-4-(trifluoromethyl)benzoyl]amino]benzoate (3.811 g, 84%) as a white solid. ESI-MS m/z calc. 341.07, found 342.2 (M+1)+; Retention time: 1.64 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.02-7.96 (m, 2H), 7.96-7.89 (m, 2H), 7.89-7.83 (m, 2H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 3.85 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([NH2:8])[CH2:5][C@H:4]([CH3:9])[O:3]1.[CH3:10][Si:11]([CH3:49])([CH3:48])[CH2:12][CH2:13][O:14][CH2:15][N:16]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:17]1[N:22]2[N:23]=[CH:24][C:25]([C:26]3[CH:27]=[N:28][C:29]4[C:34]([CH:35]=3)=[CH:33][C:32]([F:36])=[CH:31][CH:30]=4)=[C:21]2[N:20]=[C:19]([CH:37]=O)[C:18]=1[Br:39].CC(O)=O.[BH3-]C#N.[Na+]>ClCCCl.C(O)C.C(Cl)Cl>[Br:39][C:18]1[C:19]([CH2:37][NH:8][CH:6]2[CH2:5][C@H:4]([CH3:9])[O:3][C@H:2]([CH3:1])[CH2:7]2)=[N:20][C:21]2[N:22]([N:23]=[CH:24][C:25]=2[C:26]2[CH:27]=[N:28][C:29]3[C:34]([CH:35]=2)=[CH:33][C:32]([F:36])=[CH:31][CH:30]=3)[C:17]=1[N:16]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:48])([CH3:49])[CH3:10]
Reactant: C[C@@H]1CC(N)C[C@H](C)O1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C=O)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H]1CC(NCc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To crude (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-amine (0.18 g) in DCE (4.2 ml) and Ethanol (4.2 ml) was added 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (0.19 g, 0.3 mmol) followed by AcOH (0.03 ml, 0.6 mmol). After stirring for 30 minutes at room temperature, NaBH3CN (37.8 mg, 0.6 mmol) was added and stirring was continued further for 30 minutes more. LC/MS showed no starting material remaining. After the solvent was rotoevaporated, the crude was dissolved with DCM (20 ml), washed with sat. NaHCO3 (1×5 ml), water (1×5 ml), brine (1×5 ml), dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-60%) gave desired 6-bromo-5-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ylamino)methyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (68 mg, 30%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.O.[Br-:21].[Li+]>CN(C)C=O.[Cl-].[NH4+]>[Br:21][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: [Br-]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Br
Yield: 69 %

Procedure:
2,6-dimethyl-4-nitrophenyl trifluoromethanesulfonate (5.0 g, 17 mmol) was dissolved in N,N-dimethylformamide (40 mL). Lithium bromide monohydrate (4.7 g, 45 mmol) was added and the reaction was refluxed overnight. The reaction was diluted with saturated ammonium chloride and the layers were separated. The organics were washed with water (3×40 mL) and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (2% ethyl acetate in petroleum ether) gave 2-bromo-1,3-dimethyl-5-nitrobenzene (2.7 g, 69%) as a light yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.94 (s, 2H), 2.50 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32].[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:10]=[C:9]3[C:5]([N:6]([CH3:11])[CH:7]=[N:8]3)=[C:4]([O:12][CH3:13])[N:3]=2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32]
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: COc1nc(Cl)nc2ncn(C)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1c(Cl)ccc(-c2nc(OC)c3c(ncn3C)n2)c1F
Reaction time: 2 h
Yield: 67 %

Procedure:
2-Chloro-6-methoxy-7-methyl-7H-purine (1.2 g, 6.0 mmol, see Monatshefte fuer Chemie (1985), 116(3), 341-51 for preparation), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.1 g, 8.6 mmol), Pd(PPh3)2Cl2 (300 mg, 0.42 mmol) and cesium fluoride (1.6 g, 11 mmol) were combined in 10 mL dry, deaerated acetonitrile and heated to reflux. After 2 h, the mixture was cooled and mixed with ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated under vacuum. The residue was purified by flash chromatography on silica gel with 20% ethyl acetaete/hexane to give the title compound (1.3 g, 67% yield: mp 191-192° C.: 1H NMR (CDCl3) δ 8.0 (s, 1H), 7.90 (dd, 1H), 7.22 (dd, 1H), 4.22 (s, 3H), 4.08 (s, 3H), 4.02 (s, 3H).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=2[OH:20])=[O:19])=[CH:17][CH:16]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(CCc1ccc(F)cc1)OC
Agent: C=O
Agent: CN
Product: CON(CCc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 38 %

Procedure:
3-{[2-(4-Fluorophenyl)-ethyl]-methoxy-carbamoyl}-2-hydroxy-acrylic acid methyl ester (Compound 52-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (38% yield); mp 157° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.96 (2H, t, J=7.6 Hz, CH2), 3.14 (3H, s, NCH3), 3.71 (3H, s, OCH3), 3.93 (2H, t, J=7.6 Hz, CH2), 4.14 (2H, s, NCH2), 7.01 (2H, m, aromatics), 7.2 (2H, m, aromatics), 11.55 (1H, broad s, OH). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.52; H, 5.66; N, 8.89.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[Br:10].[Li+].CC([N-]C(C)C)C.[Li]CCCC.[C:24](=[O:26])=[O:25]>>[Br:10][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([CH:4]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: Fc1ccc(Br)c(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Reaction time: 1.25 h

Procedure:
To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent is added strong base (such as LDA, nBuLi, LiHDMS) under nitrogen atmosphere. The reaction is generally carried out at low temperature (−50-−80° C., prefer −78° C.). The reaction is kept stirring for some time (0.5-12 h, preferably select 0.5-2 h) and is added dry ice. The resulting mixture is kept stirring for some time (3-12 h, prefer 5-10 h) and 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventional workup.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.[C:18](Cl)(=[O:22])[C:19](C)=[CH2:20]>C(C(C)=O)C>[C:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:16][CH:17]=1)(=[O:22])[CH:19]=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: C=CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
1.3 g (16.25 mmoli) of NaOH 50% water solution, were added to a solution of 3 g (15.21 mmol) of 4-hydroxybenzophenone in 20 cc of methyl ethyl ketone. After 30 minutes under stirring, a solution of 1.59 g (15.21 mmol) of methacryloyl chloride in 5 mL of methyl ethyl ketone were added dropwise. After the addition the reaction mixture was stirred for 1 hour, filtered and the solvent was evaporated. The oil residue was purified by flash chromatography on silica gel (eluent CH2Cl2) to obtain 2.74 g of a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[N:4][CH:3]=1.[ClH:29]>C(Cl)(Cl)Cl.CO.O1CCOCC1>[ClH:29].[ClH:29].[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl {1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}carbamate (1.591 g, 4.079 mmol) in chloroform (15 ml) and MeOH (15 ml) was added 4M HCl in 1,4-dioxane (15 ml). The reaction was stirred at rt for 0.5 h before evaporation to provide the desired compound as a slightly impure white solid which was used without further purification (1.633 g, 110%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: COC(=O)CBr
Reactant: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccsc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccsc1
Yield: 64.3 %

Procedure:
23 g of N-(4-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine, 6.1 g of 50% sodium hydride and 21.8 g of methyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 18.6 g of methyl 3-(4-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate are thereby obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[C:15](OCC)=[O:16])[CH3:9].O.CCOC(C)=O>C1COCC1>[CH3:7][CH:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH2:15][OH:16])[CH3:9]
Reactant: CCOC(=O)c1scnc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ncsc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a 0° C. mixture of lithium aluminum hydride (300 mg, 7.9 mmol) in anhydrous THF (10 mL) was slowly added a solution of ethyl 4-(propan-2-yl)-1,3-thiazole-5-carboxylate (1.06 g, 6.1 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at room temperature for 1.5 hours. After cooling to 0° C., water (20 mL) and EtOAc (40 mL) were added. The mixture was stirred for 30 minutes. The solid material was removed by filtration. The organic layer was recovered. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried in vacuo, affording [4-(propan-2-yl)-1,3-thiazol-5-yl]methanol (802 mg, 96% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[C:12](Cl)(=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>O1CCCC1>[OH:2][CH2:1][CH2:3][NH:4][C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCO
Reactant: CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(=O)NCCO
Reaction time: 18 h

Procedure:
A solution of ethanolamine (8.00 mL, 133 mmol) and triethylamine (20.0 mL, 143 mmol) in tetrahydrofuran (200 mL) was cooled to 0° C., and a solution of heptanoyl chloride (20.0 mL, 129 mmol) in tetrahydrofuran (50 mL) was added dropwise over 30 minutes. After stirring an additional 18 hours, the reaction mixture was poured into water (400 mL), and extracted with methylene chloride (2×300 mL). The extracts were combined, dried over anhydrous magnesium sulfate and evaporated to afford the solid product (N-(2-hydroxyethyl)-heptanamide), which was recrystallized to purity from ether-hexane (22.3 g, 129 mmol, 100%), melting point 91°-93° C. 1H NMR (CDCl3): 6.31 (1H, br s); 3.75-3.68 (2H, m); 3.55-3.39 (3H, m); 2.21 (2H, t, J=7.2 Hz); 1.69-1.58 (2H, m); 1.39-1.24 (6H, m); 0.88 (3H, t, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22](O)[CH3:23])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]1(=[O:59])[NH:53][C:52](=[O:54])[C:51]2=[CH:55][CH:56]=[CH:57][CH:58]=[C:50]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]([N:53]2[C:49](=[O:59])[C:50]3[C:51](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:52]2=[O:54])[CH3:23])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:20])([F:21])[F:19])[CH:14]=[CH:13][CH:12]=2
Reactant: CC(O)c1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethanol (0.08980 g, 0.2546 mmol) in tetrahydrofuran (2.546 mL, 0.2546 mmol) were added triphenylphosphine (0.2003 g, 0.7637 mmol), phthalimide (0.1124 g, 0.7637 mmol), and diisopropyl azodicarboxylate (0.1504 mL, 0.7637 mmol). The reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 20 min and 50% isocratic of EtOAc for 10 min as eluent to give 2-(1-(3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethyl)-isoindoline-1,3-dione as a yellow solid: LC-MS (ESI) m/z 482.0 [M+H]+.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH:27]4[N:37]5[C:38]6[N:29]([C:30](=[O:40])[CH:31]=[CH:32][C:33]=6[CH2:34][CH2:35][C:36]5=[O:39])[CH2:28]4)[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>O1CCOCC1>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH:27]4[N:37]5[C:38]6[N:29]([C:30](=[O:40])[CH:31]=[CH:32][C:33]=6[CH:34]=[CH:35][C:36]5=[O:39])[CH2:28]4)[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CC2Cn3c4c(ccc3=O)CCC(=O)N42)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CC2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl){1-[(4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-1-yl)methyl]-4-piperidinyl}carbamate (80 mg, 0.145 mmol) and DDQ (49.4 mg, 0.218 mmol) in 1,4-dioxane (5 ml) was stirred at 120° C. for 2 h. A further 0.5 eq of DDQ (17 mg) was added and the solution stirred for a further 2 h. The mixture was allowed to cool to rt and was treated with sat NaHCO3 (10 ml). The aqueous layer was extracted with 20% MeOH/DCM (3×100 ml). The organic layers were combined, dried MgSO4, filtered and concentrated to afford the crude product (64 mg, 83%).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:11])[C:4](=[N:8][O:9][CH3:10])[C:5](Cl)=[O:6].[NH2:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][C:17]([CH:38]=[CH:39][O:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42])=[C:18]2[C:22]([O:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:25]([O:24][C:22]([C:18]1[N:19]2[CH:14]([S:15][CH2:16][C:17]=1[CH:38]=[CH:39][O:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42])[CH:13]([NH:12][C:5](=[O:6])[C:4](=[N:8][O:9][CH3:10])[C:3](=[O:11])[CH2:2][Br:1])[C:20]2=[O:21])=[O:23])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CON=C(C(=O)Cl)C(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride syn isomer (2 g) in acetone (10 cc) is added, in the course of 7 minutes, to a solution, cooled to -10° C., of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene, E-form (4.7 g) in acetone (50 cc), water (5 cc) and sodium bicarbonate (2.8 g). The mixture is stirred for 1 hour at -10° C. and is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). Crude 2-benzhydryloxycarbonyl-7-(4-bromo-2-methoxyimino-3-oxo-butyrylamino)-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (11 g) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:11]#[C:12][CH3:13])[C:3]=1[CH:4]=O.[NH3:14].CO>>[F:10][C:8]1[CH:7]=[C:6]2[C:3](=[C:2]([F:1])[CH:9]=1)[CH:4]=[N:14][C:12]([CH3:13])=[CH:11]2
Reactant: CC#Cc1cc(F)cc(F)c1C=O
Reactant: N
Solvent: CO
Product: Cc1cc2cc(F)cc(F)c2cn1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of 2,4-difluoro-6-prop-1-ynylbenzaldehyde (Description 71, 8.7 g; 48.8 mmol) and 2.0M ammonia in methanol (244 ml; 488 mmol) were heated together at 80° C. in a Parr apparatus (approx 35 psi achieved) for 5 hours. The cooled mixture was evaporated and the residue purified by column chromatography on silica-elution with 100% dichloromethane to give the title compound (5.2 g, 59%) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:7]#[N:8])([O-])=O.C(O)(=O)C.[Sn](Cl)Cl>CCO.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzonitrile (500 mg, 2.31 mmol) and acetic acid (6.62 mL, 116 mmol) in EtOH (10 mL) and water (10 mL) is added tin (II) chloride (2.61 g, 11.6 mmol) and the reaction mixture is heated at 80° C. for 6 h. The solvent is removed in vacuo and then the residue is portioned between DCM and 4 N HCl solution. The organic layer separated and then dried over anhydrous Na2SO4, filtered and concentrated. The residue is then separated via FCC (10-100% EtOAc/heptane) to give the compound as a yellow oil (213 mg, 49%). MS (ESI) m/z 185.3 (M+1).