Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[CH2:24]([O:26][C:27](=[O:36])[CH:28](Br)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH2:24]([O:26][C:27](=[O:36])[CH:28]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25]
Reactant: CCOC(=O)C(Br)C1CCCCC1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 100 °C
Yield: 75.9 %

Procedure:
To the solution of 75 g (0.28 mol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole in 750 ml N,N-dimethylformamide 116 g (0.33 mol) cesium carbonate and 88 g (0.35 mol) bromo-cyclohexyl-acetic acid ethyl ester (commercially available) were added. The mixture was heated to 100° C. and after stirring for 90 min. another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 6 h another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 22 h (total reaction time) the reaction mixture was cooled to 30° C. and was poured on 1 L ice water and 2 L ethyl acetate. The phases were separated and the aqueous phase extracted with 500 mL ethyl acetate. The combined organic phases were washed three times with 500 ml ice water and once with brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using n-heptane:ethyl acetate (9:1 v/v) as eluant. The product-containing fractions were pooled and the solvent evaporated until a suspension had formed. The suspension was cooled in an ice bath and filtered to give 92 g (75%) of the desired product as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:11]([O:15][C:16]([NH:18][C:19]([CH3:24])([C:21](O)=[O:22])[CH3:20])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[F:1][C:2]1[C:3]([NH:9][NH:10][C:21](=[O:22])[C:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:24])[CH3:20])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: NNc1ncc(F)cc1F
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NNc1ncc(F)cc1F

Procedure:
This compound was prepared (66%) from 3,5-difluoro-2-hydrazinopyridine and N-(tert-butoxycarbonyl)-2-methylalanine following the experimental procedure described for the synthesis of Intermediate 21, step a.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:10](N(OC)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOC(C)=O>[CH2:27]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[CH:10]=[O:11])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CON(C)C(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a 500 mL round-bottomed flask was added (S)-2-(dibenzylamino)-N-methoxy-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (6.22 g, 13.6 mmol), THF (100 mL), and lithium aluminum hydride (1.0 M solution in THF (27.3 mL, 27.3 mmol)), dropwise at 0° C. After 30 minutes, TLC (2:1 hexanes:EtOAc) showed that no starting material remained. The mixture was quenched by dropwise addition of water (6.82 mL), 2 N NaOH (6.82 mL), and water (9.83 mL). The solids were removed by filtration through a medium scintered glass funnel. The filtrate was dried over sodium sulfate and evaporated. The residue was taken up in EtOAc (200 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate and evaporated to provide (S)-2-(dibenzylamino)-3-(4-(trifluoromethyl)phenyl)propanal (4.51 g, 83.3% yield) as a light yellow oil. LCMS (ES+) m/z=398.2. 1H NMR (400 MHz, CDCl3) δ ppm 2.96 (dd, J=13.89, 5.67 Hz, 1H) 3.18 (dd, J=13.89, 7.43 Hz, 1H) 3.52-3.55 (m, 1H) 3.66-3.72 (m, 2H) 3.82-3.88 (m, 2H) 7.21-7.33 (m, 12H) 7.50 (d, J=8.02 Hz, 2H) 9.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([CH2:17][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=2)[N:5]=[CH:6][C:7]1=[O:13])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(=O)cnc2cc(Cl)c(Cl)cc21)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Under a nitrogen atmosphere 6,7-dichloroquinoxalin-2(1H)-one (10.0 g, 46.5 mmol) (Liebigs Ann. Chem, (1982), 754) was suspended in 135 ml of dry DMF and sodium hydride (2.23 g, 55.8 mmol (60% mineral oil dispersion)) was added. After stirring for 2 h, benzyl bromoacetate (9.18 ml, 58.6 mmol) was added and the mixture was stirred for 3.5 h. The reaction mixture was poured onto 300 g of crushed ice and the precipitate was filtered off, washed with water and dried. The product was triturated with ether (500 ml), the precipitate filtered off, washed with ether and dried to afford 13.3 g of 1-benzyloxycarbonylmethyl-6,7-dichloroquinoxaline-2(1H)-one. 1H-NMR (DMSO-d6):δ5.18(s, 2H), 5.23(s, 1H), 8.18(s, 1H), 8.38(s, 1H).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:26](O)=O)[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:51][C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][C:62]([C:65]#[N:66])=[C:61]([F:67])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[NH2:58]>C(#N)C>[C:65]([C:62]1[CH:63]=[CH:64][C:59]([C:54]2[CH:55]=[CH:56][C:57]3[NH:58][C:26]([C@@H:2]([NH:1][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:51][C:52]=3[CH:53]=2)=[CH:60][C:61]=1[F:67])#[N:66]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of Boc-Asn(Trt)-OH (100.4 mg, 0.2116 mmol) in acetonitrile (2.0 mL) cooled in an ice water bath was added 4-methylmorpholine (0.059 mL, 0.53 mmol) and isobutyl chloroformate (0.027 mL, 0.21 mmol). After stirring for 60 minutes, 3′,4′-diamino-3-fluoro-[1,1-biphenyl]-4-carbonitrile (Preparation 81, 42.7 mg, 0.188 mmol) was added and the mixture allowed to warm to room temperature. After stirring for 18 hours the reaction mixture was concentrated in vacuo and redissolved in acetic acid. After stirring at room temperature for 6.5 hours, the mixture was concentrated in vacuo, redissolved in ethyl acetate, washed with water, 0.5M HCl, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (75 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[N+]([C:15]1[O:19][C:18]([CH:20]=[O:21])=[CH:17][CH:16]=1)([O-])=O.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:15]1[O:19][C:18]([CH:20]=[O:21])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(F)cc2F)o1
Reaction time: 0.67 h
Yield: 32.5 %

Procedure:
To a solution of 2,4-difluorophenol (6.54 mL, 68.0 mmol) in dimethylsulfoxide (70 mL) was sodium hydride (4534 mg, 68.0 mmol, 60% in oil), which was then stirred for 40 minutes. 5-Nitro-2-furaldehyde (8000 mg, 56.7 mmol) was added to the reaction solution, and the solution was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate), and the title compound (4134 mg, 18.44 mmol, 33%) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: Clc1nc2ccccc2s1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4nc5ccccc5s4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-benzothiazole:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:16][N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(N)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:18]([N:17]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)cn(Cc3ccccc3)c2CC1
Solvent: NCc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(Cn2cc(-c3ccccc3)c3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Benzyl-3-phenyl-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylic acid tert-butyl ester. A solution of the compound (0.53 g) from Example 59, Step B, and 272 μL of benzylamine in benzene (10 mL) was heated at reflux for 24 h using a Dean-Stark apparatus. The solvent was removed, the crude material was dissolved in toluene (10 mL), and 0.38 g of (2-nitro-vinyl)-benzene was added. The mixture was stirred for 24 h at RT and concentrated in vacuo. Chromatography on SiO2 (1 to 20% EtOAc/hexanes) afforded 108.0 mg of the desired compound. MS (ESI): exact mass calculated for C26H30N2O2, 402.53. found, m/z 403.2 [M+H]+.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][NH:20][CH2:21][CH2:22][OH:23].N1C=CN=C1>CN(C)C=O>[O:23]([CH2:22][CH2:21][NH:20][CH3:19])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 5.5 h
Yield: 38.5 %

Procedure:
Under nitrogen atmosphere, an N,N-dimethylformamide (33 ml) solution of tert-butylchlorodiphenylsilane (8.78 g, 32.0 mmol) was dropwise added at room temperature to an N,N-dimethylformamide (100 ml) solution of N-methylethanolamine (2.00 g, 26.6 mmol) and imidazole (2.72 g, 39.9 mmol), and stirred for 5.5 hours. The solvent was evaporated away under reduced pressure, then the residue was dissolved in ethyl acetate, and the solution was washed with saturated sodium hydrogencarbonate water, water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate gave the entitled compound (3.21 g, 39%) as a pale yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([Cl:24])[C:9]2[O:13][C:12]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)O)=[CH:11][C:10]=2[CH:23]=1>C1CCCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([Cl:24])[C:9]2[O:13][C:12]([CH:14]([Cl:3])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:11][C:10]=2[CH:23]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc2cc(Cl)cc(Cl)c2o1
Reactant: O=S(Cl)Cl
Solvent: C1CCCCC1
Product: Clc1ccc(C(Cl)c2cc3cc(Cl)cc(Cl)c3o2)cc1

Procedure:
To 0.35 mole of thionylchloride in 300 ml of cyclohexane, 0.31 mole of (5,7-dichlorobenzofuran-2-yl)(p-chlorophenyl)carbinol are portions-like added followed by 3-hour agitation at ambient temperature; then the solution is concentrated, filtered out and crystallized from cyclohexane: m.p. 72°-74° C.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[C:12]([CH3:24])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.N>CO.[Pd]>[NH:1]([C:8]1[N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]2[N:11]=[C:12]([CH3:24])[C:13]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc1/C=C/C(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Agent: N
Solvent: O=CO
Solvent: CO
Product: Cc1nc2c(cc1C=CC(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 86.8 %

Procedure:
To a stirred suspension of 2-anilino-6-[(E)-3-hydroxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propenoic acid (34.5 mg, 86%): LCMS RT: 2.31 min, MH+: 400.4, Rf=0.61 (4:1 EtOAc:MeOH).
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH3:19][Se:20][Se]C.C(OCC)(=O)C>C1COCC1>[CH3:19][Se:20][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[Se][Se]C
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Se]c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a solution of 500 mg (2.0 mmol) of 2-bromo-3-nitrobenzoic acid in anhydrous THF (15 mL) was added 2.80 mL (4.47 mmol) of n-BuLi (1.6 M soln. in Hex.) slowly at −78° C. After 10 minutes, a solution of 383 mg (2.03 mmol) of dimethyl diselenide in THF (5 mL) was added. After 30 minutes, the reaction mixture was warmed to room temperature. After additional stirring for 2 hours, ethyl acetate was added. The organic layer was washed with 1 N HCl solution, dried over MgSO4, and concentrated under reduced pressure. 470 mg of crude product was obtained and used for the next reaction without further purification.
Reaction SMILES: [CH:1]([CH:4]([C:10]([CH3:12])=O)[C:5]([O:7]CC)=O)([CH3:3])[CH3:2].[F:13][C:14]([F:19])([F:18])[C:15]([NH2:17])=[NH:16].O(C)[Na]>CO>[CH3:12][C:10]1[N:16]=[C:15]([C:14]([F:19])([F:18])[F:13])[NH:17][C:5](=[O:7])[C:4]=1[CH:1]([CH3:2])[CH3:3]
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Agent: CO[Na]
Solvent: CO
Product: Cc1nc(C(F)(F)F)[nH]c(=O)c1C(C)C
Yield: 63.6 %

Procedure:
Ethyl 2-isopropylacetoacetate (35.8 mL, 0.2 mol) was mixed with trifluoroacetamidine (23 g, 0.2 mol) in MeOH, and then NaOCH3 (21.6 g, 0.4 mol) was added. The mixture was refluxed for 18 h then evaporated to dryness. The residue was taken up in H2O (200 mL) and extracted with ether. The aqueous solution was reduced in volume and acidified with acetic acid to pH 5 then extracted with EtOAc. The combined organic extracts were washed with a small quantity of water, dried over Na2SO4, then evaporated to afford 28 g of an oil. The crude product was purified by flash chromatography (CHCl3) to provide 16 g (36% yield) of pure compound.
Reaction SMILES: [CH2:1]([O:17][C:18](=[O:35])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[C:43](Cl)(=[O:47])[C:44]([CH3:46])=[CH2:45].[OH-].[K+]>O1CCCC1>[CH2:1]([O:17][C:18]([CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:43](=[O:47])[C:44]([CH3:46])=[CH2:45])=[CH:23][CH:22]=1)=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(OCCCCCCO)cc1
Reactant: C=C(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Yield: 12.5 %

Procedure:
To an ice-cooled solution of 3-[4-(6-hydroxy-hexyloxy)-phenyl]-acrylic acid hexadecyl ester (2.6 g, 5.3 mmol), triethylamine (0.99 ml, 7.4 mmol) and 4 crystals of BHT in tetrahydrofuran (30 ml) was added dropwise methacryloyl chloride (0.68 g, 6.9 mmol). The reaction mixture was allowed to react for 7.5 hours, warming to room temperature. Potassium hydroxide solution (5 wt %, 50 ml) was added and the solution extracted 3×100 ml ethyl acetate. The combined organic layers were washed with 100 ml portions of 1M HCl, water, brine and then dried with magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane, followed by recrystallization from hexane, to give 0.37 g white solid, 95% pure by HPLC. H1 NMR (CDCl3): 7.65 (d, 1H, J=16 Hz), 7.49 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=8.8 Hz), 6.33 (d, 1H, J=15.8 Hz), 6.12 (m, 1H), 5.57 (m, 1H), 4.19 (m, 4H), 4.00 (m, 2H), 1.96 (m, 3H), 1.8-1.4 (m, 8H), 1.28 (s, 32H), 0.90 (vt, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[NH2:7][C:8]1[CH:13]=[C:12](OC)[C:11](OC)=[CH:10][C:9]=1[C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21]>C1C=CC=CC=1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:3])=[CH:10][C:9]=1[C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21]
Reactant: CS(C)=O
Reactant: COc1cc(N)c(C(=O)CS(C)=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(N)c(C(=O)CS(C)=O)c1

Procedure:
This compound was prepared by reacting a solution of 44 g of NaH (57%) in a mixture of 600 ml. of DMSO and 1200 ml. of benzene with 50 g of methyl 5-methyl anthranilate (J. Med. Chem. 11 500) in analogous fashion to 2'-amino-4',5'-dimethoxy-2-(methylsulfinyl)acetophenone. The material was recrystallized from ethyl acetate with the aid of charcoal, m.p. 145°-47°; yield 30 g (47%).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](Cl)=[O:42]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccn4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.98 g, 6.48 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, picolinoyl chloride hydrochloride (0.41 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCL (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-pyridylcarboxamide (0.40 g, 55%) as a white solid: mp 155-157° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.50 (t, J=6.2 Hz, 1H), 8.70 (d, J=4.6 Hz, 1H), 8.08-7.98 (m, 2H), 7.82-7.62 (m, 4H), 5.21-5.14 (dd, J=5.4 and 12.6 Hz, 1H), 4.97 (d, J=6.3 Hz, 2H), 2.99-2.84 (m, 1H), 2.65-2.50 (m, 2H), 2.10-2.06 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 169.85, 167.59, 166.99, 164.38, 149.59, 148.56, 139.02, 137.87, 134.79, 132.95, 131.57, 127.16, 126.76, 122.05, 121.87, 48.87, 38.37, 30.94, 21.97; Anal. Calcd. For C20H16N4O5+0.08H2O: C, 61.08; H, 4.13; N, 14.25. Found: C, 61.48; H, 4.22; N, 13.87.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([Cl:19])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(O)COc1ccc(OC(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1ccc(OC(F)(F)F)cc1
Reaction time: 14 h

Procedure:
(4-Trifluoromethoxyphenoxy)-acetic acid (20.7 g, 88 mmol) was dissolved in thionyl chloride (100 mL). DMF (3 drops) was added to the solution. The solution was stirred for 14 hours. The thionyl chloride was removed in vacuo. The resulting oil was dissolved in dichloromethane, filtered through sodium sulfate and concentrate in vacuo to afford the title compound as a paste-like solid (21.8 g, 97% from the phenol): MS (EI-GCMS) for C9H6ClF3O3: 254 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=1.Cl.[N:17]1([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=3)[CH2:21][CH2:22]2)=[N:24]1
Reactant: CC(=O)N(C)c1ccc(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: Cl
Product: CC(=O)N(C)c1ccc(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C
Yield: 45 %

Procedure:
Starting with N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-N-methyl-acetamide (0.195 g, 0.863 mmol) and 3-piperazin-1-yl-1H-indazole hydrochloride (0.309 g, 1.24 mmol) and following the procedure as outlined in Example 501, N-(4-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl]-ethyl}-2-methyl-phenyl)-N-methyl-acetamide was obtained as its hydrochloride salt (0.152 g, 0.388 mmol). Yield=45%. 100% purity @ 254 nm; LCMS (APCI): 392.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.57 (bs, 1H), 7.79 (d, J=8.91 Hz, 1H), 7.37 (d, J=8.91 Hz, 1H), 7.32–7.24 (m, 2H), 7.24–7.13 (m, 2H), 6.99 (t, J=6.93 Hz, 1H), 3.97 (bd, J=9.77 Hz, 2H), 3.64 (bm, 2H), 3.48 (bs, DMSO-H2O), 3.44–3.24 (m, 6H), 3.10–3.02 (m, 2H), 3.00 (s, 3H), 2.47 (DMSO), 2.15 (s, 3H), 1.60 (s, 3H).