Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[C:6]1([P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[C:19]1([P:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][C:3](=[O:5])[CH3:4])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 23.3 %

Procedure:
A solution of 1-chloropropan-2-one (50 g, 540.4 mmol) in chloroform (150 mL) was added dropwise to a solution of triphenylphosphine (141.72 g, 540.4 mmol) in chloroform (150 mL) under nitrogen. The mixture was stirred at 70° C. for 12 hr, and the resulting phosphonium salt was filtered. The precipitate was washed with ethyl acetate and dried under vacuum. The dried phosphonium salt was suspended in a mixture of water (250 mL) and methanol (250 mL), and the mixture was stirred for 1 hr. Aqueous sodium hydroxide (2.00 M) was added to the mixture until a pH between 7 and 8 was reached. The mixture was then stirred vigorously for 1 hr. The phosphorane precipitate was filtered and washed with water. After drying in vacuum, the phosphorane was recrystallized from ethyl acetate and dried under vacuum to afford 1-(triphenylphosphoranylidene)propan-2-one (40.00 g, 23.3%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)OS1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[CH2:1]([NH:8][CH2:12][C@H:11]([N:21]=[N+:22]=[N-:23])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S1O[C@@H](c2ccc(Cl)cc2)CN1Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H](CNCc1ccccc1)c1ccc(Cl)cc1
Yield: 84.2 %

Procedure:
A solution of (2RS,5S)-3-benzyl-5-(4-chlorophenyl)-1,2,3-oxathiazolidine 2-oxide (16.2 g, 52.6 mmol) and sodium azide (17.11 g, 263.2 mmol) in N,N-dimethylformamide (100 ml) was heated at 70° C. for 24 hours. The reaction mixture was partitioned between ether and water, and the organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10-20% ethyl acetate-hexane) to afford (R)-N-benzyl-2-azido-2-(4-chlorophenyl)ethylamine (12.7 g, 83.8%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[OH-].[Na+]>C1COCC1>[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][S:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)(=[O:11])=[O:12])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc23)CC1
Yield: 99.1 %

Procedure:
By a method similar to Example 31, using 4-nitrobenzenesulfonyl chloride (997 mg, 4.05 mmol) was added to a mixture of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (777 mg, 3.4 mmol) in 0.2 N sodium hydroxide (18.6 mL, 3.7 mmol) and THF (20 mL) gave 1.4 g of an orange foam. The product was crystallized from ethyl acetate/hexanes to give 485 mg (35%) of an orange powder. The mother liquors were purified by flash chromatography (silica gel, 5%,7% 2M ammonia in methanol/methylene chloride) to give 800 mg (57%) of the title compound as yellow foam: Total yield was 92%: mp=171-172° C.; MS(m/e): 416 (M+1), 414 (M−1); Calculated for C20H21N3O5S: C, 57.82; H, 5.09; N, 10.11. Found: C, 57.35; H, 4.96; N, 9.88.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.CCN(CC)CC.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=1)=[O:33]>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=2)=[O:33])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COc1ccc(C(=O)CBr)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(=O)COC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (1.0 g, 5.42 mmol) in acetonitrile (20 mL) were added Et3N (5.54 mL, 43.4 mmol) and 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.07 g, 3.65 mmol) under an inert atmosphere. The reaction mixture was then stirred at RT for 1 h and concentrated in vacuo to obtain the crude product. The crude material was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-(3-chloro-4-methoxyphenyl)-2-oxoethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 29%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1 g, 5.84 mmol), 4-hydroxypiperidine (0.65 g, 6.42 mmol) and 4 Å molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0) to give 3-(4-Hydroxypiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.34 g, 23%). 1H NMR (CDCl3, 400 MHz) δ 3.92 (t, J=7.8 Hz, 2 H); 3.87-3.72 (m, 3 H); 3.07 (m, 1 H); 2.68-2.63 (m, 2 H); 2.09-2.03 (m, 2 H); 1.96-1.91 (m, 2 H); 1.69-1.55 (m, 2 H); 1.43 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(N(CC)CC)C.[F:43][C:44]([F:50])([F:49])[S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][S:45]([C:44]([F:50])([F:49])[F:43])(=[O:47])=[O:46])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 69.8 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]Isoindolinone (550 mg, 1.12 mmol) was dissolved in dichloromethane (22 mL), and the solution was treated with triethylamine (0.78 ml, 5.56 mmol) and trifluoromethanesulfonyl chloride (0.356 mL, 3.34 mmol), followed by purification by flash chromatography (chloroform, chloroform/methanol=99/1, 95/1) to obtain 4-chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (491 mg, yield 71%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Br:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:8][C:6]1[C:5]([Br:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[NH2:1])[CH:12]=[CH2:11]
Reactant: Nc1cc(O)c(Br)cc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(N)c(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.9 %

Procedure:
5-Amino-2-bromo-4-fluorophenol (30.9 g), allyl bromide (21.8 g) and potassium carbonate (22.77 g) were suspended in acetonitrile (300 ml), and the mixture was stirred at room temperature for 12 hours. After the reaction, the precipitates were filtered, the solvent was distilled off, and this was extracted with ethyl acetate. After washing with water, it was dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain the objective 5-allyloxy-4-bromo-2-fluoroaniline (12.14 g).
Reaction SMILES: N[C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.[BrH:19].N([O-])=O.[Na+].[Cl-].[Na+]>O.C(O)C>[Br:19][C@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: Br
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Yield: 50 %

Procedure:
To an ice-cooled mixture of t-butyl 7β-amino-3-methyl-3-cephem-4-carboxylate (1.3 g, 0.0048 mol), ethanol (30 ml), water (8.5 ml), hydrobromic acid (48%, 5.83 ml), sodium nitrite (0.48 g, 0.00696 mol) was added portionwise over 15 minutes and the mixture was stirred at ice-temperature (-5° C.) for 3 hours, saturated with sodium chloride, extracted with ethyl acetate (3 times). The combined ethyl acetate extract was washed with water, brine, dried and concentrated to give 800 mg (50%) of pure t-butyl 7α-bromo-3-methyl-3-cephem-4-carboxylate.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[CH2:4][CH3:5].[CH2:13](Br)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]>O1CCCC1>[CH3:16]/[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:13][CH:7]([C:3](=[O:6])[CH2:4][CH3:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: CCOC(=O)CC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C/C=C(\C)CCC=C(C)C)C(=O)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a suspension of 3.92 g (97.5 mmol, 3 equiv) of 60% NaH in mineral oil (washed three times with pentane) in 200 mL of tetrahydrofuran at 0° C. under argon was added dropwise a solution of 15.3 mL (107 mmol, 3.3 equiv) of ethyl propionylacetate. After 0.5 hour, a solution of 7.04 g (32.4 mmol) of (E)-geranyl bromide in 20 mL of tetrahydrofuran was added dropwise over 45 minutes. The mixture was stirred one hour at 0° C. and one hour at room temperture, quenched with NH4Cl and diluted with 500 mL of diethyl ether. The organic layer was washed with water and brine, and dried over MgSO4 to obtain 20.157 g of crude product as a yellow oil. Purification by flash chromatography on 800 g of silica gel, eluted with 3:97 ethyl acetate:hexanes provided 7.024 g (77%) of pure product as a clear, colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([C:26]2[C:25]([CH3:31])=[CH:24][C:23]([O:22][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:28][C:27]=2[CH3:29])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 568.2 [M−H]−.
Reaction SMILES: FC(F)(F)C(O)=O.[Na].[C:9]([CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:10].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[CH2:22][NH:23][NH2:24]>O1CCOCC1>[NH2:10][C:9]1[N:23]([CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[F:19])[N:24]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1
Reactant: NNCc1ccccc1F
Reactant: CCOC(=O)C(=O)CC#N
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid are added to 100 g (0.613 mol) of the sodium salt of ethyl cyanopyruvate (preparation in analogy to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) in 2.51 of dioxane under argon with efficient stirring at room temperature, and the mixture is stirred for 10 min, during which most of the precursor dissolves. Then 85.93 g (0.613 mol) of 2-fluorobenzyl-hydrazine are added, and the mixture is boiled overnight. After cooling, the sodium trifluoroacetate crystals which have separated out are filtered off with suction and washed with dioxane, and the crude solution is reacted further.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:30][CH:29]([CH2:31][NH2:32])[O:28][N:27]=2)=[CH:22][CH:21]=1>>[N:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:30][CH:29]([CH2:31][NH:32][C:17]([C:15]3[CH:16]=[C:11]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=4[CH3:10])[CH:12]=[N:13][CH:14]=3)=[O:19])[O:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCC1CC(c2ccncc2)=NO1
Product: CCc1cc(-c2cncc(C(=O)NCC3CC(c4ccncc4)=NO3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-amine to afford the title compound. MS: m/e=418 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:20])=[C:16]([CH2:18][OH:19])[CH:17]=1>>[F:20][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[CH:17][C:16]=1[CH:18]=[O:19]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: Cc1cncc(C(=O)Cl)c1
Product: Cc1cncc(C(=O)Nc2ccc(F)c(C=O)c2)c1

Procedure:
The title compound is prepared according to the reaction sequence described above using 5-methylnicotinoyl chloride and (5-amino-2-fluorophenyl)methanol followed by oxidation of the crude alcohol: LC-MS A: tR=0.60 min; [M+H]+=258.88.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]2[CH2:15][N:14]([CH3:16])[CH2:13][CH:12]2[CH2:17][C:18]([O-:20])=O)=[CH:5][C:4]=1[O:21][CH3:22])[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>>[CH2:1]([C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C@@H:11]3[C@H:12]([CH2:17][C:18](=[O:20])[C:7]=2[C:8]=1[O:9][CH3:10])[CH2:13][N:14]([CH3:16])[CH2:15]3)[CH3:2]
Reactant: CCc1c(OC)cc(C2CN(C)CC2CC(=O)[O-])cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(OC)cc2c(c1OC)C(=O)C[C@@H]1CN(C)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
A mixture of 150 mg (0.41 mmol) of (4-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-pyrrolidin-3-yl)-acetate, 1.5 ml trifluoroacetic acid and 0.15 ml of trifluoroacetic acid anhydride was stirred at room temperature over 2 hours. The reaction mixture was subsequently poured on to 50 ml of ice-water, made basic with 28% NaOH and extracted twice with 100 ml of methylene chloride each time. The combined organic phases were washed once with 50 ml of saturated sodium chloride solution, dried (MgSO4) and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (methylene chloride/methanol/NH4OH 15:1:0.1). 15 mg (13%) of cis-7-ethyl-6,8-dimethoxy-2-methyl-1 ,2,3,3a,4,9b-hexahydro-benzo[e]isoindol-5-one were obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.O=[CH:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:22][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH3:20])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NC[C@H](c2ccc(F)cc2)C12CCNCC2
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](CN1CCC2(CC1)C(=O)NC[C@@H]2c1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A reaction mixture containing 0.25 g (1.0 mmol) of (R)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one, 0.25 g (1.44 mmol) of the (S)-tert-butyl 1-oxopropan-2-ylcarbamate, 2 mL of THF, 1 mL of DCM, and 1 g (2.5 mmol) of MP-sodium triacetoxyborohydride resin was rotated overnight. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was subjected to silica gel chromatography to give 250 mg (61%) of tert-butyl (S)-1-((R)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)propan-2-ylcarbamate as a colorless oil. 1HNMR (400 MHz, CD3OD) δ ppm 7.35-7.31 (m, 2H), 7.10-7.06 (m, 2H), 3.85 (brs, 1H), 3.73-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.39-3.27 (m, 1H), 3.10-2.87 (m, 2H), 2.78-2.59 (m, 3H), 2.01-1.72 (m, 5H), 1.42 (s, 9H), 1.32-1.20 (m, 1H), and 1.11 (d, 3H, J=2.4 Hz); LCMS m/z: 406.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1>CN(C)C=O.O>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=[C:18]1[CH2:17][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:12])[C:3]([OH:2])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: ClCc1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCc2cc3ccccc3o2)cc1
Reaction time: 0.17 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.52 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.405 g), stirred for 10 minutes and treated with 2-chloromethylbenzofuran (1.4 g). The mixture was stirred at room temperature under argon for 3 hours, diluted with water, and extracted with ethyl acetate. Evaporation of the organic extracts provided crude methyl ester as a liquid. Treatment of a portion of this ester (1.02 g) with potassium hydroxide (0.18 g) in a methanol-water mixture, followed by acidification of the mixture with hydrochloric acid and filtration provided 4-[[2-benzofuranyl)methoxy]-alpha-oxobenzeneacetic acid as a white solid, mp 120° C.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.C(O[CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>>[NH:1]1[C:5]([NH:6][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=[N:2]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccn[nH]1
Product: CCOC(=O)C(=CNc1ccn[nH]1)C(=O)OCC
Temperature: 200 °C

Procedure:
A mixture of 1H-pyrazol-5-amine 1 (2 g, 24.1 mmol) and diethyl 2-(ethoxymethylene)malonate (10.4 g, 48.2 mmol) was heated at 200° C. until the starting material was consumed completely. The reaction mixture was allowed to cool to room temperature and EtOH (10 mL) was added. A precipitate formed, which was removed by filtration, washed with EtOH and dried under vacuum to give diethyl 2-((1H-pyrazol-5-ylamino)methylene)malonate; 4.0 g (66%). 1H NMR (300 MHz, CDCl3) δ 10.95 (d, J=13.5 Hz, 1H), 8.60 (d, J=13.8 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 6.08 (d, J=2.4 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[F:42])=[O:33])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[F:42])=[O:33])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of ethyl 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate (45 mg, 0.078 mmol) in 10 ml of THF was added 3 ml of 1M NaOH (3.0 mmol). The mixture was heated at 60° C. for 3 hours, cooled to room temperature and poured into 100 ml of water. 2M HCl was added until pH=5. The precipitates were filtered, washed with water, and dried to give 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid as grey solid. Yield: 40 mg, 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1

Procedure:
Following the general procedure of Example 39, Step 2, and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.2982 g) and 1-[3-(trifluoromethyl)phenyl]piperazine (Aldrich; 0.34 mL) are converted to product, followed by chromatography on silica gel using methanol/dichlormethane (2/98). Crystallization from ethyl acetate and then from ethyl acetate/dichloromethane gives 0.053 g of the title compound; mp 145-145.5° C.; MS m/z 394; IR (mineral oil) 1117, 1163, 1451, 1073, 1339 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.28, 3.78, 7.12, 7.34, 7.52, 7.54, 8.14.