Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)C.[OH:20]O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([CH2:12][CH2:11][C:4]1([C:5]([OH:10])=[O:20])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: OO
Reactant: CC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
To a solution of 2-acetyl-2-[2-(tert-butoxycarbonyl)-ethyl]-cyclohexanone (see Preparations 1 and 2) (2.0 g, 7.45 mmol) and concentrated sulphuric acid (98% w/w, one drop) in toluene (6.0 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (1.05 ml, 9.31 mmol) at room temperature. The mixture was stirred for 68 hours at room temperature, treated with a further quantity of a 30% aqueous solution of hydrogen peroxide (0.4 ml, 3.72 mmol) and stirred for a further 16 hours at room temperature. The mixture was partitioned between toluene (25 ml) and 5% aqueous sodium sulphite solution and the layers separated. The toluene layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 4×25 ml). The combined aqueous extracts were washed with toluene (25 ml), acidified to pH 2-3 with 5.0N aqueous hydrochloric acid solution and extracted with toluene (3×25 ml). The combined toluene extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an oil, (1.11 g, 61%). The crude product was crystallized from pentane (7.5 ml/g) to give the title compound as a colorless solid. Rf. 0.28 (silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3):=1.45 (s, 9H). 1.45-1.60 (m, 2H), 1.62-1.78 (m, 4H), 1.92-1.99 (m, 2H), 2.11-2.21 (m, 2H), 2.21-2.33 (m, 2H) ppm. Analysis %: Found: C, 64.26; H, 9.27; C13 H22O4 requires: C, 64.44; H, 9.15.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[F:1][C:2]([F:9])([F:8])[CH:3]([OH:7])[C:4]([O:6][CH2:15][CH3:16])=[O:5]
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)C(F)(F)F
Reaction time: 43 h
Yield: 68 %

Procedure:
The step (b) of the present invention was conducted as follows. At first, 2.84 g of the crude product obtained by Example 1 (containing 16.07 mmol (1.00 eq.) of 3,3,3-trifluoro-2-hydroxypropionic acid) and 19.6 mg (0.20 mmol, 0.01 eq.) of 98% sulfuric acid were added to 20 ml of ethanol, followed by stirring for 43 hr with heating under reflux. The resulting reaction liquid itself was subjected to a vacuum distillation (52° C./3,500 Pa), thereby obtaining 1.87 g of white, needle-like crystals of ethyl 3,3,3-trifluoro-2-hydroxypropionate of the following formula 8. The yield was 68%. The obtained crude product (the white, needle-like crystals) was used in the following step (c) of Example 3 without conducting a further purification.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:29](=[O:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:3]1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1>[C:42]([NH:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:29](=[O:35])[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])=[CH:3]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2NC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.3 %

Procedure:
To the suspension of 2-{1-Amino-5-[4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide (100 mg, 0.21 mmol) in anhydrous THF (3 mL) was added pyridine (60 uL, 0.63 mmol) and acetyl chloride (45 uL, 0.63 mmol) at 0° C. The mixture became clear and was stirred continually at RT for 72 h. The reaction mixture was evaporated in vacuo. The crude material was added water and it was extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by radial chromatography with 0-3% MeOH/CHCl3 to give 30 mg (28%) of the desired product. M+H+(523).
Reaction SMILES: C(O)(=O)CC.C(O)(=O)CC.[OH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:33])[CH2:24][C@@H:25]1[CH3:32])[CH2:20][CH2:19]3.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:33])[CH2:24][C@@H:25]1[CH3:32])[CH2:20][CH2:19]3
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCC(=O)O
Product: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO

Procedure:
A solution of 17α,19-dihydroxy-1α-methyl-4-androsten-3-one dipropionate in methanol is refluxed for about two hours with aqueous sodium carbonate. The solvent is removed and the residue dissolved in chloroform. The chloroform extract is washed well with water, dried over magnesium sulfate and evaporated under vacuum. The residue which remains is crystallized from acetonitrile to yield 17β,19-dihydroxy-1α-methyl-4-androsten-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH2:13]([C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:24][C:23]3[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:3][CH:4]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)[CH3:14]
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: O=Cc1c(F)cccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (300 mg, 1.14 mmol) and 2-chloro-6-fluorobenzaldehyde (360 mg, 2.27 mmol) in 5% HOAc/MeOH (6 mL) at room temperature under argon was added sodium cyanoborohydride (180 mg, 2.86 mmol). The reaction mixture was stirred at room temperature for 4 h and then concentrated, diluted with water, extracted into ethyl acetate and washed with brine. The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 25-50% EtOAc in hexane) to provide the title compound as an oil which solidified on trituration with ether/petroleum (152 mg, 32%). m.p. 123-5° C. NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.6 (br, 1H); 8.2 (br, 1H); 7.4-7.2 (overlapping m, 5H), 7.05 (m, 1H), 6.8 (d, 2H), 6.6 (s, 1H), 4.6 (s, 2H), 4.4 (br, 1H), 2.7 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [C:1]12([S:11][CH2:12][CH2:13][N:14]([N:20]=O)[C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O>C(OC(=O)C)(=O)C>[C:1]12([S:11][CH2:12][CH2:13][N+:14]3[N-:20][O:19][C:17](=[O:18])[C:15]=3[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C[C@@H](C(=O)O)N(CCSC12CC3CC(CC(C3)C1)C2)N=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1c(=O)o[n-][n+]1CCSC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The N-[2-(1-adamantylthio)ethyl]-N-nitrosoalanine prepared in Example 6 is dissolved in 163 parts of acetic anhydride, then allowed to stand at room temperature for 24 hours. The solution is heated briefly to 65° on a steam bath and allowed to cool to room temperature. Then the solution is added to 1000 parts of water and stirred for 3 hours. The solid which forms is collected by filtration, washed successively with water, and saturated sodium bicarbonate and water, and dried. Recrystallization of the solid from methylene chloride-ether affords pure 3-[2-(1-adamantylthio)ethyl] 4-methylsydnone, melting at about 92°-93° and represented by the following structural formula ##STR8##
Reaction SMILES: [CH2:1]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[CH2:1]([S:8](/[CH:11]=[CH:12]/[C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccccc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccccc1
Yield: 78 %

Procedure:
A solution of benzyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 78% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](\[NH2:7])/[CH3:6].N1C=CC=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH2:20][CH2:21][CH2:22][C:23]([NH:7]/[C:5](/[CH3:6])=[CH:4]\[C:3]([O:2][CH3:1])=[O:8])=[O:24]
Reactant: O=C(Cl)CCCOc1cccc(F)c1
Reactant: COC(=O)/C=C(/C)N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C(/C)NC(=O)CCCOc1cccc(F)c1
Yield: 27.5 %

Procedure:
To a solution of (Z)-methyl-3-aminobut-2-enoate (1.70 g, 14.8 mmol) and pyridine (1.20 g, 15.2 mmol) in DCM (25 mL) was added a solution of 4-(3-fluorophenoxy)butanoyl chloride (3.28 g, 15.1 mmol) in DCM (5 mL) with stirring and the mixture was stirred for 1 h. It was then washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (1.20 g, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.CN1CCOCC1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>CN(C=O)C>[S:12]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:1][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:3]2)([OH:15])(=[O:13])=[O:14]
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1
Reactant: O=C1CCC(=O)O1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)Nc1ccc2c(S(=O)(=O)O)cccc2c1

Procedure:
6-Amino-1-naphtalenesulfonic acid (Dahl's acid) (1 eq, 0.5 mmol,) was dissolved in DMF containing N-methylmorpholine (NMM) (2 eq), and succinic anhydride (10 eq) was then added. After over night reaction the solvent was removed under reduced pressure and the product was purified by preparative RP-HPLC (Reversed Phase HPLC). The column (Phenomenex Luna C18 10μ, 22×250 mm) was eluted at 10 ml/min with a gradient of 5 to 15% acetonitrile (ACN) in 0.1% aq TFA over 40 min. The desired peak fractions collected from six consecutive runs were pooled and lyophilized affording 146 mg of pure N-(−5-Sulfo-naphthalen-2-yl)-succinamic acid 2. Analytical RP-HPLC: tR=16.7 min, (Phenomenex Luna 5μ, 4.6×250 mm, 5-15% ACN in 0.1% aq TFA over 20 min at 1 ml/min, λ=214 nm). Electrospray MS: [M+H]+ of product expected at 324.0 m/z, found at 324.0 m/z.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH2:30]>C(#N)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1Cl

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3,4-dichlorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a graded solvent mixture of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=419.
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:20])([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:21])[CH:9]=2)[N:4]=[CH:3]1.[C:22]1(=[O:36])[N:26]([CH2:27][C:28](Cl)=[O:29])[C:25](=[O:31])[C:24]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:23]12>N1C=CC=CC=1>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([Cl:21])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:28](=[O:29])[CH2:27][N:26]1[C:22](=[O:36])[C:23]2[C:24](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:31])[C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:31])[C:24]2[C:23](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:22]1=[O:36])=[O:20]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1c(F)cccc1F
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 1, 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-(2,6-difluorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(2,6-difluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:33][CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: NCCCc1ccccc1
Solvent: COCCOC
Product: Nc1nc(NCCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 3-phenylpropylamine in DME. ES-MS m/e (%): 340 (M+H+, 100).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:22])([F:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([NH:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([F:6])([F:21])[F:22])=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a solution of butyraldehyde (0.114 mL, 1.26 mmol) in anhydrous CH2Cl2 under nitrogen, was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.3 g, 1.26 mmol). After 15 mins sodium triacetoxyborohydride (0.375 g, 1.77 mmol) was added portion wise, followed by acetic acid (0.072 mL, 1.26 mmol). After stirring the mixture for 18 h the reaction was quenched by cautious addition of sat. sodium bicarbonate aq. (20 mL) and extracted with CH2Cl2 (2×30 mL). The organic extract was separated by hydrophobic frit and the solvents removed in vacuo. Purification by SPE (Silica, 10 g) eluting with 99:1 cyclohexane:EtOAc, afforded the title compound as a colourless oil (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccn2)c(F)cc1Cl
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a solution of methyl 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (212 mmol) in THF (400 mL), was added 2-bromopyridine (33.4 g, 211 mmol), potassium carbonate (117 g, 848 mmol) and water (64 mL). The mixture was degassed with argon for 30 minutes. To this mixture was added tetrakis(triphenylphosphine)palladium (12.2 g, 10.6 mmol) and the mixture heated at reflux for 1.5 h. The mixture was cooled to room temperature and filtered through Celite, washing with EtOAc (1.2 L) and water (800 mL). The filtrate was diluted with saturated aqueous brine solution (200 mL) and the aqueous layer separated and extracted with EtOAc (600 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel, eluting with EtOAc:hexane (3:17 to 1:4) and concentrated in vacuo to a slurry, which was diluted with heptane (100 mL) and cooled to 0° C. The solid was collected by filtration to afford the title compound (37.6 g, 67%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH:27][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][CH:10]=2)[CH3:26])=[N:23][CH:24]=1
Reactant: O=C(O)Cc1ccc(N2CCCC2)cc1
Reactant: COc1ccc([C@@H](C)N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(N3CCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (4-pyrrolidin-1-ylphenyl)acetic acid (U.S. Pat. No. 3,641,040) (0.50 g, 2.4 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethylamine hydrochloride (0.57 g, 3.0 mmol), and HATU (1.2 g, 3.1 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (1.7 mL, 9.7 mmol) and the mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was partitioned between water and EtOAc. The organic layer was washed with brine and water, dried over MgSO4, and purified by normal phase chromatography (10-100% EtOAc/hexanes) to give N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]-2-(4-pyrrolidin-1-ylphenyl)acetamide as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (m, 1H), 7.11 (m, 4H), 6.54 (m, 3H), 5.09 (m, 1H), 3.83 (s, 3H), 3.48 (d, J=3.2 Hz, 2H), 3.28 (t, J=6.4 Hz, 4H), 2.01 (m, 4H), 1.36 (d, J=6.4 Hz, 3H); MS (Electrospray): m/z 340.4 (M+H)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])O.[Na+]>CC(C)=O>[CH2:19]([O:18][C:16]([O:1][N:2]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C(=NO)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)ON=C(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.7 %

Procedure:
A mixture of diethyl 2-hydroxyiminomalonate (18.9 g), water (50 ml) and acetone (8 ml) is cooled at 0°C, and ethyl chloroformate (9.8 g) is dropwise added thereto. The resulting mixture is, after adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate, stirred at room temperature for 4 hours. The reaction mixture is extracted with ether, and the ether layer is washed with an aqueous solution of sodium chloride, dried and concentrated to give diethyl 2-ethoxycarbonyloxyiminomalonate (24 g) as an oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:11]([N:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[O:29]([Si](C)(C)C)[Na]>C1COCC1>[OH:29][C:2]1[CH:3]=[C:4]([S:11]([N:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Reactant: C[Si](C)(C)O[Na]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc([N+](=O)[O-])c(O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To a solution of 3-fluoro-N-(4-methoxybenzyl)-4-nitro-N-(thiazol-2-yl)benzenesulfonamide (9.0 g, 21.2 mmol) in THF (80 mL) was added a THF solution of NaOSi(Me)3 (4.76 g, 42.5 mmoles, 1 M, Aldrich) at 0° C. and the resulting mixture was stirred at 25° C. for 2 h. After completion of the reaction (monitored by TLC), reaction mass was quenched with 1N HCl (70 mL). The organic compound was then extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated to get the 9.20 g of crude material, 3-hydroxy-N-(4-methoxybenzyl)-4-nitro-N-(thiazol-2-yl)benzenesulfonamide as yellow semi-solid which was used for next step as is.
Reaction SMILES: [C:1]([O:4]CC(=O)CC1C=CC(Cl)=C(Cl)C=1)(=[O:3])[CH3:2].[S:17]1[CH:21]=[C:20]([CH2:22][C:23](=[O:26])[CH2:24]Cl)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]1=2.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:24][C:23](=[O:26])[CH2:22][C:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[S:17][CH:21]=1)(=[O:3])[CH3:2]
Reactant: O=C(CCl)Cc1csc2ccccc12
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1csc2ccccc12
Yield: 51 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-(benzo[b]thiophen-3-yl)-3-chloropropan-2-one (0.661 g, 2.94 mmol) with acetic acid (0.34 mL, 0.35 g, 5.9 mmol) and triethylamine (0.82 mL, 0.59 g, 5.9 mmol). Flash chromatography over silica gel (10-40% ethyl acetate in hexanes) gave pure product (0.372 g, 51% yield): 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H) 3.98 (s, 2H) 4.71 (s, 2H) 7.34-7.44 (m, 3H) 7.67-7.70 (m, 1H) 7.86-7.89 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([O:29][C:30]([N:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:36]=[CH:35][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccn4C(=O)OC(C)(C)C)cc32)N=C1N
Temperature: 120 °C
Yield: 1.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.099 mmol) in 1,4-dioxane (1.2 mL), Cs2CO3 (2 N, 0.3 mL) and 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (30 mg, 0.142 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure tert-butyl 2-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-1H-pyrrole-1-carboxylate (0.8 mg, 2%). 1H-NMR (MeOD): 1.40 (s, 9H), 2.44 (m, 1H), 2.61 (m, 1H), 3.25 (s, 3H), 5.85 (d, 1H), 6.14 (m, 1H), 6.23 (m, 1H), 7.05 (m, 1H), 7.16 (m, 1H), 7.32 (m, 2H), 7.49 (m, 5H).