Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:6]([CH:12]=[O:13])=[N:7]2.[CH2:21]1COCC1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:6]([CH:12]([OH:13])[CH3:21])=[N:7]2
Reactant: C1CCOC1
Reactant: O=Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring heterogeneous mixture of 5-chloro-3-(3-fluorophenyl)quinoxaline-2-carbaldehyde (0.4405 g, 1.537 mmol) in THF (14.95 mL, 1.537 mmol) was added methylmagnesium bromide 3 M in diethyl ether (1.024 mL, 3.073 mmol) dropwise at 0° C. and the mixture was then allowed to warm to room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined orgainc layers were washed with water (50 mL×1), brine (50 mL×1), 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 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1 H, dd, J=8.4, 1.2 Hz), 8.06 (1 H, dd, J=7.6, 1.4 Hz), 7.87 (1 H, dd, J=8.4, 7.6 Hz), 7.56-7.71 (3 H, m), 7.37-7.46 (1 H, m), 5.50 (1H, d, J=6.1 Hz), 5.04-5.13 (1 H, m), 1.48 (3 H, d, J=6.3 Hz); LC-MS (ESI) m/z 303.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:9](#[N:12])[CH2:10]O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([CH:3]([CH2:10][C:9]#[N:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: N#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C#N)CC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl cyanoacetate (916.0 g, 8.10 mol) in N,N-dimethylformamide (2.5 L) was added slowly glycolonitrile (700.0 g, 6.75 mol) in water (55% solution). To the mixture was added potassium carbonate (932.7 g, 6.75 mol), over 1.5 h, ensuring that the reaction temperature did not rise above 30° C. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was filtered and the filtrate adjusted to pH 3 by addition of acid. The organic phase was separated and partially concentrated in vacuo. To the concentrate was added diethyl ether (1 L) and the solution was washed with water (5×1 L), dried (MgSO4) and concentrated in vacuo to give Preparation 46 (803 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25](OCC)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[BH4-]>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH2:25][OH:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2[nH]c(CO)cc2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (1.18 g, 3.0 mmol) was added to a solution of LiBH4 (132 mg, 6.0 mmol) in THF (10 mL) and water (0.1 mL). The mixture was allowed to stir for 16 h at 25° C. before it was quenched with water (10 mL) and slowly made acidic by addition of 1 N HCl. The mixture was extracted with three 50-mL portions of ethyl acetate. The organic extracts were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(hydroxymethyl)-1H-indol-5-yl)cyclopropanecarboxamide (770 mg, 73%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 350.4. found 351.3 (M+1)+; retention time 2.59 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH2:10].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2](/[CH:10]=[CH:9]/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: C=Cc1ccncc1
Reactant: Brc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Brc1cncc(/C=C/c2ccncc2)c1
Yield: 36 %

Procedure:
A solution of 3,5-dibromopyridine (5.56 g, 23.4 mmol), 4-vinylpyridine (5.1 mL), palladium acetate (1.05 g), tri-o-tolylphosphine (5.00 g) and triethylamine (33 mL) in acetonitrile (100 mL) was heated overnight at 80° C. and concentrated. The residue was partitioned between 5% NaHCO3 and dichloromethane and filtered. The filtrate was separated and the organic layer was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product (2.18 g, 36%). (DCI/NH3) m/e 261, 263 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C(O[CH:13]=[C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][CH:13]=[C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(C)C
Reactant: COc1ccc(N)cn1
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)C(C)C

Procedure:
Ethyl 2-(((6-methoxypyridin-3-yl)amino)methylene)-4-methyl-3-oxopentanoate was prepared with conditions described in Example 99 using 2-methoxy-5-aminopyridine and ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate.
Reaction SMILES: C([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)OC(C1C=CC=CC=1)=C(O)C2=O)=C.BrC1C=CC([CH:32]=[O:33])=CC=1>>[C:21]1([C:4]2[CH:3]=[CH:12][CH:11]=[CH:10][CH:5]=2)[CH:22]=[CH:23][C:24]([CH:32]=[O:33])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=Cc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1-c1ccccc1
Product: O=Cc1ccc(-c2ccccc2)cc1

Procedure:
Alternatively, a vinyl phenyl hydroxyflavone may be prepared by synthesizing 4-styrene trimethyltin and combining it with 4-bromobenzaldehyde to produce 4'-vinyl, 4-biphenyl aldehyde. This intermediate compound is then reacted with 2-hydroxyacetophenone to produce the vinyl phenyl hydroxyflavone. This reaction scheme proceeds as follows: ##STR14##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:20][NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]1.[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43]([N:21]([CH2:20][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:18])([F:17])[F:19])=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:23]1)=[O:44]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 31 (220 mg, 0.43 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (120 mg, 0.52 mmol) using Method D to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[Br:15][CH2:16][C:17](Br)=[O:18].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:15][CH2:16][C:17]([NH:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
6-chloro-2-phenylpyrimidin-4-amine (4) (830 mg) was dissolved in anhydrous DCM (50 ml). To this was added dropwise a solution of bromoacetylbromide (1.05 ml in 10 ml DCM), forming a precipitate after 10 min. To this was then added dropwise a solution of N,N-diisopropylethylamine (1.06 ml in 10 ml DCM) and the solution left for 1 hr. The solvent was removed in vacuo, then the crude solid purified by flash chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (1:9 then 1:1v/v), furnishing the title compound as a solid (1.09 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].[C:27]([O:33][CH2:34][N:35]1[C:39]2=[N:40][CH:41]=[C:42](Br)[N:43]=[C:38]2[C:37]([C:45](=[O:51])[NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:36]1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.[Cu]I.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>[C:27]([O:33][CH2:34][N:35]1[C:39]2=[N:40][CH:41]=[C:42]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=4)[N:9]([CH3:13])[N:8]=3)[N:43]=[C:38]2[C:37]([C:45](=[O:51])[NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:36]1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)C)cc12
Reactant: CC(C)(C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)C)cn3COC(=O)C(C)(C)C)nn2C

Procedure:
A mixture 5-isopropyl-1-methyl-3-(tributylstannyl)-1H-indazole, (2-bromo-7-(tert-butylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (0.408 g, 1 mmol), CuI (0.06 g, 0.32 mmol) and Pd(PPh3)4 (0.06 g, 0.052 mmol) in 40 mL of DMF was stirred at 80° C. under nitrogen for 4 hours. The solvent was removed under reduced pressure and the residue was triturated with water (15 mL) and petroleum ether (30 mL) then decanted and dried to give crude (7-(tert-butylcarbamoyl)-2-(5-isopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (0.15 g) as a yellow solid, which was used into next step without further purification. LCMS: (M+H)+=505.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]2[CH3:30])=[CH:9][C:8]=1[CH3:31])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]([CH3:30])[CH:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:32])=[O:5])=[C:8]([CH3:31])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example I4) (0.67 g) in dichloromethane (15 ml) was added trifluoroacetic acid (“TFA”) (1.05 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The dichloromethane was evaporated and ethyl acetate was added. The mixture was washed with water, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-benzoic acid as a mixture of diastereoisomers (0.56 g). 1H-NMR (CDCl3, 400 MHz): 8.05 (m, 1H), 7.45-7.15 (m, 5H), 3.90-3.60 (m, 1H), 3.35-2.60 (m, 9H).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:16][C:5]1[N:1]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[O:14][CH3:15])[CH:2]=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(C=O)ccc1-n1ccnc1
Solvent: ClC(Cl)Cl
Product: COc1cc(C=O)ccc1-n1cncc1Cl
Yield: 23.9 %

Procedure:
To a chloroform (3 mL) solution of the 4-(1H-imidazol-1-yl)-3-methoxybenzaldehyde (50 mg) obtained in Example 111, N-chlorosuccinimide (35 mg) was added, and the reaction solution was heated to reflux for 1.5 hours. The reaction mixture was allowed to be cooled and then purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 4-(2-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (13 mg) and 4-(5-chloro-1H-imidazol-1-yl)-3-methoxybenzaldehyde (14 mg) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:16][CH2:17][CH:18]([O:21][S:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=4)(=[O:30])=[O:29])[CH2:19][CH2:20]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(c1cccc2c(Cl)nccc12)N1CCC(O)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3cccc4c(Cl)nccc34)CC2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 40 ml of pyridine were added 3.11 g of the thus obtained 1-(1-chloro-5-isoquinolinesulfonyl)-4-hydroxypiperidine and 3.81 g of p-toluenesulfonyl chloride. The resulting mixture was stirred at a temperature of 15° C. to 20° C. for 24 hours. To the reaction mixture was added 100 g of ice water, followed by extraction twice with 100 ml each of dichloromethane. The dichloromethane layer was dried with anhydrous magnesium sulfate and the dichloromethane was removed under reduced pressure to obtain 4.46 g of 1-(1-chloro-5-isoquinolinesulfonyl)-4-p-toluenesulfonyloxypiperidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:3]=1.[NH:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[N:3]=[C:2]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH:21]=[CH:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: Fc1ccccc1-c1nc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(-n2ccc3cnccc32)c2ccccc2n1
Temperature: 100 °C

Procedure:
4-Chloro-2-(2-fluoro-phenyl)-quinazoline from Step C (0.1 g, 0.38 mmol) was dissolved in N,N-dimethylformamide (1 ml) and to it was added 1H-pyrrolo[3,2-c]pyridine (0.046 g, 0.38 mmol) followed by cesium carbonate (0.134 g, 0.41 mmol). The mixture was magnetically stirred and heated to 100° C. for 0.5 hr. The solvent was removed and title compound was obtained pure after column purification on a HPLC reverse phase column, using a water and acetonitrile gradient containing 0.1% trifluoroacetic acid to yield (0.072 g, 56%). MS (ES) 340.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N[C:16](N)=[O:17]>COCCOCCOC>[NH:1]1[C:2]2[C:3]3[CH:4]=[CH:5][CH:6]=[N:7][C:8]=3[CH:9]=[CH:10][C:11]=2[NH:12][C:16]1=[O:17]
Reactant: NC(N)=O
Reactant: Nc1c([N+](=O)[O-])ccc2ncccc12
Solvent: COCCOCCOC
Product: O=c1[nH]c2ccc3ncccc3c2[nH]1
Yield: 91 %

Procedure:
Quinolino[5,6-d]imidazolinone (2f) was prepared from 5-amino-6-nitroquinoline by hydrogenation and subsequent treatment with urea in diglyme. Overall yield: 91%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.Cl.Cl.[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH2:40])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH:40][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=1[O:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1])=[O:15])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)[C@@H](N)CCN1CCCCC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCN1CCCCC1)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (0.050 g, 0.14 mmol), (S)-2-amino-4-piperidin-1-yl-butyric acid methyl ester dihydrochloride (0.043 g, 0.16 mmol), EDCI (0.033 g, 0.17 mmol) and HOBt (0.023 g, 0.17 mmol) in dichloromethane was added dropwise DIEA (0.093 g, 0.72 mmol). The reaction mixture was stirred at room temperature until HPLC analysis showed consumption of the starting material and then was diluted with dichloromethane and washed with saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed to afford 0.051 g of product (67% yield).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[CH3:14])[O:3]1.CC(C)=O>O>[CH3:14][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[B:4]([OH:5])[OH:3]
Reactant: Cc1sccc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(C)=O
Solvent: O
Product: Cc1sccc1B(O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane (1.52 g, 6.78 mmol), acetone (15 mL) and water (15 mL) is added NaIO4 (2.90 g, 13.56 mmol). The solution is stirred at ambient temperature for 24 hours, then heated to a reflux for 24 hours. The solution is concentrated dissolved in EtOAc (1450 mL), washed with water (100 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.75 g, 5.49 mmol, 78%). 1H NMR (CDCl3), δ 2.93 (s, 3H), 7.10 (d, J=5.3 Hz, 1H), 7.51 (d, 5.3 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[S:10](Cl)(=[O:13])(=[O:12])[NH2:11]>C(Cl)Cl>[O:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][O:1][S:10](=[O:13])(=[O:12])[NH2:11]
Reactant: O=C1CCCN1CCO
Reactant: NS(=O)(=O)Cl
Solvent: ClCCl
Product: NS(=O)(=O)OCCN1CCCC1=O
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 6.5 g (0.05 mole) of 1-(2-hydroxyethyl)-2-pyrrolidone (Fluka) in 100 ml of methylene chloride was treated with 5.8 (0.05 mole) of sulfamoyl chloride. The solution was stirred for 2 hr, then concentrated under vacuum. The residue was crystallized twice from 2-propanol to give 6.9 g (66%) of the title compound as white crystals, mp 110°-112° C. The compound was noted to be slightly hygroscopic.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.I[CH3:22].CO>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N:14]([CH3:22])[C:15]1[CH:20]=[N:19][CH:18]=[N:17][CH:16]=1
Reactant: COC(=O)c1ccc(F)c(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(F)c(N(C)c2cncnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium hydride (110 mg, 4.58 mmol, 1.10 eq) was dissolved in THF (10 mL), added to dry, argon purged flask, and cooled to 0° C. Compound 19 (1.0 g, 4.0 mmol, 1.0 eq) was dissolved in THF (10 mL) and added to sodium hydride solution. The reaction stirred at 0° C. for 30 minutes. Iodomethane (630 mg, 4.44 mmol, 1.10 eq) was added. The reaction warmed to rt and stirred overnight. Methanol was added and the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel afforded 600 mg (57%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.26 (s, 2H), 7.99 (dd, J=7.8, 2.0 Hz, 1H), 7.93 (ddd, J=8.5, 4.8, 2.2 Hz, 1H), 7.51 (dd, J=10.8, 8.7 Hz, 1H), 3.86 (s, 3H), 3.35 (s, 3H); ES-MS [M+1]+:262.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[C:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[CH:9]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[NH:8]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C/N=C/C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(C2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 37.3 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-cyclohexyl-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 50a (1.2 g, 5.3 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1 g, 3.7 mmol) prepared in Example 1b, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.69 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([O:17][CH2:18][CH:19]2[O:21][CH2:20]2)[CH:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][CH2:20][CH:19]([OH:21])[CH2:18][O:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC1CO1
Reactant: CC(C)(C)N
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC(O)CNC(C)(C)C
Yield: 82.4 %

Procedure:
A stirred mixture of ethyl 3-[4-chloro-2-(2,3-epoxypropoxy)benzoyl]propionate (3.0 g, 0.01 mole) methanol (28 ml) and t-butylamine (6.7 ml, 0.0625 mole) was heated under reflux for 70 minutes. The mixture was evaporated to an oily residue which was purified on a silica column by elution with mixtures of chloroform and methanol and recrystallisation from ether-petroleum ether (b.p. 40°-60°) to give ethyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-chlorobenzoyl]propionate (3.18 g, 88%, m.p. 70°).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([NH:15][C:16](OC2C(O)=C(C3C=CC=CC=3)S(=O)(=O)C=2C2C=CC=CC=2)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH2:1]([NH:8][C:16]([NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Nc1ccccc1)OC1=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)Nc1ccccc1

Procedure:
540 mg of benzylamine are added to 2.1 g of 3-(N-phenylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 20 ml of ethyl acetate. The solution is boiled under reflux for 1 hour and then washed three times with 25 ml of concentrated aqueous NaHCO3 solution and three times with 20% strength aqueous citric acid solution. The wash liquors are extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. After evaporating the filtrate, the crystalline residue is recrystallized from dilute ethanol.