Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH2:13])[CH:11]=[O:12])([O-:3])=[O:2].[CH:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15].[O-]CC.[Na+]>C(O)C>[CH2:26]([O:25][C:23]([C:17]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:11]([OH:12])[N:16]1[CH:14]=[O:15])=[O:24])[CH3:27]
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Reactant: C=C(C=O)c1ccccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccccc2[N+](=O)[O-])C(O)N1C=O
Reaction time: 1 h

Procedure:
To a stirred, icebath-cooled mixture of 42.5 g. (0.24 mol) of acrolein of Example 1 and 50.4 g (0.25 mol) of diethyl formamidomalonate in 200 ml. of absolute ethanol was added, over 15 minutes, 4 ml. of a 1M solution of sodium ethoxide in ethanol. The mixture was stirred at 5° for 1 hour as the Michael adduct crystallized out. After the suspension had been stored for 4 hours at -20°, the product was collected by filtration washed with ethanol (-60°) and dried to yield 82.4 g (90%) of offwhite crystals, m.p. 109-111°. The analytical sample was prepared by recrystallization from ethanol: white crystals, m.p. 113-115°.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13](O)=O)[CH:10]=2)[N:5]=[CH:4][NH:3]1.[C:16]1([C:22]2[N:27]=[N:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[C:16]1([C:22]2[CH:23]=[CH:24][C:25]3[N:26]([C:13]([CH2:12][C:9]4[CH:10]=[C:11]5[C:6](=[CH:7][CH:8]=4)[N:5]=[CH:4][NH:3][C:2]5=[O:1])=[N:29][N:28]=3)[N:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: O=C(O)Cc1ccc2nc[nH]c(=O)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc12
Temperature: 150 °C

Procedure:
A mixture of 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetic acid (0.10 g, 0.5 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0.6 mmol) and p-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) in 3 mL of dioxane was heated with microwave at 150° C. for 1 hour in a microwave tube. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow solid as desired product 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one. MS (ESI, pos. ion) m/z: 355.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:16])[C:9](=[O:22])[CH2:8][CH2:7]2)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH:15]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH3:16])[C:9](=[O:22])[CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: CC(CN1C(=O)CCc2cc([N+](=O)[O-])ccc21)N1CCCC1
Agent: [Pd]
Solvent: CCO
Product: CC(CN1C(=O)CCc2cc(N)ccc21)N1CCCC1

Procedure:
A suspension of 6-nitro-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (585 mg, 1.93 mmol) and palladium on activated carbon (10%, 103 mg, 0.096 mmol) in 15 mL ethanol was stirred under a balloon of hydrogen overnight. The suspension was filtered through a pad of silica gel. The filter pad was rinsed with 20 mL of 2M NH3 in methanol and the filtrate was concentrated to give a viscous oil. The crude product was used without further purification. (490 mg, 92.9%). 1H-NMR (CDCl3) δ: 7.20 (d, J=8.7 Hz, 1H), 6.63 (dd, J=2.4, 8.7 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 3.58 (brs, 2H), 2.82-2.77 (m, 2H), 2.63-2.58 (m, 2H), 2.1 (br s, 4H), 1.80-1.62 (br s, 5H), 1.30 (d, J=6.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8]2=[O:13])=[O:4].O.[OH-].[Li+]>C1COCC1.CO.O.O>[O:13]=[C:8]1[CH2:7][CH:6]2[CH2:12][CH2:11][CH:9]1[CH2:10][CH:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1CC2CCC1CC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC2CCC1CC2C(=O)O
Yield: 87.4 %

Procedure:
5-Oxo-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (Preparation 73, 390 g, 2.14 mol, 1.0 eq) was taken up in a mixture of THF:MeOH:water (2:2:1, 2.0 L). A solution of lithiumhydroxide monohydrate (198 g, 4.71 mol, 2.2 eq) in water (1.0 L) was added dropwise while a dark green solution emerged. The temperature was kept below 30° C. by cooling with a waterbath. The reaction mixture was washed with DCM (2×500 mL). The combined organic layers were extracted with water (300 mL). The combined aqueous layers were brought to pH ˜1 with concentrated HCl solution and subsequently extracted with DCM (4×300 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure and stripped with toluene (2×). This furnished title compound as a brownish solid (314 g, 1.87 mol, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>[Pt]>[NH2:1][CH:2]1[CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3]1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Pt]
Product: NC1CCC(C(=O)O)CC1
Yield: 67 %

Procedure:
p-Aminobenzoic acid is hydrogenated in the presence of a platinum catalyst to give a yield of 67% of theory of 4-aminocyclohexylcarboxylic acid; m.p. 256°-258° C. The reaction with phosphorus trichloride/phosphorous acid takes place in the manner described in Example 1 and gives the desired compound in a yield of 32% of theory; m.p. 235°-238° C. (decomp.); Mrel =0.27.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8](=[O:15])[CH2:7]2)([O-:3])=[O:2].C[C:17]([O:19][C:20](C)=O)=O.CN(C)C=O.C(OC)(OC)OC>CCOCC>[CH3:17][O:19]/[CH:20]=[C:7]1/[C:8](=[O:15])[NH:9][C:10](=[O:14])[C:11]2[C:6]/1=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1
Solvent: CCOCC
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc([N+](=O)[O-])cc21

Procedure:
To a stirred mixture of 0.41 g (2.0 mmol) of 6-nitroisoquinoline-1,3(2H,4H)-dione, 3.2 ml (34 mmol) of Ac2O, and 0.80 ml of N,N-DIMETHYLFORMAMIDE is added 0.44 ml (4.0 mmol) of trimethyl orthoformate. The mixture is heated to 125° and maintained for 30 m, cooled, diluted with ether, and stirred for 10 m. The resulting brown solid is filtered, washed with ether, and dried to give 372 mg (74%); 1H NMR (DMSO-d6) δ 11.55 (s, 1H), 8.99 (d, J=2.0 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.19 (dd J=2.0, 8.6 Hz, 1H), 4.33 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[N:7]=[CH:17][CH:15]=[CH:14]2
Reactant: OCC(O)CO
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc([N+](=O)[O-])c2ncccc2c1
Temperature: 45 °C
Yield: 42 %

Procedure:
4-Methoxy-2-nitroaniline (20.0 g, 119 mmol), 34.0 g (369 mmol) glycerol, 24.0 g (107 mmol) 3-nitrobenzensulfonic acid sodium salt, 25 mL H2O and 34 mL H2SO4 are refluxed for 12 h. The reaction mixture is cooled to 45° C., poured into 1 L of cold H2O and vigorously stirred with 500 mL of CH2Cl2 for 30 min. The resulting bi-phasic solution is filtered through celite, and the aqueous layer is extracted with 3×300 mL CH2Cl2. The combined organics are washed with 1×400 mL H2O, 1×400 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography of the crude product on SiO2 gel, eluting with hexanes/EtOAc (4/1), gives 10.0 g (49.0 mmol, a 42% yield) of the title compound as a tan solid. MS (ES) m/z 205 (MH)+.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].IC.CCCCCC.CCOC(C)=O>C1COCC1.C(OCC)C>[Cl:9][C:10]1[C:17]([CH3:1])=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(F)ccc(C#N)c1Cl
Temperature: -65 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Stir the lithium diisopropylamide (LDA) solution for 1 h at 0° C. and then transfer it via canula, over 1 h, to a −78° C. solution of 2-chloro-4-fluoro-benzonitrile (68.7 g, 0.442 mol) in THF (1 L). Allow the temperature of the reaction mixture to warm to about −65° C. during the initial addition of the LDA solution; however, keep the internal temperature below −70° C. during the remainder of the LDA addition. Keep the temperature of the resulting dark red-orange reaction mixture below −70° C. for 5 h and add iodomethane (251.2 g, 1.77 mol, 3 mL/min) at such a rate that the reaction temperature is maintained below −65° C. during the addition. Allow the reaction mixture to slowly warm overnight. After stirring for 14 h, the temperature of the reaction mixture is −5° C. Quench the reaction with saturated aqueous ammonium chloride (500 mL) and water (750 mL) and dilute with diethyl ether (about 2 L). Separate the layers and extract the aqueous layer with diethyl ether (about 1 L). Dry the combined organic layer (about 5.5 L) over MgSO4, filter, and concentrate to afford the crude title compound as a red-brown oily solid (about 86.7 g). Subject the crude residue (dry loaded on silica gel using methylene chloride) to flash chromatography (silica gel (10×30 cm), gradient of 99:1 to 93:7 hexane/EtOAc) to obtain the title compound (56.7 g, 76%) as a white solid. m.p. 63-65° C.; 1H NMR (300 MHz, CDCl3): δ 7.54 (dd, J=8.6, 5.6 Hz, 1H), 7.08 (dd, J=8.6, 8.6 Hz, 1H), 2.36 (d, J=2.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: COc1cccc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.1 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (1 g, 6.09 mmol) and 3-methoxyacetophenone (0.91 g, 6.09 mmol) in methanol (30 ml) was added 50% w/v solution of aqueous sodium hydroxide (9.7 ml, 0.122 mol). The reaction mixture was stirred at room temperature for 24 h. A precipitate was isolated by filtration, washed with cold methanol and subsequently recrystallised from methanol to afford 0.38 g (21%) of pale yellow crystals. 1H-NMR δ (CDCl3), 1.6 (t, 3H), 1.85 (m, 2H), 3.9 (s, 2H), 3.95 (t, 2H), 6.9 (d, 2H), 7.1 (1H), 7.38 (m, 2H), 7.55 (m, 4H), 7.8 (d, 1H). 13C-NMR (CDCl3) δ 190.3, 161.3, 159.9, 139.9, 127.4, 69.6, 22.5. Mass Spectrum m/e (M+1) 297. Anal. Calcd. for C19H20O3: C, 77.00; H, 6.80. Found C, 76.86; H, 6.94.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10](=[O:19])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]([N:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:31]=[CH:30][C:5]=2[N:6]=1)=[O:19]
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc(N)cc3s2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc(NS(C)(=O)=O)cc3s2)cc1OC
Yield: 24.8 %

Procedure:
A mixture of 33.2 mg (0.07 mmol) N-(6-Amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide in 0.7 ml DCM, 18.2 mg (0.18 mmol) NEt3 and 10.3 mg (0.091 mmol) methanesulfonyl chloride in 0.2 ml DCM was reacted for 16 h at room temperature. After evaporation of all volatiles the residue was taken up in DMF/acetonitrile and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield 9.6 mg (25%) of the title compound. MS (m/e): 552.1 (MH+, 100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH:18]1([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:41])C=CC=CC=1>O1CCCC1.[Cl-].[NH4+]>[CH:18]1([CH:23]([OH:41])[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C(CC1CCCC1)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A 0.5 M potassium bistrimethylsilylamide-toluene solution (67.2 mL, 33.6 mmol) was added to anhydrous tetrahydrofuran (30 mL), and the mixture was cooled to −78° C. under nitrogen stream. To this mixture was added dropwise a solution of benzyl cyclopentylacetate (6.11 g, 28 mmol) in anhydrous tetrahydrofuran (30 mL) over 1 h. After the mixture was stirred at −78° C. for 30 min, a solution of Davis oxaziridine reagent (8.78 g, 33.6 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise over 1 h. The reaction mixture, which had been stirred at −78° C. for 1 h, was diluted with a saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the organic solvent in the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1) to give 6.157 g of benzyl 2-cyclopentyl-2-hydroxyacetate (yield: 94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[N:8]=2)[CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].O>CN(C=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:10]1[CH:11]=[CH:12][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][C:9]1=[O:13]
Reactant: ClCCCCBr
Reactant: O=c1nc(-c2cccnc2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2cccnc2)ccn1CCCCCl
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of 4-pyridin-3-yl-1H-pyrimidin-2-one (50 mg, 0.29 mmol) in dry DMF (11 ml), 60% NaH (15 mg, 0.37 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (43 μl, 0.37 mmol) was added at room temperature and the mixture was stirred overnight. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated to give 40 mg of the title compound as a solid (54% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[CH:24](=[O:26])[CH3:25]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:24]([OH:26])[CH3:25])[C:5]([F:8])=[CH:4][N:3]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To a 250-mL 3-neck flask was added a THF solution (20 mL) of 2-bromo-5-fluoropyridine (8.80 g, 50 mmol). At −78° C., to the solution was added LDA (25.0 mL, 50 mmol, 2.5 M in THF) dropwise. After stirring for 5 min, diisopropylamine (7.0 mL, 50 mmol) was added dropwise via a syringe and the mixture was stirred at −78° C. for 4 h. A THF solution of acetaldehyde (11 mL, 55 mmol, 5M in THF) was added dropwise via a syringe. The contents were removed from the cold bath and stirred with warming to room temperature overnight. The mixture was diluted with water (150 mL) and vigorously stirred for 5 min. The contents were concentrated under reduced pressure and the residue was extracted with ethyl ether (3×150 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford yellow oil, which was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 5:1) to afford 325b (8.0 g, 72.7%) as a yellow solid. MS-ESI: [M+H]+ 220.1. 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=1.5 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 5.17 (d, J=6.5 Hz, 1H), 2.18-2.16 (m, 1H), 1.52 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[OH:30].[CH2:31](OC(OCC)OCC)C>CN(C=O)C.O>[O:30]1[C:3]2[CH:4]=[C:5]([N:8]3[C:15](=[S:16])[N:14]([C:17]4[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=4)[C:13](=[O:29])[C:9]43[CH2:12][CH2:11][CH2:10]4)[CH:6]=[CH:7][C:2]=2[N:1]=[CH:31]1
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(N)c(O)c3)C2=S)cc1C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc4ncoc4c3)C2=S)cc1C(F)(F)F
Temperature: 100 °C
Yield: 37.1 %

Procedure:
A mixture of 5-(5-(4-amino-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (60 mg, 0.14 mmol) and triethylorthoformate (0.050 mL, 0.28 mmol) in anhydrous DMF (1 mL) was heated at 100° C., 1 h. The mixture was diluted with water, extracted with EtOAc (3×), the organics combined and washed with water (2×), brine, dried (MgSO4) and concentrated. Purification by column chromatography, eluting with 30% EtOAc/hexanes provided 23 mg of 5-(5-(benzo[d]oxazol-6-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.95 (s, 1H), 8.78 (d, 1H), 8.05 (d, 1H), 7.94 (d, 1H), 7.45 (dd, 1H), 2.74-2.61 (m, 2H), 2.59-2.47 (m, 2H), 2.03-1.90 (m, 1H), 1.61-1.48 (m, 1H). LCMS [M+1]+ 444.0.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:73])=[O:74])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(S(=O)(=O)N2CCOCC2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(S(=O)(=O)N2CCOCC2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 8.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 2-methoxy-4-(morpholinosulfonyl)aniline (Matrix) (0.29 g, 1.1 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(morpholine-4-sulfonyl)-phenyl]-amide as a white solid (Yield 0.04 g, 8%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[S:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([NH:24][C:25](=[O:27])[CH3:26])[CH2:18]2)(=[O:14])(=[O:13])[NH2:12].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN1C(=O)CCC1>[F:8][C:7]([F:10])([F:9])[C:4]1[S:3][C:2]([NH:12][S:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH:19]([NH:24][C:25](=[O:27])[CH3:26])[CH2:18]3)(=[O:13])=[O:14])=[N:6][N:5]=1
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: CC(=O)NC1Cc2ccc(S(N)(=O)=O)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(F)(F)F)s3)cc2C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The mixture of 300 mg of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazol, 300 mg of N-(5-sulfamoyl-indan-2-yl)-acetamide, 1.8 g cesium carbonate und 10 ml of NMP was stirred at 70° C. for 3 hours. After cooling to room temperature 50 ml of water were added and with 2N hydrochloric acid a pH=3 was adjusted. The product was extracted twice with 30 ml of ethyl acetate, the organic layer was washed with 20 ml of water, dried over sodium sulfate and evaporated in vacuo. The resulting crude material was purified by column chromatography (silica gel, eluent: dichloromethane:methanol=90:10).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:32])[NH:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1)=[O:19])[CH2:12]2.C(=O)(O)[O-].[Na+].O>CN(C)C=O.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>[CH2:29]([NH:28][C:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]([N:13]2[CH2:12][C:11]3[C:15](=[CH:16][CH:17]=[C:9]([CH:1]=[CH2:2])[CH:10]=3)[CH2:14]2)=[O:19])=[CH:26][CH:25]=1)=[O:32])[CH2:30][CH3:31]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc2c(c1)CN(C(=O)Nc1ccc(C(=O)NCCC)cc1)C2
Temperature: 85 °C

Procedure:
In a sealed vial under nitrogen, a mixture of potassium vinyltrifluoroborate (100 mg, 0.75 mmol), 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (150 mg, 0.37 mmol), bis(triphenylphosphine)palladium(II) chloride and saturated aqueous sodium bicarbonate (0.62 ml) in dimethylformamide was heated at 85° C. for 5 hours. The reaction was poured into water, filtered, dried and purified by reverse-phase chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.57 (s, 1H), 8.25 (t, J=5.7 Hz, 1H), 7.75-7.78 (m, 2H), 7.63-7.67 (m, 2H), 7.47 (s, 1H), 7.42 (dd, J=7.9, 1.5 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 6.77 (dd, J=17.6, 10.9 Hz, 1H), 5.85 (dd, J=17.6, 1.0 Hz, 1H), 5.27 (d, J=11.0 Hz, 1H), 4.77-4.78 (bs, 4H), 3.16-3.22 (m, 2H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 350 (M+H)+.