Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]2>CN(C=O)C>[N:3]1([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]3)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C1CCCc2cc(OCCCl)ccc21
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.5 %

Procedure:
A suspension of NaH (0.29 g, 7.2 mmol, 60% oil dispersion prewashed with dry hexanes) in 18 mL of dry DMF under a nitrogen flow was cooled to 0° C. and imidazole (0.49 g, 7.2 mmol) was added portionwise. The ice bath was removed and the reaction stirred at room temperature 20 minutes. The reaction was cooled to 0° C. and a solution of 6-(β-chloroethoxy)-1-tetralone (1.07 g, 4.8 mmol) in 12 mL of dry DMF was added over several minutes. The ice bath was removed and the reaction stirred at room temperature overnight. The reaction was partitioned between 20 mL of water and 200 mL of EtOAc. The organic portion was removed, and the aqueous portion was extracted with EtOAc (5×50 mL). The combined extracts were washed successively with water and brine, dried, filtered, and concentrated under vacuum to afford 1.6 g of crude product. Purification by flash chromatography (silica gel, 130 g, 8% MeOH in DCM) afforded 0.83 g (67%) of an off-white crystalline solid: CI-MS m/e 256 (M+), 257 (M++1);
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C@H:12]([CH2:13][CH:14]=C)[CH2:11][CH2:10][C:9]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[O:20]=[O+][O-]>CO>[O:16]=[C:9]1[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@H:12]([CH2:13][CH:14]=[O:20])[CH2:11][CH2:10]1
Reactant: C=CC[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=CC[C@@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of (S)-1-(phenylmethyl)-5-(2-propenyl)-2-pyrrolidinone (44.8 g, 0.208 mol) in 800 mL of 1:1 methanol:methylene chloride was cooled to -78° C. and was ozonized using a Welsbach ozonizer for 6.5 h, approximately 1 h longer than the time required to observe a light blue color of ozone in the solution. Excess ozone was flushed out of the system with oxygen, and the solution was treated with methyl sulfide (80 mL). The solution was then allowed to come to room temperature and to stand overnight. The solvents were removed on a rotary evaporator, and the residual liquid was dissolved in 700 mL of methylene chloride, washed with water, and dried over Na2SO4. Evaporation of the solvent afforded 43.0 g of crude (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidineacetaldehyde. Chromatography on silica gel (1 kg) eluting with 4% methanol in methylene chloride afforded 38 g (84.4% yield) of the pure (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidineacetaldehyde. 1H NMR (CDCl3) δ 1.60-2.60 (m, 4 H, CH2), 2.77 (half of ABX, 1 H, Jgem =18,Jvic =4 Hz, CH2CHO), 3.98 (m, 1 H, NCH), 4.10 and 4.82 (AB, 2 H,Jgem =15 Hz, CH2Ph), 7.15-7.40 (m, 5 H, phenyl), 9.65 (s, 1 H, CHO).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18].[BH4-].[Na+]>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:17][CH3:18]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCNCc1cccc(Oc2ccccc2)c1
Temperature: 80 °C
Yield: 57.3 %

Procedure:
3-Phenoxybenzaldehyde (2.00 mL, 2.29 g, 11.6 mmol), n-propylamine (0.95 mL, 0.68 g, 11.5 mmol), and p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol) were dissolved in absolute ethanol (15 mL), then heated to 80° C. in a sealed tube for 2.5 hours. The reaction was cooled to room temperature, transfered to a round-bottom flask, then sodium borohydride (440 mg, 11.6 mmol) was added, followed by heating under reflux for 2.5 hours. The reaction was concentrated, the residue partitioned between water and EtOAc, the EtOAc layer washed with water and brine. After drying with Na2SO4, filtration, and concentration, the residue was purified by chromatography on silica gel eluting with 4:6 followed by 3:7 hexane-EtOAc to give 1.59 g (57%) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 7.30 (m, 3H), 7.08 (m, 2H), 7.00 (m, 3H), 6.88 (dd, 1H), 3.77 (s, 2H), 2.60 (t, 2H), 1.53 (m, 2H), 0.92 (t, 3H). MS (DCl/NH3) m/e 242 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.II.Cl[P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:23]([P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: FC(F)(F)c1ccc(-c2ccccc2Br)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)P(c1ccccc1-c1ccc(C(F)(F)F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 10.7 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with magnesium turnings (90 mg, 3.69 mmol), 2-bromo-4′-(trifluoromethyl)biphenyl (1.01 g, 3.35 mmol), and a crystal of iodine. The tube was purged with argon for 5 minutes, then THF (6 mL) was added through a rubber septum and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and cuprous chloride (365 mg, 3.69 mmol) and chloro-di-t-butylphosphine (0.765 mL, 4.03 mmol) were added. Heating was resumed for 14 hours. The reaction mixture was then cooled to room temperature and diluted with ether (40 mL). The suspension was filtered to isolate the solid. The solid was partitioned between ethyl acetate (60 mL) and 38% ammonium hydroxide (75 mL). The aqueous layer was extracted with ethyl acetate (60 mL). The -combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The product was crystallized from MeOH (10 mL) to afford 131 mg (11%) of pale yellow needles. A second crop was isolated by concentrating the mother liquor and recrystallizing the solid from MeOH (20 mL) and water (2 mL) to afford 260 mg (21%) of the product.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([C:22]#[C:23][CH2:24][N:25]([CH2:33][CH2:34][CH2:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Rh]>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([CH2:22][CH2:23][CH2:24][N:25]([CH2:33][CH2:34][CH2:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:16]=3)=[O:14])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)CCCOC1CCCCO1
Agent: [Rh]
Product: CC(C)(C)OC(=O)N(CCCOC1CCCCO1)CCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Yield: 68.1 %

Procedure:
A stirred suspension of tert-butyl 3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate (Example 2(iii)) (0.35 g) and 5% rhodium on carbon (0.020 g) was stirred under a positive pressure (2 barr) of hydrogen until no further uptake was observed. The mixture was filtered and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:acetone (19:1 to 9:1) to afford the sub-titled compound (0.24 g) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Br[CH2:16]CCC.C(Cl)Cl>O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH3:1])[CH:7]=1)[CH2:10][CH2:11][CH3:16]
Reactant: CCCCBr
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1
Solvent: ClCCl
Solvent: O
Product: CCCCOc1ccc([N+](=O)[O-])c(C)c1
Yield: 99 %

Procedure:
This compound was prepared in a similar manner to that for 404b except 1-bromobutane was deployed for the alkyl ether adduct and the partition step during workup utilized DCM (150 mL) and water (150 mL) to provide a yellow oil (2.0 g, 99%): TLC Rf 0.70 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (d, 1H, J=8.88 Hz), 6.79-6.76 (m, 2H), 4.03-4.01 (t, 2H, J=6.48 Hz), 2.63 (s, 3H), 1.80-1.78 (quin, 2H, J=7.44 Hz), 1.53-1.47 (sex, 2H, J=7.44 Hz), 1.0-0.97 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, CDCl3) δ 162.7, 141.9, 137.1, 127.6, 117.9, 112.2, 68.3, 31.0, 21.8, 19.1, 13.8. Elemental analysis calculated for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.25; H, 7.09; N, 6.69.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([F:16])[CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:12])=[C:9]([F:16])[CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A solution of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoic acid (Preparation 44, 400 mg, 1.19 mmol), DMAP (365 mg, 2.97 mmol, 2.5 eq), diisopropylethylamine (0.7 mL, 2.97 mmol) and EDCl (700 mg, 2.97 mmol) in dichloromethane (10 mL) was allowed to stir for 10 minutes at room temperature under nitrogen. Methane sulphonamide (400 mg, 3.57 mmol) was added in one portion and the reaction mixture left to stir for 16 hours. The reaction was quenched with 6N HCl (20 mL) and the organic layer removed. The DCM layer was extracted into 1N NaOH (30 mL) and the organic layer discarded. The aqueous phase was adjusted to pH 5 using acetic acid and extracted into ethyl acetate (2×30 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the title compound as a white solid (168 mg, 34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(CCc1ccccc1F)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCc1ccccc1F)C(=O)O
Yield: 101.3 %

Procedure:
A mixture of diethyl 2-(2-(2-fluorophenyl)ethyl)malonate (381.8 g, 1.35 mol) and potassium hydroxide (227.3 g, 4.1 mol) and potassium hydroxide (227.3 g, 4.1 mol) in ethanol (500 mL) and water (500 mL) was refluxed for 24 h. The reaction mixture was placed in an ice bath and hydrochloric acid (6N, 442 mL) was added. The ethanol was removed in vacuo and the aqueous residue was extracted with diethyl ether. The extracts were dried (MgSO4) and concentrated in vacuo to give 309.3 g (100%) of 2-(2-(2-fluorophenyl)ethyl)malonic acid as an off-white solid. This product was used without further purification. NMR (DMSO-d6): d 6.8-6.2 (m, 4H, ArH), 2.4 (t, 1H, CH), 1.9 (q, 2H, CH2), 1.3 (t, 2H, CH2). IR (KBr) 1691 CM-1.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:9][C:8]=1[Cl:36])C.C1COCC1.[OH-].[Na+].Cl>O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[C:11]([Cl:13])=[CH:12][C:7]=1[CH:6]=[CH:5][C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-acrylic acid ethyl ester (74 mg, 0.14 mmol, 1.0 equiv) in a 1:1 mixture of THF and water (2 mL) was added sodium hydroxide (11 mg, 0.28 mmol, 2.0 equiv; [CAS RN 1310-73-2]) and the reaction mixture heated by microwave irradiation to 100° C. for 10 min. The crude reaction product was taken up in water (50 mL), acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over MgSO4 and the product purified by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water yielding 21 mg (30%) of the title compound as a yellow viscous oil. MS (ISP): 509.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[NH2:17].[N:22]#[C:23]Br>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[CH2:7][C:8]2[C:9](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[N:17]=[C:23]1[NH2:22]
Reactant: N#CBr
Reactant: COc1ccccc1CNCc1ccc([N+](=O)[O-])cc1N
Product: COc1ccccc1CN1Cc2ccc([N+](=O)[O-])cc2N=C1N

Procedure:
The title compound was synthesized according to EXAMPLE 63, section 1.8 starting from 2-[(2-methoxybenzylamino)methyl]-5-nitrophenylamine by reaction with cyanogen bromide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([C@H:12]3[CH2:15][CH2:14][C@H:13]3[C:16](O)=[O:17])=O)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19].O.[NH2:21][NH2:22]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:12]4[CH:13]([C:16](=[O:17])[NH:21][N:22]=3)[CH2:14][CH2:15]4)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19]
Reactant: O=C1Cc2cc(C(=O)[C@H]3CC[C@H]3C(=O)O)ccc2N1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc(C3=NNC(=O)C4CCC34)ccc2N1
Yield: 92.1 %

Procedure:
5.22 g (0.02 mole) of cis-2-(indolin-2-on-5-oyl)-cyclobutanecarboxylic acid are refluxed with 1.1 g (0.022 mole) of hydrazine hydrate and 50 ml of ethanol for 11 hours. The product is filtered off under suction at room temperature and recrystallized from dimethylformamide/water to give 4.7 g (92%) of 2-(indolin-2-on-5-yl)-3,4-diazabicyclo[4.2.0]oct-2-en-5-one of melting point 309°-312° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C-:18]#[N:19].[K+]>CS(C)=O.CCOC(C)=O>[NH2:17][C:4]1[N:5]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:18]#[N:19])[N:3]=1
Reactant: CCN(c1ccccc1)c1nc(N)nc(Cl)n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-N-ethyl-N-phenyl-[1,3,5]triazine-2,4-diamine (Intermediate 37, 400 mg, 1.60 mmol) was dissolved in anhydrous DMSO (5 mL) before the addition of potassium cyanide (200 mg, 3.07 mmol). The reaction mixture was stirred at 120 C in a pressure tube for 2 h before allowing to cool to room temperature. The product mixture was diluted with EtOAc (20 mL), extracted with water (2×10 mL), saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The desired product was obtained and used directly without further purification (300 mg, 78%). Method C HPLC-MS: MH+ requires m/z=241. Found: m/z=241, Rt=1.27 min (89%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3][C:2]1=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]([CH2:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O:18][CH3:19])=[O:17]>C(=S)=S>[C:16]([CH2:20][CH:21]([CH3:25])[C:22]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[NH:3][CH2:4]2)=[O:23])([O:18][CH3:19])=[O:17]
Reactant: O=C1NCc2ccccc2N1
Reactant: COC(=O)CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)CNC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dihydro-2(1H)-quinazolinone (3.6 g) is added to a stirred suspension of anhydrous aluminum chloride (16.5 g) in carbon disulfide (120 ml) under nitrogen. 3-Carbomethoxy-2-methyl-propionyl chloride (4 g) is added dropwise to the stirred suspension, and the reaction mixture refluxed for about 18 hours, cooled to RT and further cooled to 0° C. in an ice bath. The liquid phase is decanted and ice and cold water slowly added to the residue. The aqueous mixture is filtered and the filtered solid suspended and stirred in the anhydrous diethyl ether overnight. The suspension is filtered and the filtered solid used in the next step without further purification.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1.Br[CH:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH:14]([CH:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26])[C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCC(Br)c1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(c1ccc(C(=O)OC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a suspension of KOtBu (980 mg, 8.73 mmol) in anhydrous DMF (15 mL) at 0° C. was added tert-butyl 4-chlorophenylacetate (1.80 g, 7.94 mmol). After stirring for two minutes, a solution of methyl 4-(1-bromobutyl)benzoate in DMF (5 mL) was added dropwise. The mixture was allowed to warm to room temperature. After stirring for 20 minutes, water was added then the solution was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with saturated NH4Cl (aq) (20 mL) then saturated NaCl (aq) (20 mL), dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 2% EtOAc/petroleum ether to afford the title compound: 1H NMR (300 MHz, CD3OD) δ 7.98-8.02 (m, 2 H), 7.77-7.81 (m, 2 H), 7.38-7.44 (m, 2 H), 7.09-7.13 (m, 2 H), 3.91 (s, 3 H), 3.79-3.81 (m, 1 H), 3.34-3.40 (m, 1 H), 1.20-1.30 (m, 2 H), 1.03 (s, 9 H), 0.91-1.02 (m, 2 H), 0.68 (t, J=7.4 Hz, 3 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].C[O-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.O>CO>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][CH2:18][CH2:17][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: BrCCOC1CCCCO1
Reactant: O=C1C(=NO)Oc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(=NOCCOC2CCCCO2)Oc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
5 g (0.03 mol) of benzofuran-2,3-dione 2-oxime (XI-1) are dissolved in 30 ml of methanol, and at 20° C. 15 ml of a 2 molar solution of sodium methoxide in methanol are added dropwise. The solvent is distilled off under reduced pressure. The crystalline residue is dissolved in 30 ml of N-methyl-2-pyrrolidinone and treated with 6.27 g (0.03 mol) of 2-(2-bromoethoxy)-tetrahydropyran at 20° C. The reaction mixture is stirred for 16 hours at 20° C., poured into 100 ml of water and the resulting mixture is extracted twice with 100 ml of dichloromethane each time. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using a mixture of diethyl ether/dichloromethane/petroleum ether (1:1:2). 5.55 g (62.1% of theory) of benzofuran-2,3-dione 2-{O-[2-(tetrahydropyran-2-yloxy)-ethyl]-oxime} (XIV-2) are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)o3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 50 mg (0.10 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl]piperidine and 21 mg (0.20 mmol) of 5-hydroxypentanal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[O:21][C:20]([C:22](O)=[O:23])=[CH:19][CH:18]=1>>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22]([C:20]3[O:21][C:17]([Br:16])=[CH:18][CH:19]=3)=[O:23])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1

Procedure:
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-bromo-2-furancarboxylic acid by method E. The product with a molecular weight of 378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) was obtained as hydrotrifluoroacetate.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:30]#[N:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)C1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (40%).