Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=1.[CH:16]1([CH:19]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[N:20]2[CH2:25][CH2:24][C:23]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][C:21]2=[O:37])[CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([CH:19]([C:38]2[CH:43]=[CH:42][C:41]([C:8]3[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=3)=[CH:40][CH:39]=2)[N:20]2[CH2:25][CH2:24][C:23]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][C:21]2=[O:37])[CH2:17][CH2:18]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: CC(C)(O)CC1(c2ccccc2)CCN(C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc(C(C3CC3)N3CCC(CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.69 mL) was added to a mixture of 4-bromo-1-methyl-1H-pyridin-2-one (0.14 g) and 3-{cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (pure diastereomer; 0.35 g) in N,N-dimethylformamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (57 mg) was added. The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling the mixture to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 0.36 g (52% of theory); LC-MS (Method 1): tR=3.31 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14]C)=O.C[Si](C)(C)N[Si](C)(C)C.[Li].C1COCC1.[NH4+].[Cl-]>C1COCC1>[C:12]1(=[O:14])[C:4]2[CH:5]=[C:6]3[N:11]([C:3]=2[CH2:2][NH:1]1)[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: COC(=O)c1cc2n(c1CN)CCCC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: O=C1NCc2c1cc1n2CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 238c (1.3 g, 6.25 mmol, 1.0 eq.) and THF (20 mL). At −78° C., to the solution was added lithium hexamethyldisilazane/THF (18.7 mL, 18.7 mmol, 3.0 eq.). It was then stirred at room temperature for 2 hrs. After the reaction was completed, saturated aqueous NH4Cl solution (30 mL) was added and the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (3×50 mL) and the combined organic layer was evaporated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 238d (585 mg, 53%) as a yellow solid. MS: [M+H]+ 177.3. 1H NMR (500 MHz, DMSO-d6) δ 7.38 (s, 1H), 5.82 (s, 1H), 4.13 (s, 2H), 3.86 (t, J=6.5 Hz, 2H), 2.73 (t, J=6.5 Hz, 2H), 191-1.88 (m, 2H), 1.75-1.73 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>CN(C)C=O>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccnc2)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 47.6 parts of 1H-imidazole, 33.6 parts of sodium hydride dispersion 50% and 750 parts of N,N-dimethylformamide was stirred at room temperature for 15 minutes. The resulting solution was added to 106 parts of 3,6-dichloropyridazine in 750 parts of N,N-dimethylformamide and the whole was further stirred for 2 days at room temperature. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystalized from methanol. The product was filtered off, washed with petroleumether and dried, yielding 48.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine; mp. 182.9° C. (compound 1).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[C:16](\[Cl:24])/[C:17]([O:19]C(C)(C)C)=[O:18])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(OC)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[C:16](\[Cl:24])/[C:17]([OH:19])=[O:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1/C=C(\Cl)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CON=C(C(=O)OC)c1ccccc1/C=C(\Cl)C(=O)O
Yield: 82 %

Procedure:
29 g of methyl 2-methoxyimino-2-{2-[2-chloro-2-tert-butyloxycarbonyl-(Z)-ethenyl]phenyl}acetate from Example 3 are stirred in a mixture of 40 ml of trifluoroacetic acid and 160 ml of dichloromethane for 2.5 hours at room temperature. The dark solution is then stirred into 500 ml of saturated sodium carbonate solution (pH 9). After the addition of 200 ml of methyl tert-butyl ether, the organic phase is separated off. The aqueous phase is again extracted with methyl tert-butyl ether and the pH is adjusted to 2-3 with 6N hydrochloric acid. The product separates out as an emulsion and is isolated by extracting three times with methyl tert-butyl ether and ethyl acetate. The combined organic phases are washed until neutral with saturated NaCl solution and dried over sodium sulfate. The solvent is removed, leaving 20 g of the title compound as a dark oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:23][C:24]([O:26]C)=[O:25])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.C1COCC1.[OH-].[Li+].Cl>O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:23][C:24]([OH:26])=[O:25])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ccc2c(N(CCN3CCOCC3)S(C)(=O)=O)cccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O
Yield: 62.4 %

Procedure:
To a solution of methyl 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetate (1.08 g, 2.73 mmol) in a 1/1 mixture of THF and water (30 ml), lithium hydroxide (0.654 g, 27.3 mmol) was added, and the mixture reacted for 1 hour at room temperature. The mixture was acidified with aqueous 12 N HCl (pH=5) and the desired compound was extracted with EtOAc (3×50 ml). The organic phase was dried over sodium sulfate and the solvent was removed; the residue was purified by flash chromatography (DCM/MeOH 9/1) recovering 2-(4-(N-(2-morpholinoethyl)-methylsulfonamido)-1H-indol-1-yl)acetic acid (650 mg, 1.704 mmol 62.4% yield, MS/ESI+ 381.9 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:14]Br>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:14])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 45 °C
Yield: 48.2 %

Procedure:
A suspension of 2-amino-5-chloropyridine (5.14 g, 40 mmol) and anhydrous sodium acetate (3.29 g, 40 mmol) in acetic acid (25 mL) was mechanically stirred and warmed to a bath temperature of 45° C. A solution of bromine (2.1 mL, 40 mmol) in acetic acid (2 mL) was added over 1 hour. The resulting orange mixture was cooled to 15° C. and filtered. The solids were taken up in 400 mL of water, the suspension made basic by addition of 1 N NaOH and the suspension extracted with ethyl acetate (5×100 mL). The combined extracts were washed with 10% NaHSO3 (1×100 mL) and were dried over MgSO4. Concentration afforded 2-amino-3-bromo-5-chloropyridine (4 g, 48), mp 82-84° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:5]2=1.C1C(=O)N([Br:40])C(=O)C1>C(#N)C.O>[Br:40][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[CH:17]=1)=[CH:3][C:2]([CH3:1])=[N:11][CH:10]=3
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Yield: 39.1 %

Procedure:
To the stirred solution of (S)-tert-butyl (1-((2,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (40 mg, 0.069 mmol) in acetonitrile (3 mL) at room temperature was added NBS (12 mg, 0.069 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-bromo-2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (30 mg, 0.027 mmol, 40% crude yield) as a yellow oil. The material was carried forward without further purification. LC/MS (ESI) m/e 518.2 [(M+H)+, calcd for C25H33BrN3O4 518.2]; LC/MS retention time (method E): tR=1.25 min.
Reaction SMILES: O[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:15]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: Nc1ccccc1
Product: O=C(O)c1cc2ccccc2cc1Nc1ccccc1

Procedure:
reacting 3-hydroxy-2-naphthoic acid and aniline to produce 3-anilino-2-naphthoic acid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7](O)[C:6]=2[CH:18]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:19][CH:7]1[C:6]2[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[CH2:8]1
Reactant: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reaction time: 8 h

Procedure:
103 G. of 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol, 500 ml. of benzene and 38.4 g. of finely powdered calcium chloride are saturated with hydrogen chloride gas at 15° C. and stirred overnight. The precipitate is removed by filtration, washed with benzene, evaporated under reduced pressure, and there is obtained 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin which melts at 63°-64° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH:25]([N:28]=[C:29]=[S:30])([CH3:27])[CH3:26]>CC(C)=O>[C:1]([C:3]1[C:4]([S:15]([NH:18][C:29]([NH:28][CH:25]([CH3:27])[CH3:26])=[S:30])(=[O:16])=[O:17])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2]
Reactant: CC(C)N=C=S
Reactant: CCOC(=O)Nc1sc(C)c(C#N)c1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Nc1sc(C)c(C#N)c1S(=O)(=O)NC(=S)NC(C)C
Temperature: 55 °C

Procedure:
A mixture of 4-cyano-2-ethoxycarbonylamino-5-methyl-thiophene-3-sulfonamide (0.50 g), potassium carbonate (0.36 g) and isopropyl isothiocyanate (300 μl) in 10 ml of dry acetone was heated at 55° C. for 18 h and then evaporated to dryness. The residue was dissolved in 10 ml of water, and pH was adjusted to 2 by dropwise addition of 1M hydrochloric acid. The precipitate was filtered off, rinsed with a small amount of water and dried to give 0.34 g of the title compound; m.p. 169-171° C.
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.[Cl:25][C:26]1[C:27]([F:49])=[CH:28][C:29]([OH:48])=[C:30]([C:32]2(O)[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:33]2=[O:46])[CH:31]=1>>[Cl:25][C:26]1[C:27]([F:49])=[CH:28][C:29]([OH:48])=[C:30]([CH:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:33]2=[O:46])[CH:31]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(Cl)c(F)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(c2cc(Cl)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-chloro-4-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (99%): 1H NMR (300 MHz, CDCl3) δ 10.0-9.70 (br, 1H), 7.45-7.18 (m, 3H), 6.98 (d, 1H), 6.90-6.82 (m, 2H), 5.01 (s, 1H), 3.75-3.66 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 348 (M+1).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3I)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: c1ccc(-c2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)cc1

Procedure:
(R)-Indan-1-yl-(5-iodo-quinolin-2-yl)-amine (150 mg, 0.39 mmol) was dissolved in 5 mL 1,2-dimethoxyethane and 2.5 mL 1M sodium carbonate solution. Phenylboronic acid (59 mg, 0.48 mmol) was added. Argon was bubbled through the solution for 2 minutes to remove oxygen. Triphenylphosphine (11 mg, 0.04 mmol) and Palladium acetate (4 mg, 0.02 mmol) were added. The reaction mixture was refluxed overnight. The reaction was diluted with 50 mL water and the mixture was extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The title compound was obtained as a colorless solid (114 mg, 87%), MS: m/e=337.4 (M+H+).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]#[N:12])=[N:6]1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[K+].[Br:18]Br>C(O)(=O)C>[Br:18][C:8]1[C:7]([C:11]#[N:12])=[N:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9]=1[CH3:10]
Reactant: BrBr
Reactant: CCCCn1nc(C#N)cc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCn1nc(C#N)c(Br)c1C
Yield: 101.1 %

Procedure:
1-Butyl-5-methyl-1H-pyrazole-3-carbonitrile (6.58 g, 38 mmol) was treated with potassium acetate (57.2 mmol) and bromine (41.9 mmol) in acetic acid (50 mL) according to a modification of the method described in Part F of Examples 1-4. The reaction provided 9.3 g of 4-bromo-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile as a colorless oil that crystallized upon standing. The crystals were used without purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].CC([Si](C)(C)[O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH2:37][CH2:38][NH:39][CH2:40]2)=[CH:35][C:34]=1[O:43][CH3:44])(C)C.C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][C:33]([OH:32])=[C:34]([O:43][CH3:44])[CH:35]=3)[CH2:40]2)[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(SC1CCCCC1)c1ccc(OC)c(OC)c1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 150.7 %

Procedure:
A mixture, under argon, of 2.17 g of product from Example 113, 1.8 g of product from Example 28, 13.0 ml of N,N-diisopropyl ethylamine and 80 ml of acetonitrile is heated under reflux temperature for 8 hours. The reaction is cooled and concentrated in vacuo and dried under high vacuum for 1 hour. The crude residue is dissolved in 70 ml of tetrahydrofuran and 10.0 ml of 1M tetrabutyl ammonium fluoride in tetrahydrofuran is added and the mixture is stirred at room temperature, under argon, for 2.5 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried, filtered, and concentrated in vacuo to give 4.0 g of a brown oil. The oil is purified by chromatography (silica gel: 1%, 1.5% and 2% methyl alcohol/methylene chloride)to give 2.1 g of the desired product.
Reaction SMILES: [OH-].[Na+].[ClH:3].Cl.[CH3:5][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][C:16](=N)N)=[CH:11][CH:10]=1)[CH3:7].BrC[C:21]1[CH:34]=[CH:33][C:24]2[N:25]=[C:26]([N:28]([CH2:31][CH3:32])C=O)[O:27][C:23]=2[CH:22]=1>O.CO.O1CCCC1>[ClH:3].[ClH:3].[CH3:7][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][C:21]2[CH:34]=[CH:33][C:24]3[N:25]=[C:26]([NH:28][CH2:31][CH3:32])[O:27][C:23]=3[CH:22]=2)=[CH:11][CH:10]=1)[CH3:5]
Reactant: CCN(C=O)c1nc2ccc(CBr)cc2o1
Reactant: CN(C)Cc1ccc(CSC(=N)N)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc2ccc(CSCc3ccc(CN(C)C)o3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of sodium hydroxide (464 mg) in water (4.18 ml) was added to a solution of S-(5-dimethylaminomethylfuran-2-yl)methylisothiourea dihydrochloride (1.00 g) in methanol (10 ml) and the mixture was stirred for 1 hour at ambient temperature. A solution of 6-bromomethyl-2-(N-ethylformamido)benzoxazole (1.10 g) in a mixture of methanol (20 ml) and tetrahydrofuran (5 ml) was dropwise added thereto at 0° C. and the mixture was stirred for 2 hours at the same temperature. The solvent was evaporated in vacuo. The residue was mixed with water (20 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel by eluting with chloroform-methanol (20:1, V/V). The pure base was converted to the hydrochloride in a usual manner and recrystallized from a mixture of ethanol and diisopropyl ether to give 6-[(5-dimethylaminomethylfuran 2-yl)methylthiomethyl]-2-ethylaminobenzoxazole dihydrochloride (0.33 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])=[CH:15][CH:14]=1.CN(C)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[O:24]=[C:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CCCC2=O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4.27 g (25.03 mmol) of benzyl chloroformate are slowly added to 4 g (22.7 mmol) of 1-(4-aminophenyl)pyrrolidin-2-one and 3.6 ml (28.4 mmol) of N,N-dimethylaniline in 107 ml of tetrahydrofuran at −20° C. The mixture is stirred at −20° C. for 30 minutes and then allowed to reach room temperature. 0.5 l of ethyl acetate is added, and the organic phase is washed with 0.5 l of saturated NaCl solution. The removed organic phase is dried with MgSO4, and the solvent is evaporated in vacuo. The residue is triturated with diethyl ether and filtered off with suction. 5.2 g (73.8% of theory) of benzyl 4-(2-oxo-1-pyrrolidinyl)phenylcarbamate are obtained as pale beige crystals with a melting point of 174° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[C:39]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH:38]=[CH:37][N:36]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCN(c2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)cc3)ccn2)CC1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (6.8 g) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (5.0 g) are dissolved in DME (300 mL). Under an inert gas atmosphere are added (Ph3P)3PdCl2 (2.1 g) and 2M Na2CO3-solution (44 mL). The mixture is heated to 100° C. for 2.5 h. After filtration and extraction, the crude product from the organic phase is purified by silica gel flash chromatography. By means of chloroform/EtOH (30:1-19:1). 5.3 g of the title compound are obtained as brownish oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][C:13]#[N:14])([O-])=O.[Cl-].[NH4+].C1(C)C=CC=CC=1>CO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCCCc1ccccc1N

Procedure:
450 mg of 4-(2-nitrophenyl)butyronitrile, dissolved in 12.5 ml of methanol, are added dropwise to a mixture of 412 mg of iron powder (7.5 mmol) and 663 mg of ammonium chloride (12.5 mmol) in 12.5 ml of water at room temperature and under protective gas in a 100 ml glass round-bottomed flask. The mixture is heated for 5 hours with reflux. 25 ml of water are added to the cooled mixture and extraction is performed with toluene. The combined toluene phases are dried and the solvent distilled off under reduced pressure. The residue is purified by column chromatography on silica gel (eluent toluene/ethyl acetate 10:1 v/v). Yield: 276 mg (1.73 mmol, 72%).
Reaction SMILES: [CH2:1]([N:4]([CH2:34][CH2:35][CH3:36])[C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)[CH2:2][CH3:3].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.O>[CH2:34]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[N:6]([CH3:33])[C:7](=[O:32])[C:8]2[C:13]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])=[CH:12][NH:11][C:9]=2[N:10]=1)[CH2:35][CH3:36]
Reactant: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2Cc2ccc(OC)cc2)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)c1nc2[nH]cc(-c3c(C)cc(C)cc3C)c2c(=O)n1C
Yield: 15.6 %

Procedure:
A Solution of 2-(dipropylamino)-5-mesityl-7-(4-methoxybenzyl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.21 mmol) in trifluoroacetic acid (3 ml) and anisole (0.1 ml) was refluxed for 3 days. The mixture was diluted with water (20 ml), neutralized with sodium hydrogen carbonate and extracted with ethyl acetate (20 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 12 mg (15%) of the title compound.