Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:3]=1[NH2:4].C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:73][O:74][C:75]1[N:80]=[CH:79][C:78](B(O)O)=[CH:77][CH:76]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:73][O:74][C:75]1[N:80]=[CH:79][C:78]([C:2]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:3]=2[NH2:4])=[CH:77][CH:76]=1
Reactant: Nc1cc(N2CCOCC2)ccc1Cl
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(N3CCOCC3)cc2N)cn1
Temperature: 90 °C
Reaction time: 21 h

Procedure:
A stirred mixture of 2-chloro-5-morpholinoaniline (608 mg, 2.86 mmol), grounded 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl, (S-Phos) (236 mg, 0.57 mmol), palladium (II) acetate (64.7 mg, 0.29 mmol), 6-methoxypyridin-3-ylboronic acid (876 mg, 5.72 mmol), and potassium phosphate tribasic (1.82 g, 8.59 mmol) in DMF (7.0 mL) and water (0.3 mL) was purged 3 times with argon and placed under vacuum 3 times. The reaction mixture was carefully heated to 90° C. After 21 h, the reaction was cooled to rt, then diluted with water and extracted 3 times with EtOAc. The organic extractions were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified over basic alumina (0-20% EtOAc in hexanes) to afford a tan solid as 2-(6-methoxypyridin-3-yl)-5-morpholinoaniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (1H, d, J=1.8 Hz), 7.69 (1H, dd, J=8.6, 2.5 Hz), 6.92 (2H, m), 6.34 (1H, d, J=2.3 Hz), 6.28 (1H, dd, J=8.4, 2.5 Hz), 4.68 (2H, s), 3.87 (3H, s), 3.78 (4H, m), 3.12 (4H, m). Mass Spectrum (pos.) m/e: 286.1 (M+1).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4](=[O:12])[CH2:3][C:2]1=[O:13].[Br:14]Br>CC(O)=O>[Br:14][CH:3]1[C:2](=[O:13])[CH2:1][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4]1=[O:12]
Reactant: BrBr
Reactant: O=C1CC(=O)CC2(CCCCC2)C1
Solvent: CC(=O)O
Product: O=C1CC2(CCCCC2)CC(=O)C1Br

Procedure:
To a stirred solution of spiro[5,5]undecane-2,4-dione (1.29 g, 5 mmol) in AcOH (10 mL) at r.t. was added bromine (0.8 g, 0.25 ml, 5 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid which was used without further purification. LCMS (ES+) 258.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>C1COCC1.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:25][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a mixture of N-benzyloxycarbonyl-L-leucine (2.7 g, 10.2 mmol), L-phenylalanine methyl ester hydrochloride (2.2 g, 10.2 mmol), and triethylamine (1.4 mL, 10.2 mmol) in dry THF (150 mL) was added N-ethyl-N'-dimethylaminopropyl-carbodiimide (EDCI) (2.2 g, 11.2 mmol) with stirring at room temperature. After the mixture was stirred overnight at room temperature, it was rotary evaporated. The residue was mixed with ethyl acetate and then washed successively with water, 1N HCl, and brine; the solution was dried (MgSO4) and evaporated to give a white solid residue. Recrystallization (EtOAc-hexane) gave 2.9 g (66%) of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine methyl ester, m.p. 91°-93° C. A mixture of this ester (2.8 g, 6.6 mmol) in 2:1 dioxane-water (150 mL) was treated at 0° C. with 1N NaOH solution (7.3 mmol). After stirring the solution for 2-3 hours at room temperature, it was acidified at 0° C. by the addition of 1N HCl, and then rotary evaporated. The residue was mixed with ethyl acetate and then washed successively with water, 1N HCl, and brine; the solution was dried (MgSO4) and evaporated to give 2.7 g of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine as a white solid, m.p. 120°-122° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1c2n(c3c(-c4ccc(F)nc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (71 mg, 89%), MS (ISP) m/z=321.5 [(M+H)+], mp 272° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][N:2]([C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C(=O)c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl 4-[methyl(phenylcarbonyl)amino]-1-piperidinecarboxylate D14 (1.66 g) was dissolved in DCM (5 mL) then TFA (4.02 mL, 52.1 mmol) was slowly added. The reaction was stirred at room temperature for 30 minutes. TFA and DCM were removed in vacuo. The crude mixture was poured on a top of an Isolute Si—SCX-2 cartridge, eluting with DCM then MeOH then a 2M NH3 in MeOH solution. Fractions containing desired compound were evaporated in vacuo to give title compound D15 in 1.18 g. LCMS [M+H]+219.01@0.45 min (2 min run)
Reaction SMILES: [NH2:1][C:2]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Br>C1COCC1>[NH2:1][C:2]1[C:3]([C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[O:5])=[CH:10][C:11]([Br:14])=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1cc(Br)cnc1N
Temperature: -55 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
To a flame-dried 100 ml round bottomed flask were added 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide (661 mg, 2.54 mmol) and anhydrous THF (15 ml). The solution was stirred at −55° C. for 5 minutes under nitrogen, then a 0.5 M solution of 2-methoxyphenyl magnesium bromide in THF (18 ml, 9.0 mmol) was added dropwise over 3 minutes. The resulting solution was allowed to warm to room temperature over 2 hours then quenched by addition of 1 M citric acid. (25 ml). Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated to give a sticky yellow solid. Recrystallization from ethanol provided 619.5 mg (79%) of (2-amino-5-bromo-pyridin-3-yl)-(2-methoxy-phenyl)-methanone as yellow needles. MS m/z: 308 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=[O:15]>>[CH3:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:17]1[CH:18]=[N:19][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccnc(F)c1
Reactant: Cc1cc(I)ccc1N
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)O

Procedure:
synthesized as intermediate 1 by reacting 4.7 mmol of 2-methyl-4-iodoaniline with 7.0 mmol 2-fluoroisonicotinic acid. LC/MS [(5.3 min; 355 (M+1)]. See detailed procedure in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25](F)=[C:26]([CH:29]=1)[C:27]#[N:28].C(N(CC)C(C)C)(C)C.C(#N)C>CCOC(C)=O>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: COc1ccc(CNc2ncnc3c2CNCC3)cn1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2CN(c2ccc(Br)cc2C#N)CC3)cn1

Procedure:
A mixture of N-((6-methoxypyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (350 mg, 1.3 mmol), 5-bromo-2-fluorobenzonitrile (640 mg, 3.2 mmol), N,N-diisopropylethylamine (0.67 mL, 3.9 mmol), and acetonitrile (4 mL) was subjected to microwave irradiation at 180° C. for 3 h. After that additional 5-bromo-2-fluorobenzonitrile (450 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. After cooling, the mixture was diluted with EtOAc (100 mL) and washed with aq. Na2CO3 solution and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column (EtOAc: 100%) to yield a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24]Cl)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Agent: [I-]
Agent: [K+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CN1CCOCC1
Yield: 44 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.45 g, 0.94 mmole) was dissolved in morpholine (7.5 ml) and stirred at ambient temperature overnight in the presence of potassium iodide (10 mg). The solvent was evaporated and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (98/2). The fractions containing the expected product were combined and evaporated under vacuum to give the title product as a foam (0.22 g, 44%); 1H NMR Spectrum: (CDCl3) 1.91-2.01 (m, 1H); 2.06-2.14 (m, 2H); 2.19-2.27 (m, 1H); 2.48-2.53 (m, 2H); 2.62-2.68 (m, 2H); 3.18 (q, 2H); 3.41-3.52 (m, 1H); 3.56-3.72 (m, 5H); 4.01-4.08 (m, 4H); 4.53 (d, 1H); 4.72 (t, 1H); 7.11-7.28 (m, 3H); 7.96 (m, 1H); 8.36 (s, 1H); 8.60 (s, 1H); 8.63 (s, 1H); Mass Spectrum: (M−H)− 528.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.[C:19]([O:22][CH2:23]OC)(=O)C>FC(F)(F)S(O)(=O)=O.C(O)(C)C>[CH3:19][O:22][CH2:23][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: COCOC(C)=O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(C)O
Product: COCn1cc(C)c(=O)[nH]c1=O
Temperature: 90 °C
Yield: 86.1 %

Procedure:
A mixture of thymine (100 g, 0.79 mol), trifluoromethanesulfonic acid (2 mL, 20 mmol) and HMDS (418 mL, 1.98 mol) was heated 16 hours with stirring at 90° C. and briefly at reflux and then distilled in vacuo at 80° C. to remove the excess HMDS. The mixture was treated with trifluoromethanesulfonic acid (1.5 mL, 20 mmol) and then methoxymethyl acetate (88 mL, 0.89 mol) was added at a rate such that the reaction temperature did not exceed 95° C. The mixture was heated 20 minutes at 70° C. and then distilled in vacuo to remove the trimethysilyl acetate formed as byproduct. The reaction mixture was poured into isopropanol (800 mL) and stirred 18 hours. The solids were collected, washed with ethyl acetate and dried to give 1-methoxymethyl-5-methyl-2,4(1H,3H)-pyrimidinedione (116 g, 0.68 mol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1>C(O)C.[Pt]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccnc(Cl)n2)c1
Agent: [Pt]
Solvent: CCO
Product: Nc1cccc(-c2ccnc(Cl)n2)c1
Reaction time: 24 h
Yield: 90 %

Procedure:
Intermediate 5 was dissolved in ethanol along with 5 mol % of 5% Pt/C. The mixture was stirred under an atmosphere of H2 for 24 hours and then filtered through a pad of Celite to remove catalyst. Removal of the solvent gave product in 90% yield. LC-MS showed purity>95% and the expected M+H+ of 206.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]([CH:30]3[CH2:32][CH2:31]3)[C:16]([CH2:18][C:19]([NH:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[N:17][C:13]=2[C:12]([F:33])=[C:11]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[C:10]=1[F:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:44]=[O:45]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]([CH:30]3[CH2:32][CH2:31]3)[C:16]3=[CH:18][C:19](=[O:20])[N:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:44](=[O:45])[N:17]3[C:13]=2[C:12]([F:33])=[C:11]([N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)[C:10]=1[F:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(nc(CC(=O)NOCc4ccccc4)n3C3CC3)c2F)CC1
Product: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(c2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Yield: 21 %

Procedure:
2-[7-Benzylamino-1-cyclopropyl-4,6-difluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-N-benzyloxy-acetamide (2.6 g, 4.64 mmol) is reacted with N,N'-carbonyldiimidazole (1.5 g, 9.28 mmol) in dimethylformamide (50 ml) at room temperature for 1 day. At the end of the reaction, the volatiles are evaporated under reduced pressure and the residue chromatographed on silica gel (eluent: 5% methanol-dichloromethane). The relevant fractions are concentrated in vacuo until crystals form. Filtration affords 0.57 g of 6-benzylamino-2-benzyloxy-5-cyclopropyl-7,9-difluoro-8-(4-methyl-piperazin-1-yl)-1,2,3,5-tetrahydro-pyrimido[1,6-a]benzimidazole-1,3-dione as colorless crystals (21%): mp: 214° C.; NMR (DMSO-d6): 0.97 (m,2H),1.18(m,2H),2.23(s,3H),2.42(m,4H),3.13 (m,5H),4.35(d,J=6.5 Hz,2H),5.05(s,2H),5.36(s,1H),7.22-7.61 (m,11H).
Reaction SMILES: [F:1][C:2]1[C:3]([I:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12](N(OC)C)=[O:13])[O:7][CH2:6][CH2:5]2.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[C:3]([I:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]=[O:13])[O:7][CH2:6][CH2:5]2
Reactant: CON(C)C(=O)C1OCCc2c1ccc(F)c2I
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=CC1OCCc2c1ccc(F)c2I
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 6-fluoro-5-iodo-N-methoxy-N-methyl-3,4-dihydro-1H-isochromene-1-carboxamide (700 mg, 0.2 mmol) in 30 mL of anhydrous THF was cooled to −30° C. and then DIBAL-H (0.3 mmol) was added. The mixture was stirred at −30° C. for 1 hours. The reaction was quenched with water, and extracted with DCM. The orgainc layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was used for the next step without purification.
Reaction SMILES: CC(C)([O-])C.[K+].C1O[CH2:23][CH2:22]OCCOCCOCCOCCOC1.[C:25]1(C=O)[C:38]2[C:39]3=[C:40]4[C:35](=[CH:36][CH:37]=2)[CH:34]=[CH:33][CH:32]=[C:31]4[CH:30]=[CH:29][C:28]3=[CH:27][CH:26]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)C>[CH:25]([C:38]1[C:39]2[C:40]3=[C:22]4[C:23](=[CH:27][CH:28]=2)[CH:29]=[CH:30][CH:31]=[C:32]4[CH:33]=[CH:34][C:35]3=[CH:36][CH:37]=1)=[CH2:26]
Reactant: O=Cc1ccc2ccc3cccc4ccc1c2c34
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 8 h
Yield: 3859.4 %

Procedure:
A 250 mL round-bottomed flask, equipped with a magnetic stirrer, an argon inlet and a Claisen adapter bearing an addition funnel and an argon outlet leading to a mineral oil bubbler, was dried in an oven, assembled hot and cooled under a stream of argon. The flask was charged with methyltriphenyl phosphonium bromide (8.4788 g, 23.73 mmole), potassium t-butoxide (23.7 mL of a 1.0M solution in tetrahydrofuran) and 18-crown-6 (0.180 g). Dry tetrahydrofuran (70 mL) was transferred to the flask under nitrogen using a cannula and the resultant reaction mixture was cooled to 0° C. using an ice-salt bath. Pyrene-1-carboxaldehyde (5.0 g, 21.7 mmole) was dissolved in dry THF (25 mL) and this solution was transferred to the addition funnel, under a nitrogen atmosphere, using a cannula, and then added dropwise to the cold reaction mixture over a period of 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight under an argon atmosphere. The solid which precipitated was filtered, washed with THF (15 mL) on the frit and the combined filtrate was concentrated on a rotary evaporator to give a solid residue, which was dissolved in dry diethyl ether (50 mL). The ether solution was passed through a short bed of neutral alumina washed with ether and the combined ether filtrate was concentrated to give a yellow solid (6.0 g). This yellow solid was chromatographed on silica gel with hexanes as eluent and the chromatographed material thus obtained was further purified by crystallization from 5% water/ethanol to give an off-white crystalline material (2.1655 g), melting point 88°-89° C. (89° C. according to Kamat, P. V.; Basheer, R.; and Fox, M. A. Macromolecules 18, 1366 (1985)).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.CCCCCC.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>O1CCCC1.CCOCC.O>[O:4]=[C:3]([CH2:5][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
Ethyl acetoacetate (100 ml, 0.79 mole) in dry tetrahydrofuran (400 ml) was added dropwise with stirring under nitrogen to 50% sodium hydride (41.8 g, 0.87 mole) in dry tetrahydrofuran (80 ml) at 0° C. The resulting solution was stirred for 15 minutes at 0° C. before adding dropwise a solution of n-butyllithium in hexane (460 ml, 1.95 M; 0.90 mole). The resulting orange solution was stirred for a further 15 minutes at 0° C. before adding benzyl chloride (135 ml, 1.18 mole) in dry ether (200 ml) and the solution was then allowed to warm to room temperature over 11/4 hours with stirring before quenching reaction by addition of conc HCl acid (100 ml) in water (200 ml) followed by ether (500 ml). The layers were separated and the aqueous further extracted with ether (3×300 ml). The combined organic layers were washed with water until the wash was neutral, dried (anhydrous MgSO4) and then concentrated. The resulting yellow oil was distilled under vacuum to give a virtually colourless oil (64.2 g, 37%), b.p. 118°-126° C. at 0.7 mmHg, n.m.r. δ(CDCl3) 7.08 (5H, s), 4.07 (2H, q, J=7 Hz), 3.23 (2H, s), 2.80 (4H, s) and 1.23 (3H, t, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=[N:13]1.[B-](Br)(Br)(Br)[S+](C)C.O>ClC(Cl)C>[CH2:14]([C:9]1[O:8][C:7]2[C:6]([Cl:10])=[CH:5][C:4]([F:11])=[C:3]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=[N:13]3)[C:2]=2[N:1]=1)[CH:15]([CH3:19])[CH3:16]
Reactant: COc1c(Cl)cc(F)c(-n2ncc(C(F)(F)F)cc2=O)c1N
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)Cc1nc2c(-n3ncc(C(F)(F)F)cc3=O)c(F)cc(Cl)c2o1

Procedure:
A mixture of 2-(2-amino-4-chloro-6-fluoro-3-methoxyphenyl)-5-trifluoromethylpyridazin-3-one (0.39 g) and borontribromide-methyl sulfide complex (1.8 g) in dichloroethane was heated at reflux temperature for 1 hour under nitrogen atmosphere. The mixture was poured into water and extracted with methylene dichloride. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound. 1H NMR (CDCl3, 300 MHz) 4.61 (3H, br s), 6.55 (1H, d, J=9.4 Hz), 7.30 (1H, m), 8.05 (1H, d, J=2.2 Hz) ppm.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18](=O)[CH:19]([O:22][CH3:23])[O:20][CH3:21].C(OCC)(=O)C>CN(C=O)C.O>[CH3:21][O:20][CH:19]([O:22][CH3:23])[C:18]1[N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:9][CH:17]=1
Reactant: N=C(N)c1ccccc1
Reactant: COC(OC)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1c[nH]c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of benzamidine 207 (1.44 g, 12 mmol) and potassium carbonate (4.1 g, 30 mmol) in anhydrous DMF (25 mL) is slowly added a solution of 3-bromo-1,1-dimethoxy-propan-2-one 206 (1.97 g, 10 mmol) in anhydrous DMF (10 mL) over 30 min. The mixture is then heated at 50–60° C. for 2 h. After cooling to room temperature, ethyl acetate (100 mL) and water (100 mL) were added. The organic phase is separated and the aqueous phase is extracted with ethyl acetate twice and the combined organic phase is washed with water (3×20 mL) and brine. Removal of solvents under reduced pressure and purification of the residue by column chromatography affords the desired product as a white solid. Yield: 2.08 g; LC-MS (MH+): 219. 1H NMR (300 MHz, CDCl3) δ 7.88–7.85 (m, 2H), 7.37–7.46 (m, 4H), 5.49 (s, 1H), 3.36 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1.[Cl:16][C:17]1[CH:30]=[CH:29][C:20]2[S:21][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:24])[C:19]=2[CH:18]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:25]([C:22]3[S:21][C:20]4[CH:29]=[CH:30][C:17]([Cl:16])=[CH:18][C:19]=4[C:23]=3[CH3:24])(=[O:27])=[O:26])[CH:12]=2)[CH2:7][CH2:6]1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CN(C)CCN1CCc2ccc(N)cc21
Product: Cc1c(S(=O)(=O)Nc2ccc3c(c2)N(CCN(C)C)CC3)sc2ccc(Cl)cc12

Procedure:
The title compound (E122) was prepared from 1-(2-dimethylaminoethyl)-2,3-dihydro-1H-indol-6-ylamine (WO95/32967 Description 4) (100 mg, 0.49 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (137 mg, 0.49 mmol) using the method of Example 1 (40 g, 18%) MH+=450/452.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][N:36]1[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:39][CH:38]=[N:37]1
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1cccc(C2=Nc3cc(N4CCOCC4)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M22) (100 mg, 0.17 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (32 mg).