Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3B3OC(C)(C)C(C)(C)O3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:43]1[S:44][CH:45]=[C:46]([Br:48])[N:47]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:43]3[S:44][CH:45]=[C:46]([Br:48])[N:47]=3)[C@H:14]2[CH3:39])[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=1
Reactant: Brc1csc(Br)n1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(Br)cs1
Temperature: 100 °C

Procedure:
In a tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (59 mg, 0.099 mmol), 2,4-dibromothiazole (60 mg, 0.247 mmol), DME (420 μL), EtOH (140 μL), and 1M Na2CO3 (296 μL, 0.296 mmol). The mixture was degassed with N2 and then Pd(PPh3)4 (5.7 mg, 4.94×10−3 mmol) was added. The mixture was degassed with N2 again, and then the tube was sealed, and the reaction was heated at 100° C. for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water and brine (10 mL) each, dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (25% EtOAc/hexanes). LCMS=635.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (bs, 2H), 7.78 (s, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.68 (dd, J=8.1, 1.0 Hz, 1H), 7.41 (s, 1H), 5.66 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.8 Hz, 1H), 4.84 (J=15.8 Hz, 1H), 4.20 (m, 1H), 0.78 (d, J=6.7 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[C:18](#[N:22])[CH2:19][C:20]#[N:21].C(N(CC)CC)C>C(O)C>[NH2:22][C:18]1[O:1][CH:2]=[C:3]([CH2:4][CH2:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)[C:19]=1[C:20]#[N:21]
Reactant: N#CCC#N
Reactant: CCOC(=O)c1ccc(CCC(=O)CO)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCc2coc(N)c2C#N)cc1

Procedure:
A mixture of 2.36 g (10 mmol) of ethyl 4-(4-hydroxy-3-oxobutyl)benzoate, 0.66 g. (10 mmol) of malononitrile, and 1.01 g (10 mmol) of triethylamine in 10 mL of ethanol is stirred at 25° C. for 10 hours. Ethyl 4-[2-(2-amino-3-cyanofur-4-yl)ethyl]benzoate is formed as a solid and can be collected by filtration. After washing with a small amount of methylene chloride and drying, a white solid is obtained; m.p. 195°-197° C. Anal. calcd for C16H16N2O3 : C, 67.60; H, 5.67; N, 9.85 Found: C, 67.85; H, 5.71; N, 10.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 370.3 %

Procedure:
3,5-Dichlorophenol (500 mg, 3.07 mmol) was dissolved in dimethylacetamide (8.0 mL), and 4-fluorobenzaldehyde (0.390 mL, 0.368 mmol) and cesium carbonate (1.50 g, 3.69 mmol) were sequentially added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 150° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 85:15 (v/v)), whereby the objective title compound was obtained as a white solid (364 mg, yield: 44%).
Reaction SMILES: C(OC([N:6]1[CH:11](OCC)[CH2:10][CH:9](Cl)[C:8]([C:16]2[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[C:19]([NH:26]C(=O)C)=[CH:18][C:17]=2[C:30]([F:33])([F:32])[F:31])=[N:7]1)=O)C.[OH-].[K+].O>CCO>[NH2:26][C:19]1[CH:18]=[C:17]([C:30]([F:31])([F:32])[F:33])[C:16]([C:8]2[N:7]=[N:6][CH:11]=[CH:10][CH:9]=2)=[CH:21][C:20]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)N1N=C(c2cc(C(=O)OC)c(NC(C)=O)cc2C(F)(F)F)C(Cl)CC1OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)c(-c2cccnn2)cc1C(=O)O
Temperature: 110 °C
Yield: 74.1 %

Procedure:
A solution of 3-(4-acetylamino-5-methoxycarbonyl-2-trifluoromethyl-phenyl)-4-chloro-6-ethoxy-5,6-dihydro-4H-pyridazine-1-carboxylic acid ethyl ester (400 mg, 0.81 mmol) in EtOH (20 mL) containing KOH (227 mg, 4.05 mmol) was heated to 110° C. for 18 h. Water (2 mL) was added and the reaction was heated to 110° C. for 8 h. The solution was poured onto ice/water/2 N aq HCl (2.5 mL) then extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and the solvent was removed in vacuo to give the title compound (170 mg, 74%). API-ES: m/z 284.0 [M+H]+, rt 2.78 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1.COC(=O)C1C=CC(O)=C([Cl:33])C=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[C:6]([Cl:33])[CH:5]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Product: COC(=O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
Following the procedure for the preparation of 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting 3-Chloro-4-hydroxy-benzoic acid methyl ester provided the title compound. MS: (M+H m/z=328.0).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.O>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(N3CCN(C)CC3)nc2N1C1CCCC1

Procedure:
Intermediate B (114 mg, 0.39 mmol) and N-methylpiperazine (2 mmol, 6 eq, 204 mg, 0.22 mL) in 1 mL of DMSO was heated at 120° C. in a microwave for 2 h. The reaction was diluted with water and extracted with EtOAc. The organic extracts were washed 5× with water, then dried with MgSO4 and evaporated. The residue was purified by reverse-phase HPLC (eluting with 10-30% acetonitrile in water with 0.1% TFA over 20 min; Phenomenex Luna C-18 column, 25×2 cm) to give the title compound after lyophylization. LCMS: 359.2 m/z (M+H)+; ret. Time: 6.72 min (Analytical Method A); 1H NMR (400 MHz, CDCl3) δ: 7.6 (s, 1H), 4.3 (ddd, 1H), 4.1 (dd, 1H), 4.8 (broad s, 4H), 3.3 (s, 3H), 2.5 (broad s, 4H), 2.3 (s, 3H), 2.1-1.6 (m, 10H) and 0.9 ppm (dd, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O[CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[CH2:22][NH:21][C:20]1=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][NH:21][C:20]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: O=C1CNC(=O)N1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1C(=O)CNC1=O
Temperature: 0 °C
Yield: 69 %

Procedure:
A mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (665 mg, 3.16 mmol), (prepared as described for the starting material in Example 4), 3-(3-hydroxypropyl)imidazolidine-2,4-dione (600 mg, 3.79 mmol) and triphenylphosphine in dichloromethane (15 ml) was stirred and cooled to 0° C. Diisopropyl azodicarboxylate (747 μl, 3.79 mmol) in dichloromethane (5 ml) was added and the mixture stirred at ambient temperature for 3 hours. Initially all material went into solution but later a precipitate formed. The mixture was concentrated and the solid residue suspended in methanol, filtered and dried in air to give 4-chloro-7-[3-(2,5-dioxoimidazolidin-1-yl)propoxy]-6-methoxyquinazoline (765 mg, 69%) as a pale yellow solid.
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:18][CH2:19]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C>[CH3:18][C:19]1[O:17][N:16]=[C:2]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[N:1]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1/C(N)=N/O
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1nc(C2CCCCN2C(=O)OC(C)(C)C)no1
Temperature: 0 °C
Yield: 33.2 %

Procedure:
In a 16 mL vial, tert-butyl 2-[(Z)-amino(hydroxyimino)methyl]piperidine-1-carboxylate (150 mg, 0.62 mmol; which may be prepared as described in Step 1) was dissolved in acetonitrile (6.2 mL) and cooled at 0° C. under nitrogen. DIPEA (324 μL, 1.86 mmol) and acetyl chloride (88 μL, 1.24 mmol) were added dropwise and the reaction mixture was allowed to warm to room temperature then heated to 100° C. for 4 h, cooled and concentrated. The residue was taken up in EtOAc and water. The two layers were separated and the aqueous phase extracted with EtOAc. The combined organics were dried on Na2SO4 and concentrated. The residue was taken up in o-xylene (7 mL) and heated to 150° C. for 3 h then concentrated. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc 7/3) to give the product (55 mg, 33%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)[NH2:24]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: OCc1ccc(Cn2ccc3ncnc(Cl)c32)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OCc1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 140 °C
Yield: 93 %

Procedure:
{4-[(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol (354 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (488 mg) were dissolved in 1-methyl-2-pyrrolidone (2.58 mL), and the mixture was stirred with heating at 140° C. for 2 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL) and partitioned with saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (588 mg) as a powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@@H:6]1[CH2:12][C@H:11]([CH3:13])[O:10][CH:8](O)[CH2:7]1)=[O:4].[N+](C1C=CC(C([Cl:25])=O)=CC=1)([O-])=O>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@@H:6]1[CH2:12][C@H:11]([CH3:13])[O:10][CH:8]([Cl:25])[CH2:7]1)=[O:4]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1C[C@@H](NC(=O)C(F)(F)F)CC(O)O1
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](NC(=O)C(F)(F)F)CC(Cl)O1
Reaction time: 12 h

Procedure:
To a solution of 1 g of compound (IX) in 10 ml of anhydrous pyridine, 2 g of p-nitrobenzoyl chloride were added. After 12 hours at room temperature, the reaction mixture was poured onto ice and the resulting precipitate was washed with water until the water was neutral. The resulting crude 1-p-nitrobenzoate (mixture of α and β anomer) was dried over phosphorus pentoxide for several hours under vacuum, and then dissolved in dry methylene dichloride and saturated at 0° with anhydrous hydrogen chloride. The precipitated p-nitrobenzoic acid was filtered off under anhydrous conditions, and the 1-chloro derivative (II) was obtained in quantitative yield by evaporation of the solvent. Compound (II) can be used for the ensuing condensation reaction without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:24].C(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[OH:5][C:6]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:24]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(O)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(O)c([N+](=O)[O-])cc2c1CCN(C(=O)OC(C)(C)C)CC2
Yield: 67 %

Procedure:
Nitric acid (65%, 0.370 ml) was added dropwise with vigorous stirring to 1,1-dimethylethyl 7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (600 mg) and silica gel (1.67 g) in DCM (5.7 ml) at −15° C. After 30 min a mixture of DCM/MeOH/conc.NH4OH: 10/3/1.5 was added and silica gel was filtered off. The solvent was evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 15/85) obtaining the desired compound (470 mg, 67% yield).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)C(Cl)Cl)C(C)C

Procedure:
To a solution of diisopropylamine (6.8 g) (0.068 mol) and 6.8 g. of triethylamine in 100 ml of anhydrous benzene was added dropwise at 15° C. with stirring and ice-bath cooling, dichloroacetyl chloride (10.0 g, 0.068 mol). The solution was stirred overnight at room temperature. The benzene solution was washed successively with 10% HCl, H2O sodium hydroxide and saturated NaCl solution and was dried over anhydrous MgSO4. The solvent was distilled off, yielding 4.9 g. of liquid product, which infrared absorption spectra indicated to be substantially pure. No further purification was considered to be necessary for the purpose of this invention.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[O:33][CH2:32][CH:31]5[CH2:34][NH:35][CH2:36][CH2:37][N:30]5[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:39]>>[CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[O:33][CH2:32][CH:31]5[CH2:34][N:35]([CH3:39])[CH2:36][CH2:37][N:30]5[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1c2ccc(-c3cc(C4CN5CCNCC5CO4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Product: Cc1c2ccc(-c3cc(C4CN5CCN(C)CC5CO4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Yield: 27 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 103 and using 5-(2-benzyl-3-methyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and iodomethane as the starting materials, 18 mg (27%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) 7.91 (s, 1 H), 7.75 (d, 1 H), 7.52 (s, 1 H), 7.34-7.19 (m, 5 H), 7.06 (dd, 1H), 6.72 (s, 1H), 5.63 (s, 2H), 5.14-5.10 (m, 1H), 3.73 (dd, 1H), 3.37-3.30 (m, 1H), 2.93 (dd; 1H), 2.75-2.63 (m, 4H), 2.61 (s, 3H), 2.41 (t, 1H), 2.25-2.06 (m, 3H), 1.57 (s, 3H); LC-MS [M+H]+=509, RT=0.28 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]2[O:19][CH2:18]2)=[CH:11][C:10]=1[N:20](C(OC(C)(C)C)=O)[S:21]([CH3:24])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH:33]1[CH2:42][NH2:43].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:19])[CH2:18][NH:43][CH2:42][CH:33]2[CH2:34][CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:32]2)=[CH:11][C:10]=1[NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Reactant: NCC1CCc2ccccc2C1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNCC2CCc3ccccc3C2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of 770 mg of 4-benzyloxy-3-(N-tert-butoxycarbonyl-N-methylsulfonylamino)-1-((2S)2,3-epoxypropoxy)benzene (1.71 mmol) and 300 mg (1.8 mmol) of 1,2,3,4-tetrahydronaphthalen-2-ylmethylamine, obtained as described in EP-A-436435, in 20 ml of absolute ethanol is heated under reflux for 16 hours. The mixture is cooled, 3 ml of an ethanol solution saturated with hydrochloric acid are added thereto and the medium is heated at 50° C. for 5 hours. The solvent is evaporated and the medium is taken up with a mixture of 50 ml of a saturated sodium bicarbonate solution and 50 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a silica gel column, eluting with a methylene chloride/methanol=95/5 mixture. The title compound is obtained in the form of a glassy solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:22]=2[N:23]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:28][C:25]3[CH:26]=[CH:27][C:21]4[S:20][C:19]([CH3:18])=[N:23][C:22]=4[CH:24]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(C)(C)C)cc4)ncn3)ccc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g, 0.61 mmol) and 2-methyl-benzothiazol-5-ol (0.14 g, 0.85 mmol, Aldrich) in DMF (10 mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil, Aldrich) at room temperature. The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, EtOAc (10 mL) was added to the residue, and the organic layer was washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After purifying the crude product by silica gel chromatography (4:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (5 mL). Water (8 mL) was added dropwise to this mixture, and a white precipitate fell out of solution, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 163–165° C. MS (ESI, pos. ion) m/z: 376 (M+1). Anal. Calcd for C23H21N3OS.(H2O)1/3: C, 69.26; H, 5.72; N, 11.01. Found: C, 69.19; H, 5.61; N, 11.03.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH:23]([CH:26]=O)[CH:24]=[O:25].CN(C)C(=O)C>O>[OH:25][CH2:24][C:23]1[S:21][C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[N:20][CH:26]=1
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(Nc1cccc2cc(-c3ncc(CO)s3)[nH]c12)c1cccs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.12 g), bromomalonaldehyde (0.90 g) and N,N-dimethylacetamide (15 mL) was stirred at 90° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (0.13 g) at 0° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.70 g, yield 60%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). melting point 209-210° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
5.20 g (21.57 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 4.3 g (21.57 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 9.84 g (25.89 mmol) of HATU, 13.53 ml (74.68 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 1 of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.2 g (69% of theory) of the title compound are isolated.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.O>[CH:18]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cccc(C=O)c1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C=O)c1OC1CCCC1
Reaction time: 55 h
Yield: 615 %

Procedure:
A mixture of 2-hydroxy-3-methoxy-benzaldehyde (10 g, 6.57 mmoles), K2CO3 (18.16 g, 131 mmoles), cyclopentyl-bromide (14.05 ml, 131 mmoles) in absolute ethanol (150 ml) under nitrogen was refluxed under stirring for 55 hours. The mixture was diluted with water, thrice extracted in ethyl acetate, washed with water, anhydrified over Na2SO4 and evaporated to dryness, the yielded oil was purified by flash chromatography on silica gel (eluent petrolatum/ethyl acetate 95:5) to give 8.9 g of the title product (yield: 61%).