Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH3:29][O:28][C:26](=[O:27])[N:11]([CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: CCCC(CCC)NCCc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(CCC)N(CCc1ccc(F)cc1Br)C(=O)OC

Procedure:
1.045 g of N-[2-(2-bromo-4-fluorophenyl)ethyl]heptan-4-amine in solution in 15 cm3 of anhydrous tetrahydrofuran and 502 mg of potassium carbonate are stirred under an inert atmosphere at a temperature in the vicinity of 20° C. 0.28 cm3 of methyl chloroformate is introduced over 10 min using a syringe. The reaction mixture is brought to reflux over 30 h, then filtered through celite and then concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual oil is put into solution in 20 cm3 of dichloromethane. The organic phase is washed successively with 10 cm3 of an aqueous solution of hydrochloric acid (pH=2), then 3×20 cm3 of distilled water. The organic phase is then dried, then concentrated to dryness using a rotary evaporator under reduced pressure (5 kPa). The residual oil is taken up with 10 cm3 of diisopropyl ether. The solid which appears is filtered and the filtrate is concentrated to dryness using a rotary evaporator under reduced pressure (5 kPa) in order to result in 778 mg of methyl[2-(2-bromo-4-fluorophenyl)ethyl](1-propylbutyl)carbamate in the form of a beige oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:30]([C:27]1[CH:26]=[CH:25][C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)(=[O:32])=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1N
Product: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 81 %

Procedure:
N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, in the same manner as described in Example 194b, from 5-amino-4-tridecyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonyl chloride in 81% yield. Purification was achieved by recrystallization from methanol/water to give an off white solid, m.p. 115-116° C.
Reaction SMILES: C([N:8]1[CH2:16][CH2:15][CH:14]2[N:17]([C:18](=[O:21])[CH2:19][CH3:20])[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[C:18]([N:17]1[CH:14]2[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][NH:8][CH2:16][CH2:15]2)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)N1C2CCCC1CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N1C2CCCC1CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution in dichloromethane (7 ml) of 3-BOC-10-propionyl-3,10-diazabicy-clo[4.3.1]decane obtained in Example 13 (0.32 g), cooled at 0° C., trifluoroacetic acid (0.83 ml) in 3 ml of dichloromethane, is added. The mixture is kept under stirring at room temperature for 3 hours. The solvent is then evaporated and the residue treated with an aqueous solution of saturated NaHCO3, then extracted with CH2Cl2. The organic phase is separated, anhydrified on sodium sulphate and evaporated. 0.21 g of a light oil corresponding to the compound 10-propionyl-3,10-diazabicyclo[4.3.1]decane (14a) are obtained.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:15]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1.O>[C:15]([O:19][C:20]([N:6]1[CH2:7][CH2:8][N:3]([CH2:2][CH2:1][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:4][CH2:5]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: C1CN(CCN2CCNCC2)CCN1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCNCC2)CC1

Procedure:
1,1'-ethylenedipiperazine (1.98 g, 10 mmol) is dissolved in 20 mL of dioxane: water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine (1.817 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifiuoroacetic acid to obtain the pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH2:27])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (1.5 g, 0.005 mol) was dissolved in dry N,N-dimethylformamide under argon and cooled to 0° C. 1,1′-Carbonyl-diimidazole (1.4 g, 0.009 mol) was added to the mixture and the reaction stirred for one hour while the temperature rose from 0° C. to room temperature. Ammonium acetate (5.6 g, 0.073 mol) was added and the reaction was stirred for one hour at room temperature. Water was added dropwise to the mixture and a precipitate appeared. The solid was filtrated, washed with water and dried under vacuum to yield 1.36 g (0.0041 mol, 91% of theory) of the title compound as a white solid. MS (m/e)=329.3(M+H)+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[I:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][C:53]=1[CH3:54])[NH2:50]>CN(C=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:50][C:49]1[CH:51]=[CH:52][C:53]([CH3:54])=[C:47]([I:46])[CH:48]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(N)cc1I
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1I
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)benzoic acid 3 (2.64 mmol, 500 mg), TBTU (2.77 mmol, 891 mg) and DIPEA (5.29 mmol, 0.873 mL) in DMF (4 mL) was stirred at 50° C. for 15 min. 3-iodo-4-methylaniline (2.77 mmol, 647 mg) was added and stirred overnight at 50° C. Quenched in citric acid solution and extracted with ethyl acetate. Organic layer was washed with brine, dried and evaporated. Purification with chromatography (30% ethyl acetate in heptane) gave 3-(2-cyanopropan-2-yl)-N-(3-iodo-4-methylphenyl)benzamide 111 (861 mg, 81%). NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.42 (s, 3H), 7.23 (d, J=8.2 Hz, 1H), 7.52 (dd, J=8.2 Hz and 7.4 Hz, 1H), 7.58 (dd, J=8.2 Hz and 2.3 Hz, 1H), 7.71 (dq, J=7.8 Hz and 1.2 Hz), 7.76 (m, 1H), 7.78 (m, 1H), 7.96 (t, J=1.6 Hz, 1H), 8.11 (d, J=2.3 Hz, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Yield: 92.8 %

Procedure:
Diethyl malonate (31.15 g, 194.48 mmoles) was first transferred at 0° C. to a stirring suspension of sodium hydride (4.67 g, 194.58 mmoles) in dry THF (200 mL). To this resulting mixture, was added dropwise (at 0° C.) a solution of t-butyl bromoacetate (23.00 g, 117.91 mmoles). Formation of a white precipitate was instantly observed. The mixture was then stirred at room temperature until complete consumption of the starting material (1.5 hours as confirmed by TLC: 20% ethyl acetate: 80% hexanes). The solvent was then evaporated and the residue was taken-up in 500 mL diethyl ether. This organic phase was washed with water (3×300 mL) and washed once with brine (200 mL) before being dried (anhydrous MgSO4) and evaporated. The obtained residue was first purified by distillation to remove excess malonate and then by flash chromatography (SiO2, 15% ethyl acetate: 85% hexanes) to afford 30.00 g (92.8% yield) of the desired compound as an oil: IR (film) 2982, 1733, 1258, 1152, 1037 cm−1; 13C NMR (CDCl3, 100 MHz) 169.5, 168.1, 80.8, 61.2, 47.7, 33.9, 27.6.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([C:21]2[CH:22]=[N:23][C:24](S(CCC)(=O)=O)=[N:25][CH:26]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([C:21]2[CH:26]=[N:25][C:24]([N:3]([CH3:4])[CH3:2])=[N:23][CH:22]=2)[CH:7]=1
Reactant: CNC
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ncc(-c2cc(Cl)ccc2OCC(=O)O)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Dimethylamine hydrochloride (0.82 g) was added to a stirred solution of the product from step (iv) (0.2 g) and N,N-diisopropylethylamine (0.9 ml) in No (5 ml). The reaction mixture was heated at 90° C. for 6 h then diluted with EtOAc, washed with water, brine, dried and evaporated under reduced pressure. The residue was dissolved in DCM (10 ml) then trifluoroacetic acid (10 ml) added and stirred for 18 h at RT. The reaction mixture was evaporated to dryness and the residue purified by reverse phase HPLC followed by trituration with methanol to give a white solid. Yield 0.035 g
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[CH:28]([CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C)C)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:21][CH:20]=1>O1CCCC1>[C:19]1([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)[CH:28]([CH2:36][CH2:37][OH:38])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A solution of tetra-n-butylammonium fluoride (1.0 M in THF; 6.2 mL, 6.2 mmol) was added dropwise over 15 min to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (3.39 g, 5.61 mmol) in tetrahydrofuran (20 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. The volatiles were evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (100 mL), dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (50% to 75% diethyl ether: cyclohexane) to give the title compound (1.6 g, 58%) as a yellow oil which was a mixture of diastereomers. LC/MS: 3.98 min; z/e 491, calcd (M+1) 491. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.45 (4H), 7.30 (5H), 6.90 (2H), 4.50 (2H), 3.80 (3H), 3.65 (2H), 2.80 (2H), 2.65 (1H major), 2.05 (1H minor), 1.85 (3H), 1.60-1.35 (11H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=[C:6]2[C:5]([CH3:31])=[N:4][CH:3]=1.[Cl-].[CH:33]([C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:45]#[N:46])[CH:41]=2)[N:36]=1)=O.O1CCCC1.N12CCCN=C1CCCCC2>>[CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:33]/[C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:45]#[N:46])[CH:41]=4)[N:36]=3)[N:10]=[C:6]2[C:5]([CH3:31])=[N:4][CH:3]=1
Reactant: N#Cc1ccc2nc(C=O)ccc2c1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ncc(C)n2nc(/C=C/c3ccc4cc(C#N)ccc4n3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.222 g, 0.483 mmol) and 2-Formyl-quinoline-6-carbonitrile (80 mg, 0.4 mmol) in dry Tetrahydrofuran (6 mL, 80 mmol) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (66 uL, 0.44 mmol) (reaction mixture turns slightly yellow for a while and precipitation changes character) and the mixture was stirred at room temperature under an atmosphere of Argon overnight. The mixture was rotovaped and the THF was evaporated off. The solid was dissolved in DCM and was chromatographed on silicagel (0-30% MeOH in EtOAc). Pure product 2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-quinoline-6-carbonitrile precipitates in one of the fractions (10): isolated by filtration. Yield: 6 mg white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13]OCC)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:17][NH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[CH:21][CH:20]=1>C(O)C>[CH2:26]([O:25][C:23]([C:22]1[CH:30]=[CH:31][C:19]([N:18]([CH3:17])[CH:13]=[N:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:20][CH:21]=1)=[O:24])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOC(=O)c1ccc(NC)cc1
Reactant: CCOC=Nc1ccc(C(=O)OCC)cc1
Solvent: CCO
Product: CCCCOC(=O)c1ccc(N(C)C=Nc2ccc(C(=O)OCC)cc2)cc1

Procedure:
Ethyl N-(4-ethoxycarbonylphenyl)formimidate (Example Ia) (6.7 g, 0.03 mol) and n-butyl 4-methylaminobenzoate (6.2 g, 0.03 mol) were heated at 190° until 1.7 ml of ethanol had been collected by distillation. The solid mass which resulted upon cooling was recrystallized from hexane to yield the product, mp 83°-85° C. ##STR13##
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([O:30][CH3:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:14][C:3]1[CH:4]=[C:5]2[CH:6]=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:27]([C:26]1[N:22]([C:17]3[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:23]=[C:24]([O:30][CH3:31])[CH:25]=1)[O:12][C:11]2=[O:13]
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Reactant: Nc1c(Cl)cc2cn[nH]c2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(-c2nc3c(Cl)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 400 mg (1.89 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid in 16 mL of anhydrous tetrahydrofuran is added 479 mg (1.89 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid followed by 684 μL (8.50 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 516 μL (6.66 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 5 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained (870 mg) is engaged in the next step; LC/MS:530/532 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH:7]=[CH:6]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C>ClCCCl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:7]=[CH:6]3)=[CH:26][CH:25]=1
Reactant: COc1ccccc1CNc1ccc2cc(CN)ccc2n1
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccccc1CNc1ccc2cc(CNCc3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 53.2 %

Procedure:
A solution of (6-aminomethyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 85, step B) (390 mg, 1.33 mmol), 4-fluorobenzaldehyde (181.5 mg, 1.46 mmol) and acetic acid (319.3 mg, 5.32 mmol) in 1,2-dichloroethane (15 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-boron hydride (657 mg, 2.79 mmol) was added, the reaction mixture was allowed to stir for 60 h at room temperature, poured into ice/saturated NaHCO3 solution (30 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as colorless oil (284 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:16][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CCCc1cccc(Br)c1

Procedure:
Compound G can be obtained as described in J. Med. Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCCCC(CC)C(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCC(CC)Cc1ccccc1

Procedure:
A solution of 313.9 grams of 2-ethylhexanoylbenzene in 500 mL of acetic acid with 11.4 grams of 10% palladium on carbon (as a catalyst) was stirred at 110° C. in an atmosphere of hydrogen at 414 kPa for 34 hours. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2-ethylhexylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[CH:21][C:20]4[C:16](=[C:17]([CH3:26])[N:18]([CH2:23][CH2:24][OH:25])[N:19]=4)[CH:15]=3)[C:10](=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[CH:21][C:20]4[C:16](=[C:17]([CH3:26])[N:18]([CH2:23][CH2:24][O:25][CH2:33][CH2:34][O:35][CH3:36])[N:19]=4)[CH:15]=3)[C:10](=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1CCO
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCn1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 4-[(4-chlorobenzyl)oxy]-1-[2-(2-hydroxyethyl)-3-methyl-2H-indazol-5-yl]pyridin-2(1H)-one (30 mg) in N,N-dimethylformamide (2 ml) was added 60% sodium hydride (3.51 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. To the obtained reaction mixture was added (2-bromoethyl)methyl ether (15.3 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (28.1 mg).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=1>>[ClH:1].[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[F:37])[CH2:30][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccc(F)c(F)c1
Yield: 31.4 %

Procedure:
Using an analogous procedure to that described in Example 36, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (224 mg, 0.6 mmol), (prepared as described for the starting material in Example 22), was treated with 4-bromomethyl-1,2-difluorobenzene (149 mg, 0.72mmol) to give 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (90 mg, 31%).