Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([C:52]1[S:60][C:55]2[CH2:56][NH:57][CH2:58][CH2:59][C:54]=2[CH:53]=1)=[O:51]>CN(C=O)C>[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([C:52]1[S:60][C:55]2[CH2:56][N:57]([C:8](=[O:10])[CH2:7][O:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:58][CH2:59][C:54]=2[CH:53]=1)=[O:51]
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CNCC2
Reactant: COc1cccc(OCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cccc(OCC(=O)N2CCc3cc(C(=O)Nc4ccccc4N)sc3C2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of (3-Methoxy-phenoxy)-acetic acid (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (1.0 eq) obtained in step VII of example 216 was then added and mixture was stirred at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH2:13]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][NH:12][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(CO)c1ccc(Cl)cc1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=C(CO)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of the compound obtained in Step A (195 mmoles) and ethyl hydrazine-carboxylate (224 mmoles) in ethanol is stirred at reflux for 18 hours. The reaction mixture is cooled to 0° C. and the precipitate formed is filtered off, washed with ethyl ether and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:27]2[N:28]=[C:29]([C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(C4(C)CCCCC4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 74. 1H NMR (400 MHz, CDCl3) δ 7.16-7.13 (m, 3H), 6.79 (d, 2H, J=8.60 Hz), 6.61-6.59 (m, 1H), 6.51-6.48 (m, 1H), 6.46 (t, 1H, J=2.35 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.75 (s, 3H), 3.24 (d, 1H, J=13.68 Hz), 3.12 (d, 1H, J=13.68 Hz), 2.96 (t, 2H, J=6.25 Hz), 2.30 (s, 3H), 2.15-2.08 (m, 2H), 1.61-1.45 (m, 5H), 1.44 (s, 3H), 1.43-1.36 (m, 3H), 1.30 (s, 3H); MS (ES+) calcd for C30H38NO6: Found m/e 508.3 (M+1, 100%).
Reaction SMILES: [C:1]([C:3](C)([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[C:4](OCC)=O)#[N:2].[OH-].[Na+].[ClH:25]>>[ClH:25].[CH3:4][CH:3]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)[C:1]#[N:2]
Reactant: CCOC(=O)C(C)(C#N)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C#N)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To 45 parts of cooled ethyl α-cyano-α-methyl-1-(phenylmethyl)-4-piperidineacetate were added 250 parts of a sodium hydroxide solution 2N. After stirring overnight at room temperature, the reaction mixture was cooled, neutralized with hydrochloric acid and then evaporated. The residue was taken up in 45 parts of N,N-dimethylacetamide and the whole was heated for 5 hours at 150° C. and then evaporated again, yielding 16 parts (30.3%) of α-methyl-1-(phenylmethyl)-4-piperidineacetonitrile monohydrochloride (int. 31).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:9][CH2:8][CH2:7]1)=O)C.[CH:28]([Mg]Cl)([CH3:30])[CH3:29]>C1COCC1>[CH3:29][CH:28]([CH3:30])[C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:7][CH2:8][CH2:9]1)=[O:3]
Reactant: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Reaction time: 0.75 h

Procedure:
To a solution of 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester (Example 213b, 0.45 g, 1.21 mmol) in THF (150 mL) cooled with an ice-water bath is added iPrMgCl (2.0M in THF, 2.43 mL, 4.85 mmol) dropwise. After 45 min, the mixture is quenched with 1M aqueous NaHSO4 (5 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:2 to 1:1), followed by purification by RP HPLC on an Xbridge RP18 eluting with a gradient of acetonitrile in 0.1% aqueous NH4OH to give 2-methyl-1-(1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutyl)-propan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[O:16].C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[Cl:37][CH2:38][C:39]([N:6]([CH2:5][C:4]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[O:40]
Reactant: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)CCl)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of {2-[(2,4-dimethoxybenzyl)amino]-5-methoxyphenyl}(3-fluorophenyl)methanone (190 mg, 0.480 mmol) in 5 mL of dichloromethane was added triethylamine (0.335 mL, 2.40 mmol), followed by chloroacetyl chloride (0.115 mL, 1.44 mmol). After 30 minutes, another portion of chloroacetyl chloride (0.115 mL, 1.44 mmol) was added, and the mixture was stirred overnight. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with saturated NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a brown foam (229 mg, 100% yield) which was used in the next step without further purification ESI+MS: 472.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.C1COCC1.C([Li])CCC.Cl[P:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)P(c1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
Into a reactor were introduced 3.0 g (8.3 mmol) of the 1,1-bis(4-dimethylaminophenyl)-2-bromopropene and 10 mL of THF under a nitrogen atmosphere. The contents were cooled to −60° C. Thereto was gradually added dropwise 5.2 mL (8.3 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred for 30 minutes. Thereafter, 1.1 mL (6.0 mmol) of chlorodiphenylphosphine was added thereto and this mixture was heated to room temperature and stirred for 16 hours. Water was added to the reaction mixture. The resultant mixture was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized twice from hexane/ethanol to obtain 1.9 g (60%) of the target compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[N:11]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[NH2:11]
Reactant: COc1ccc(F)c2[nH]nc(N3C(=O)c4ccccc4C3=O)c12
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(F)c2[nH]nc(N)c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
To a suspension of 2-[7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 13) (1.36 g, 4.37 mmol) in ethanol (15 mL) at 0° C. (ice/water bath) was added hydrazine hydrate (0.638 mL, 13.11 mmol) dropwise. The ice/water bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued for a further 40 min. During this time the reaction mixture became very viscous. Acetone (10 mL) was added to the reaction and the resultant reaction mixture was allowed to stand at room temperature overnight. The solid was removed by filtration and washed with acetone (×2). The combined filtrates were concentrated in vacuo. The solid was triturated in cyclohexane-ethyl acetate (2:1; ˜25 mL) and then collected by filtration to give the title compound (479 mg, 60%) as a light brown powder. LCMS (System A) RT=0.69 min, ES+ve m/z 182 (M+H)+. The filtrate was concentrated and the resultant oil was loaded in dichloromethane (and minimum amount of methanol) to a silica cartridge 70 g and purified by chromatography on Flashmaster eluting with a 0-50% ethyl acetate-cyclohexane over 30 min. The appropriate fractions were combined and evaporated in vacuo to give another batch of the required product (316 mg, 40%) as a brown oil. LCMS (System A) RT=0.62 min, ES+ve m/z 182 (M+H)+.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:14][CH2:15][CH2:16][Cl:17]>CO>[Cl:17][CH2:16][CH2:15][CH2:14][S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of potassium hydroxide is dissolved in 40 ml of methanol and mixed with 2.3 g of 4-nitrothiophenol. The suspension is stirred for one hour at room temperature and mixed drop by drop with 1.48 ml of 1-bromo-3-chloropropane. After 4 hours of stirring at room temperature, another 0.15 ml of 1-bromo-3-chloropropane is added in drops. The mixture is stirred for 65 hours at room temperature, concentrated by evaporation in a vacuum and taken up in ethyl acetate. It is extracted with water and saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. After purification by flash chromatography, 2.54 g of 1-(3-chloro-propylsulfanyl)-4-nitro-benzene is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])C=O>N1CCCCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:20]([CH:11]=[CH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:21][C:22]=1[Cl:23]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(Cl)c(Cl)c2)cc1
Temperature: 155 °C
Yield: 27.5 %

Procedure:
A mixture of p-nitrophenylacetic acid (51.23 g, 0.28 mol) and 3,4-dichlorobenzaldehyde (49.50 g, 0.28 mol) in piperidine (50 mL) was heated to 150-160° C. for 5 hours under a N2 atmosphere. After cooling the reaction mixture, the precipitate was triturated in boiling methanol (MeOH) (50 mL) and then cooled to −5° C. for 12 hours. The crystalline precipitate was filtered off, rinsed with cold MeOH and dried at room temperature in a vacuum oven overnight to yield an orange solid, 22.71 g (0.077 mol, 27%) of the desired product.
Reaction SMILES: [BH4-].[Na+].[OH:3][CH2:4][CH2:5][S:6]([C:9]1[CH:10]=[C:11]([C:27](=[O:44])[CH2:28][CH2:29][C:30]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)=[O:31])[CH:12]=[C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])(=[O:8])=[O:7]>C(O)C.ClCCl>[OH:3][CH2:4][CH2:5][S:6]([C:9]1[CH:10]=[C:11]([CH:27]([OH:44])[CH2:28][CH2:29][CH:30]([C:32]2[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=2)[OH:31])[CH:12]=[C:13]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])(=[O:8])=[O:7]
Reactant: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCCOc1c(OCc2ccccc2)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Temperature: 75 °C

Procedure:
Sodium borohydride (0.66 g) was added to a suspension of 1-[3-(2-hydroxyethylsulfonyl)-4-propoxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (from previous experiment) in ethanol (125 mL), and the mixture was heated at 75° C. for 2 h. The solution was cooled and diluted with dichloromethane. It was then washed with 2.5N HCl (2×) and water, dried, and evaporated to a syrup, Rf 0.11 (hexane-ethyl acetate; 1:1, v/v). This material was used directly in the next experiment without further purification.
Reaction SMILES: [Na].[CH2:2](O)C.[CH:5]1[C:18]2[CH:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.CI>O>[CH:15]1[C:16]2[CH:17]([C:19]([O:21][CH3:2])=[O:20])[C:18]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CCO
Agent: [Na]
Solvent: O
Solvent: CI
Product: COC(=O)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sodium ethoxide solution is prepared from 21.75 g (0.95 mol) of sodium and 1500 mL of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is added batchwise to this solution and the suspension obtained is stirred for 1 hour at ambient temperature. Then the solid is separated off, washed with 1500 mL diethyl ether, and the isolated crystals are suspended in 1500 mL of dimethylformamide and combined with 126.73 mL (2.0 mol) of methyl iodide with stirring. The solution formed is left to stand for 24 hours at ambient temperature, then diluted with water to a total volume of 6 L, crystallized, suction filtered, washed with water, and dried. Yield: 167 g of white crystals (74% of theoretical yield); melting point: 82° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=1>O1CCOCC1.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>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 52.1 %

Procedure:
A solution of 399 (1 g, 2.40 mmol) and 6-bromonicotinaldehyde (450 mg, 2.40 mmol) in 1,4-dioxane (10 mL) was treated sequentially with bis-trimethyl tin (500 μA, 787 mg, 2.40 mmol) and Pd(PPh3)4 (270 mg, 0.24 mmol). The reaction mixture was then heated to reflux under nitrogen overnight, cooled, and concentrated. The crude product was purified by flash chromatography using the gradient 5%-10% MeOH in DCM and subsequent trituration by MeOH, providing pure 400 (494 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 9.10 (m, 1H), 8.65 (d, 1H, J=5.2 Hz), 8.62 (s, 1H), 8.51 (d, 1H, J=8.8 Hz), 8.48 (dd, 1H, J=2.8 Hz, J=10.4 Hz), 8.38 (dd, 1H, J=2.1 Hz, J=8.2 Hz), 8.20 (m, 1H), 7.73 (t, 1H, J=9.0 Hz), 7.01 (d, 1H, J=5.5 Hz). MS (m/z): (M+1) 395.9.
Reaction SMILES: [O:1]=[C:2]1C(C#N)=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][NH:3]1.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[O:1]=[C:2]1[C:22]([C:21]([OH:24])=[O:23])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)=[CH:4][NH:3]1
Reactant: CC(=O)O
Reactant: N#Cc1cc(-c2cccc(C(F)(F)F)c2)c[nH]c1=O
Agent: Cl
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)c[nH]c1=O

Procedure:
A mixture of 1.32 g. of 1,2-dihydro-2-oxo-5-[3-(trifluoromethyl)phenyl]-3-pyridinecarbonitrile and 140 ml. of 1:1 concentrated hydrochloric acid and glacial acetic acid is heated at reflux temperature for 16 hours. A white solid is separated which is collected by filtration and is washed with water and ethanol to give 1.05 g. of the product of the Example m.p. 295°-298° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>CN(C)C=O.O>[CH3:18][N:19]([CH3:23])[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)=[S:21]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)CCC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1ccc(OC(=S)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Step B, 25 g, in anhydrous dimethylformamide (DMF) (300 ml) was cooled to 0° and 99% NaH, 3.46 g, was added in two portions. The mixture was stirred for 1 hour at 0° then dimethylthiocarbamoyl chloride, 19.3 g, was added and the mixture heated at 90° under a N2 atmosphere for 1.5 hours. The mixture was cooled to room temperature and diluted with water to 1,200 mL. The resulting solution was then extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine and then dried over Na2SO4 and evaporated to dryness in vacuo to yield a residue which was purified by chromatography on silica gel to Yield the title compound, mp 62°-64°.
Reaction SMILES: [Si:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>>[Si:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1CCNCC1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN1CCN([Si](C)(C)C(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 160.3 g (0.8 mol) of 1-t-butyldimethylsilylpiperazine (Synthesis Example 1) and heated at 70° C. Once the internal temperature became steady, 75.8 g (0.88 mol) of methyl acrylate was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 219.9 g of a fraction having a boiling point of 135-137° C./0.4 kPa was collected.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22]([OH:24])=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[OH:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[OH:26])[CH2:32]3)=[O:24])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(CNC(C)=O)cc3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 65 (15% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.63 and 2.90 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.34-4.37 (m, 2H), 4.38 and 4.92 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.42-7.47 (m, 2H), 7.67-7.77 (m, 1H), 7.85-7.97 (2d, 1H), 8.02-8.17 (m, 2H), 8.42-8.50 (m, 3H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 483 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH:13][OH:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N:19]=[C:20]=[O:21])(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([N:13]([OH:14])[C:20]([NH2:19])=[O:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ON[C@H]1CC[C@@H](c2cccc(F)c2)C1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)N(O)[C@H]1CC[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a stirred solution of the compound prepared in Step 6, above (2.4 g, 12 mmol), in THF (10 ml) was added trimethylsilylisocyanate (85%, 2.4 ml, 18 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. Methanol (10 ml) was added and 10 minutes later the solvent was removed under reduced pressure to afford a white solid. Recrystallization from IPE/hexane afforded the title compound (1.6 g, 57% yield) as a colorless solid, m.p. 104.2-105.7° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:15]=[C:14]([N:16]([CH:23]=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([CH2:25][CH3:26])[C:11]=1[NH:27][C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=S)[CH3:9].[I-].ClC1C=CC=C[N+]=1C>C(#N)C>[CH2:8]([C:10]1[CH:15]=[C:14]([N:16]([CH:23]=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([CH2:25][CH3:26])[C:11]=1[N:27]=[C:28]=[N:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH3:9]
Reactant: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1N=C=NC(C)(C)C

Procedure:
With stirring, 3.2 g of triethylamine are added dropwise at room temperature to 6.0 g of N-[2,6-diethyl-4-(N-formylanilino)phenyl]-N'-tert-butylthiourea and 4.8 g of 2-chloro-1-methylpyridinium iodide in 30 ml of acetonitrile. The reaction mixture is stirred for 1 hour at 70° C. and then concentrated by evaporation at 50° C. on a rotary evaporator. The residue is taken up in 50 ml of hexane and 30 ml of cold water. The hexane phase is separated, washed with water, dried over sodium sulfate and concentrated by evaporation, to give the title compound of formula ##STR21## as a yellowish oil with refractive index nD25 : 1.5840.