Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:9][C:10]1[C:11]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[C:12]([NH2:15])[NH:13][N:14]=1>C(O)(=O)C>[CH3:9][C:10]1[C:11]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[C:12]2[NH:15][C:3]([CH3:5])=[CH:2][C:1](=[O:7])[N:13]2[N:14]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2c(C)nn3c(=O)cc(C)[nH]c23)c(C)c1
Yield: 65.5 %

Procedure:
Methyl acetoacetate (0.38 ml) was added to a solution of 5-methyl-4-(2,4,6-trimethyl-phenyl)-2H-pyrazol-3-ylamine (641 mg, 2.98 mmol) in 4 ml of acetic acid. The reaction mixture was heated at reflux for overnight. The mixture was concentrated to dryness and the residue was purified through silica gel column chromatography using 5% methanol in chloroform as eluent to give 560 mg (65.5%) of the title compound as a white solid;
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[S:20][C:19]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[Cl:21])[CH:13]=1)=[O:11].[CH2:22](I)[CH3:23]>CN(C=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:5]3[CH2:4][O:3][CH2:22][CH3:23])=[O:11])[S:20][C:19]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC[C@@H]1CO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC[C@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
NaH (80 mg, 2 mmol) was added to a solution of (2R)-(2-hydroxymethyl-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone (297 mg, 1 mmol) in DMF (5 mL), at 0° C. The reaction mixture was allowed to stir for 20 min, and EtI (234 mg, 1.5 mmol) was added dropwise. After 3 h the reaction was quenched with saturated aqueous KCN (10 mL). The aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 94:6) afforded the title compound as a white solid (145 mg, 50%). MS: 326 (MH+); HPLC Rf: 5.11 min; HPLC purity: 97%.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].O[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[I:15])[CH:10]=[O:11].C(=O)([O-])[O-:17].[K+].[K+]>C(C(C)=O)C>[CH3:2][CH2:3][CH:4]([O:11][C:10](=[O:17])[C:9]1[CH:12]=[CH:13][C:14]([I:15])=[CH:7][CH:8]=1)[CH3:5]
Reactant: CCCCI
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(I)c(O)c1
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(C)OC(=O)c1ccc(I)cc1
Temperature: 85 °C

Procedure:
21.5 ml (189 mmol) of 1-iodobutane are added to a solution of 31 g (126 mmol) of 3-hydroxy-4-iodobenzaldehyde in 350 ml of methyl ethyl ketone in the presence of 52.2 g (378 mmol) of potassium carbonate. The reaction medium is heated at 85° C. for 2 hours. The solid is filtered off and the solvent is evaporated off. The solid obtained is washed with heptane and 38 g (99%) of 3-butoxy-4-iodobenzaldehyde are obtained in the form of white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:19][C:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[ClH:12].[C:20]12([NH:19][CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Clc1ccc(SCCCBr)c(-c2ccccc2)c1
Product: Cl
Product: Clc1ccc(SCCCNC23CC4CC(CC(C4)C2)C3)c(-c2ccccc2)c1

Procedure:
A mixture of 15 g. of 2-(3-bromopropylthio)-5-chlorobiphenyl and an excess of 1-aminoadamantane was heated in an oil bath at about 120° C. for about 4 hours. The reaction mixture was worked up and the product was isolated as the hydrochloride acid addition salt in the manner described in previous examples. The product had a melting point of about 304°-305° C., and was identified as N-adamantyl-3-(5-chloro-2-biphenylylthio)propylamine hydrochloride.
Reaction SMILES: O=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17]C)=O)=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(O)(=O)C.O.[NH2:24][NH2:25]>CO>[CH2:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[C:15](=[O:17])[NH:24][N:25]=[C:2]([C:14]=2[C:13]=34)[CH2:3][CH2:4]1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A solution of compound methyl 4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate (73 mg, 0.3 mmol), acetic acid (0.15 mL, 2.6 mmol), and hydrazine hydrate (0.86 mL, 1.5 mmol) in methanol (4 mL) was heated at reflux. After 8 h, the solid was collected by hot filtration and washed with water, EtOAc, and dichloromethane, to give the target compound (42 mg, 62%). 1H NMR (DMSO-d6) δ 11.70 (s, 1H), 9.79 (s, 1H), 7.36-7.38 (m, 2H), 7.05 (t, 1H, J=7.8 Hz), 2.77-2.79 (m, 2H), 2.35-2.37 (m, 2H), and 1.92-1.93 (m, 2H). MS (ESI) m/e [M+1]+ 226.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33].CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([CH2:2][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.8 %

Procedure:
To a mixture of 4-[2-(4-chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (0.85 g), methyl 2-(2-hydroxyphenyl)acetate (0.40 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.11 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]acetate as an oil (0.57 g, 57%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][SiH:4]([CH3:10])[O:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[CH2:13]([OH:17])[CH2:14][CH:15]=[CH2:16]>>[CH3:10][Si:4]([CH2:16][CH2:15][CH2:14][CH2:13][OH:17])([O:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[O:3][Si:2]([CH3:11])([CH3:12])[CH3:1]
Reactant: C[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C=CCCO
Product: C[Si](C)(C)O[Si](C)(CCCCO)O[Si](C)(C)C
Yield: 83 %

Procedure:
The reaction of Example 2a was repeated using 1,1,1,3,5,5,5-heptamethyl trisiloxane instead of 1,1,3,3,3-pentamethyl disiloxane and 3-butenol instead of allylalcohol. After distillation at 78° C./0.1×102 Pa, 83% of a clear liquid product was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([S:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:4]2[N:3]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:14][CH:15]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cn1cnc2c(Sc3ccc(Cl)cc3)nc(Cl)nc21
Product: Cc1cc(C)n(-c2nc(Sc3ccc(Cl)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 6 from 2-chloro-6-(4-chloro-phenylsulfanyl)-9-methyl-9H-purine and 3,5-dimethylpyrazole.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](/[C:19](/[CH3:30])=[CH:20]\[C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.[Hg]>[C:1]12([C:11]3[CH:12]=[C:13](/[C:19](/[CH3:30])=[CH:20]/[C:21]4[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(/C(C)=C\c2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Hg]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(/C(C)=C/c2ccc(C(=O)OCc3ccccc3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 21.9 %

Procedure:
2 g (5 mmol) of 4-[(Z)-2-(3-(1-adamantyl)-4-methoxyphenyl)propenyl]benzoic acid obtained in Example 23(c) in 900 ml of THF are irradiated under UV by means of a HANOVIA mercury lamp (550 W) for 10 h at room temperature, to give a 1/1 mixture of E and Z isomers. After evaporation of the THF, this mixture is treated with 190 mg (6 mmol) of 80% NaH in oil and 0.83 ml (7 mmol) of benzyl bromide. After the same treatment as in Example 1(a), followed by a recrystallization from hexane, 0.54 g of benzyl 4-[(E)-2-(3-(1-adamantyl)-4-methoxyphenyl)propenyl]benzoate is isolated which melts at 230°-240° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]#[C:10][C:11]2[C:17]([C:18]#[C:19][C:20]3[C:25]([F:26])=[C:24]([F:27])[N:23]=[C:22]([F:28])[C:21]=3[F:29])=[CH:16][CH:15]=[CH:14][C:12]=2[NH2:13])[C:5]([F:30])=[C:4]([F:31])[N:3]=1.P(Cl)(Cl)([Cl:34])=O.[NH2:37][C@H:38]([C:44](O)=[O:45])[CH2:39][CH2:40][CH2:41][CH2:42][NH2:43].[ClH:47]>N1C=CC=CC=1.C1COCC1>[ClH:34].[ClH:47].[NH2:37][CH:38]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[C:44]([NH:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:17]([C:18]#[C:19][C:20]2[C:25]([F:26])=[C:24]([F:27])[N:23]=[C:22]([F:28])[C:21]=2[F:29])[C:11]=1[C:10]#[C:9][C:6]1[C:5]([F:30])=[C:4]([F:31])[N:3]=[C:2]([F:1])[C:7]=1[F:8])=[O:45]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1C#Cc1c(F)c(F)nc(F)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NCCCCC(N)C(=O)Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1C#Cc1c(F)c(F)nc(F)c1F
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
L-Boc-Lys(Boc)-OH (0.31 g, 0.91 mmol) and compound (19) (0.20 g, 0.46 mmol) were dissolved in 2 mL of pyridine. The solution was cooled to −25° C. and phosphorus oxychloride (0.14 g, 0.91 mmol) was added dropwise with vigorous stirring. After stirring for 30 min. at -25° C., the reaction mixture was stirred at room temperature for 10 h. The reaction mixture was quenched with ice/water and extracted with EtOAc. The organic layer was washed with sat. NaHSO4 three times, dried with Na2SO4 and was concentrated in vacuo. The crude product was subjected to chromatography with CH3CN:CH2Cl2=1:40 and the Boc-protected product was obtained in 26% yield. Into the solution of the Boc-protected lysine conjugate (85 mg, 0.11 mmol) in THF was gaseous HCl bubbled at 0° C. for 1 hr and the solution was stirred for 1 hour at room temperature. The solvent was evaporated and the desired product (46 mg, 65%) was purified by recrystallization with EtOH: 1H-NMR (300 MHz, CD3OD) δ 8.07 (dd, J=6.3 Hz, J=3.0 Hz, 1H), 7.69 (m, 2H), 4.26 (dd, J=7.5 Hz, J=5.4 Hz, 1H), 2.98 (t, J=H7.2 Hz, 2H), 2.01-2.21 (m, 2H), 1.75-1.81 (m, 2H), 1.60-1.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][C:4]=1[S:17]([Cl:16])(=[O:19])=[O:18]
Reactant: COc1ccc(C(=O)O)c2c1OCCO2
Reactant: O=S(=O)(O)Cl
Product: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1OCCO2
Temperature: 25 °C
Yield: 98 %

Procedure:
1045 cm3 of chlorosulfonic acid were introduced into a balloon flask provided with an agitator, a thermometer and a condenser and then, in portions, 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were added with the temperature being maintained at from 5°-10° C. The mixture was agitated at ambient temperature and then poured on ice. The precipitate was dried off, washed and dried. 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained (yield: 98%).
Reaction SMILES: O.NN.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:22])[C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([N+:19]([O-])=O)=[CH:13][CH:12]=2)=[O:8])[CH3:5]>CO.C1(C)C=CC=CC=1.[Ni]>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:22])[C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=2)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(Cl)c2cc([N+](=O)[O-])ccc2n1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(Cl)c2cc(N)ccc2n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.3 %

Procedure:
To a refluxing mixture of hydrazine hydrate (10.8 ml, 222 mmol) and Raney Ni (6 g) in MeOH (200 mL) was slowly added the product of step (b) (12.6 g), and the refluxing was continued for 6 hours. After cooling to room temperature, the Raney Ni was removed by filtration through Celite, and the solvent was removed in vacuo to give the crude product. The residue was dissolved in toluene (100 mL), and concentrated in vacuo. The residue was again dissolved in toluene (100 mL), and concentrated in vacuo, the residue was suspended in diethyl ether, and the product was collected by filtration to afford 11.3 g of the title compound.
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[CH3:4][C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2][CH2:1][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCCC(C)=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of 2.47 g of the above farnesyl bromide in 20 ml of dry dimethyformamide (DMF) at room temperature under argon was treated with 1.83 g (9.9 mmol, 1.1 eq.) of potassium phthalimide and stirred for 3 hours at room temperature. The solvent was removed under reduced pressure, the residue was triturated with 150 ml of ethyl ether, and the precipitate was filtered off. The ethereal solution was washed with 50 ml of H2O and 50 ml of brine, dried over MgSO4 and evaporated to yield 2.96 g of crude title compound as a milky oil. Purification by flash chromatography on 300 g of Merck 9385 silica, eluted with 7:93 ethyl acetate:petroleum ether afforded 2.56 g (81%) of the desired product as a colorless oil.
Reaction SMILES: CN(C)C=O.[CH:6]([O:9][N:10]=[C:11]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](O)[CH:13]=1)([CH3:8])[CH3:7].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26].[C:29](=O)([O-])[O-].[K+].[K+]>O>[CH:6]([O:9][N:10]=[C:11]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:29][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:13]=1)([CH3:8])[CH3:7]
Reactant: CC(C)ON=C(c1cccc(O)c1)n1cncn1
Reactant: CC(C)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCc1cccc(C(=NOC(C)C)n2cncn2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To 100 ml of N,N-dimethylformamide was added 1.2 g (4.9 mmol) of 1-(O-isopropyl-3-hydroxybenzohydroximoyl)-1H-1,2,4-triazole, 0.7 g (5.1 mmol) of isobutyl bromide, and 0.8 g (5.8 mmol) of potassium carbonate. The mixture was stirred for 1 hour at 80° C. to complete the reaction. The reaction mixture was allowed to sit and cool naturally. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent in the organic layer was then removed under reduced pressure. The residue was purified by column chromatography, thus obtaining 1.1 g (yield: 73%) of the desired produce having a refractive index of [nD20 ] 1.5341 at 20° C.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23]>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C1COCC(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Yield: 50.5 %

Procedure:
A mixture of tetrahydropyran-3,5-dione (Terasawa, J. Org. Chem. (1977), 42, 1163-1169) (1.4 g, 12 mmol), 3-bromo-4-fluorobenzaldehyde (3.0 g, 15 mmol), methyl 3-aminocrotonate (1.4 g, 12 mmol) and ethyl alcohol (10 mL) was processed as described in Example 2A. Purification by flash chromatography over silica gel (1% then 2% and then 5% methyl alcohol/methylene chloride) provided the title compound (2.4 g) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1(C)C=CC(S(O[CH2:21][CH2:22][Cl:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1cccc(OCCCl)c1
Yield: 70.6 %

Procedure:
To a solution of 3-hydroxybenzamide (21.6 g) in methyl ethyl ketone ("MEK") was added 2-chloroethyl p-toluenesulphonate (55.46 g) and potassium carbonate (16.0 g). After starting at reflux for 6 hours, the resultant mixture was poured onto water and a colourless solid filtered off. Crystallisation from ethanol gave the title compound, (22.2 g), m.p. 125°-126°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#N)[CH:3]=1.[OH-:18].[Na+].CC[OH:22]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]([OH:22])=[O:18])[CH:3]=1
Reactant: CCO
Reactant: CC(C)(C#N)c1cc(N)n(-c2ccccc2)n1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C(=O)O)c1cc(N)n(-c2ccccc2)n1
Yield: 39 %

Procedure:
A solution of 2-(5-amino-1-phenyl-1 H-pyrazol-3-yl)-2-methyl-propionitrile (1.0 g, 7.4 mmol) and aq NaOH (2 M, 11 mL, 22 mmol) in EtOH (10 mL) was heated to 70° C. for 12 h. The reaction mixture was partitioned between ether and water and the aqueous solution was acidified with HCl to pH 4-5. The aqueous was extracted with EtOAc (3×50 mL) and the extracts were concentrated in vacuo to give crude 2-(5-amino-1-phenyl-1 H-pyrazol-3-yl)-2-methylpropanoic acid (0.7 g, 39% yield) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.ClC(Cl)(Cl)[C:37]([N:39]=C=O)=[O:38]>N1C=CC=CC=1.CO>[C:37]([N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:34])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:30]1)(=[O:38])[NH2:39]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(N)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (240 mg, 0.52 mmol), (prepared as described for the starting material in Example 15), was dissolved in pyridine (5 ml) and cooled to 0° C. Trichloroacetyl isocyanate (61 μl, 0.52 mmol) was added and the mixture stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at 45° C. for 2.5 hours. Aqueous ammonia (1 ml) was added and the mixture was stirred at 60° C. for 1.5 hours and then at ambient temperature overnight. The solvent was removed under reduced pressure. Column chromatography of the residue using methylne chloride/methanol (90/10) followed by methylene chloride/methanol (saturated with ammonia) (90/10) gave a solid which was suspended in methanol and filtered to give 7-(3-[4-carbamoylpiperazin-1-yl]propoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (120 mg, 46%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@H:8]([NH:12][C:13](=[O:22])[C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:25]([CH2:24][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@H:8]([NH:12][C:13](=[O:22])[C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC(=O)[C@H](O)c1ccccc1)CC2
Reaction time: 5 h
Yield: 57 %

Procedure:
A mixture of 15.8 g of N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, obtained according to Example 3(b), 7.1 ml of ethyl bromoacetate, 22 g of anhydrous potassium carbonate and 1 g of potassium iodide in 600 ml of anhydrous acetone, is heated with reflux and with stirring for 5 hours and a half. The reaction mixture is filtered, evaporated to dryness and the oil which separates is left to crystallize. The solid so obtained is purified by flash-chromatography (elution with a 1/1 mixture of ethyl acetate/cyclohexane). The solid on the column is taken up and treated with 20 ml of ethyl ether, filtered and crystallized from ethyl acetate to give 11.5 g of N-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, SR 58638; m.p. 115°-117° C.; [alpha]=-98.3° (methanol, c=1%). Yield: 57%.
Reaction SMILES: [O:1]=[C:2]([CH3:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=[C:7]2[CH:6]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[O:1]=[C:2]([CH3:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=[C:7]2[CH:6]=1
Reactant: CCOC(=O)c1cnc2cc(CCC(C)=O)ccn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)CCc1ccn2c(C(=O)O)cnc2c1
Temperature: 60 °C

Procedure:
A stirring mixture of ethyl 7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylate (85) (90 mg, 0.346 mmol) and 2N LiOH (0.5 mL) in THF:MeOH (4:1, 3 mL) was heated at 60° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially concentrated and the crude product was purified by reverse phase preparative HPLC to yield 7-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (86). MS m/z 233.08 (M+1)+.