Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].Cl[C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1>>[OH:11][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH3:9])[CH3:10])=[C:2]([NH:1][C:13]2[N:18]=[C:17]([NH:1][C:2]3[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=3[CH:8]([CH3:10])[CH3:9])[C:16]([F:20])=[CH:15][N:14]=2)[CH:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)c1ccc(O)cc1N
Product: CC(C)c1ccc(O)cc1Nc1ncc(F)c(Nc2cc(O)ccc2C(C)C)n1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 3-amino-4-isopropylphenol and 2,4-dichloro-5-fluoropyrimidine were reacted to produce N2,N4-bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.93 (d, 1H, J=3.5 Hz), 7.79 (br s, 1H), 7.64 (br s, 1H), 7.13 (d, 1H, J=8.7 Hz), 7.06 (d, 1H, J=2.3 Hz), 7.05 (d, 1H, J=8.7 Hz), 6.89 (d, 1H, J=2.3 Hz), 6.66 (d, 1H, J=2.3 and 8.7 Hz), 6.57 (d, 1H, J=2.3 and 8.7 Hz), 2.96 (m, 2H), 1.25 (d, 6H, J=7.0 Hz), 1.13 (dd, 6H, J=7.0 Hz); LCMS: ret. time: 24.27 min.; purity: 97%; MS (m/e): 397 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1.C([O-])(=O)C.[NH4+]>O>[CH2:1]([O:8][C:9]1[C:10]2=[N:15][C:22]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[CH:23][C:24](=[O:25])[N:11]2[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=c1cc(-c2ccncc2)nc2c(OCc3ccccc3)cccn12
Temperature: 150 °C
Yield: 19 %

Procedure:
To a mixture of 5.02 mmol) of 3-(benzyloxy)pyridin-2-amine and 1.16 g (6.02 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added 0.774 (10.04 mmol) of ammonium acetate. The reaction mixture was heated at 150° C. for 12 hours. After cooling, water was added and the mixture was extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and evaporated. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol n the proportions 99/1 to 90/10 to give 0.32 g (19%) of the desired compound which was transformed into the hydrochloride salt in the usual manner to give the pure product as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][C:16]1([OH:23])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=O)C.O.[OH-].[Li+].Cl>O>[OH:23][C:16]1([CH2:15][N:14]2[CH2:13][CH2:12][C:7]3[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=3[C:4]2=[O:3])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCC1(O)CCN(C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Temperature: 135 °C
Yield: 232.4 %

Procedure:
A stirred mixture of 2-{2-[(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-amino]-ethyl}-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.931 g, 18.36 mmol) in glycol (257 ml) was added with lithium hydroxide monohydrate (6.169 g, 147 mmol). The resulting mixture was heated to 135° C. for 4 hours. The mixture was added with cold water (250 ml), adjusted to pH from 14 to 12 with 2N hydrochloric acid in an ice-water bath. The mixture was extracted with a 10 to 1 solvent mixture of dichloromethane and methanol (200 ml×8). The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel column chromatography with dichloromethane:methanol:ammonia (600:45:2) as eluents to give 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (11.837 g) as a light brown oil which was used as such.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7]I)(=[O:3])[CH3:2].Cl.[CH3:31][NH:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][N:32]([CH3:33])[CH3:31])(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N(CCCI)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.6 %

Procedure:
7.16 g (13.9 mmol) of the above 2-[4-[N-acetyl-N-(3-iodopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 150 mL of dimethylformamide under argon atmosphere, 5.68 g (69.5 mmol) of dimethylamine hydrochloride and 9.61 g (69.5 mmol) of potassium carbonate were added and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-6:1-chloroform:methanol:aqueous ammonia=9:1:1) to give 4.13 g of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one (yield: 69%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=O.COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[C:36](=[O:37])[N:38]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)COc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)COc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-isobutoxy-quinoline-3-carbonitrile (example 66b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutoxy-quinoline-3-carbonitrile. LC-MS m/e 353 (MH+).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[C:8]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:2])=[C:8]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:7]=1
Reactant: COc1cc(OC)cc(Oc2cc(Br)ccc2CO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cc(OC)cc(Oc2cc(Br)ccc2CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 224.1 %

Procedure:
In an argon atmosphere, 4.7 mL (F.W. 270.70, d=2.850, 49.5 mmol) of phosphorus tribromide was added to a solution of 46 g (F.W. 339.19, 135 mmol) of alcohol (23) in 100 mL of methylene chloride at 0° C. and stirred at room temperature for 30 minutes. To the reaction mixture was added ice water and the resulting solution was further stirred at room temperature for 30 minutes. The obtained solution was extracted with ethyl acetate and the extract was washed with water and then with a saturated sodium chloride aqueous solution. The resulting extract was dried with anhydrous magnesium sulfate and then, concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:5) to obtain 44.6 g (84%) of a bromide (24). (TLC; ethyl acetate:hexane=1:4).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-:39]>COCCOC>[C:1]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:39])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
Analogously to Example 1 i), 2.4 g (4.728 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-3(R)-(4-benzyloxybenzyl)-dihydrofuran-2-(3H)-one in 10 ml of 1,2-di-methoxyethane are reacted with 9.45 ml of 1M LiOH solution to yield the title compound, which is purified by crystallisation from hexane. TLC Rf (E)=0.33; tRet (IV)=18 min; FAB-MS (M+H+)=526.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[CH3:35].Cl.[C:37]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:45][CH2:44][CH2:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:46])=[O:32])=[CH:28][C:27]=1[CH3:35]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CC(C)(C)OC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCC(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C

Procedure:
Solid HATU (2.1 g, 5.6 mmol) was added to a DMF solution (25 mL) of 4-bromo-3-methylbenzoic acid (1.0 g, 4.7 mmol), i-Pr2Net (2.4 mL, 14.0 mmol), and β-alanine tert-butyl ester hydrochloride (845 mg, 4.7 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated, diluted with EtOAc, washed with water, 1N KHSO4, water, saturated aqueous NaHCO3, and brine. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22](OS(C)(=O)=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.32 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 16.86 ml of 4-methoxybenzyl mercaptan dissolved in 200 ml of dry dimethylformamide, and the mixture was then stirred at room temperature for 30 minutes. At the end of this time, a solution of 31.00 g of (3R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine [prepared as described in step (1) above] in 50 ml of dry dimethylformamide was added to the reaction mixture. The mixture was then stirred for 30 minutes whilst ice-cooling, after which it was allowed to stand overnight at room temperature. It was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of hexane and ethyl acetate), to afford 28.00 g of the title compound a pale-brown oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C:18]2[C:13](=[CH:14][C:15]([C:32]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:16][CH:17]=2)[N:12]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]2[C:18]3[C:13](=[CH:14][C:15]([C:32]4[C:37]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:16][CH:17]=3)[N:12]=[C:11]([CH2:10][N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])[N:20]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@@H]1CCCN1Cc1nc(Nc2ccc(C(C)(C)C)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(Nc2nc(CN3CCC[C@H]3C(=O)O)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-1-[4-(4-tert-butyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-pyrrolidine-2-carboxylic acid methyl ester (140 mg, 0.248 mmol) in THF (20 ml) and H2O (20 ml), add LiOH (18 mg, 0.745 mmol). Stir the mixture for 2 hours at 50° C. Concentrate, add water, extract with ether, acidify the aqueous layer to pH 6-7, extract with EtOAc, and concentrate to give (S)-1-[4-(4-tert-butyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-pyrrolidine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21](O)=[O:22])[C:16]=1[CH3:24].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:55][O:56][C:57](=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>[Cl-].[Na+].O.CN(C=O)C>[CH3:55][O:56][C:57](=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:14]=[N:13][N:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:19][C:18]=1[CH3:20])=[O:22]
Reactant: COC(=O)CCCCCCCN
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (328 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 8-aminocaprylic acid methyl ester hydrochloride (251 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (287 mg, 63% yield) as a red solid. LC-MS (m/z) 484 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13].CC1C(/C=C/C(C)=O)C(C)(C)CCC1>>[CH3:8][C:4]1([CH3:9])[CH:3]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[C:2](=[CH2:1])[CH:7]=[CH:6][CH2:5]1
Reactant: CC(=O)CCC1=C(C)C=CCC1(C)C
Agent: CC(=O)/C=C/C1C(C)CCCC1(C)C
Product: C=C1C=CCC(C)(C)C1CCC(C)=O

Procedure:
4-(2,6,6-TRIMETHYL-1,3-CYCLOHEXADIEN-1-YL)-2-BUTANONE HAVING THE STRUCTURE: ##STR2## may be synthesized according to the technique of Wolf and Zink, Volume 56, Helvetica Chimica Acta., Fasc 3 (1973) pp. 1062-1066, or according to Examples I and II of Rowland, U.S. Pat. No. 3,436,421 issued on Apr. 1, 1969 by means of bromination of -dihydroionone followed by debromination. 4-(6,6-dimethyl-2-methylene-3-cyclohexen-1-yl)-2-butanone having the structure: ##STR3## is also produced in this process as a bi-product thereof (B.P. 65° C at 0.15 mm Hg. pressure). 4-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)-2-butanone is also shown to be a bi-product in the cyclization of ionone to beta ionone by Kruk and De Boer in Volume 87 Recueil (1968) pp. 641-654 as an intermediate in preparing other perfumery compounds. The compound having the structure: ##STR4## is disclosed in Japanese Patent No. 7121,015 (Sakan and Isoe)issued June 14, 1971.
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:22]1[CH2:32][CH:23]1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(O)C.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl>[O:25]([CH2:24][CH:23]([OH:22])[CH2:32][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Reactant: c1ccc(OCC2CO2)cc1
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: OC(COc1ccccc1)CN1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1
Yield: 15 %

Procedure:
A mixture of 2.6 g (0.0093 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47), 1.4 g (0.0093 moles) of 2,3-epoxypropoxybenzene and 25.0 ml of 2-propanol was heated at reflux for 5 hours. The reaction mixture was evaporated in vacuo and gave a solid. The solid was dissolved in dichloromethane and passed through a pad of magnesium silicate. The effluent was evaporated to a solid. The solid was recrystallized from ethanol/ether/hexane, filtered, and washed with ether and gave 600 mg of the product of the Example as yellow crystals, mp 143°-145° C.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH:3](C)C.[N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.C(=O)CC(C)C>>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:1][CH2:2][CH3:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: CC(C)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: CC(C)CC=O
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: CCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
Following the general procedure described above for the synthesis of 1-isopentyl-4-(4-nitrophenyl)piperazine, treatment of 1-(4-nitrophenyl)piperazine (5.00 g, 24.1 mmol, 1.0 eq) with isovaleraldehyde (4.16 g, 5.18 mL, 48.3 mmol, 3 eq) at RT for 48 h provided the title compound as a yellow solid (5.34 g, 89% recovery, 93% purity as determined by LC/MS analysis @ UV 254 nm detection). In this case, upon addition of hexane (25 mL) to the crude residue, obtained from evaporation of the DCM extract, and stirring for 24 h the product precipitated from solution, was collected by filtration, washed with hexanes (2×25 ml), and was dried under vacuum. The crude product is used in the next step without further purification. LCMS-ESI (m/z): calcd for C13H19N3O2, 249; [M+H]+ found, 250.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:30](=[O:31])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: NCCO
Product: O=C(COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)NCCO
Yield: 85.2 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with ethanolamine (0.333 ml, 5.5 mmol) to give the title compound as a white solid (220 mg, 85%), except that the reaction was run at 45° C. for 2 days. NMR Spectrum 3.30 (m, 2H), 3.49 (m, 2H), 4.79 (m, 1H), 4.89 (s, 2H), 5.77 (s, 2H), 6.96 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.77-7.69 (m, 3H), 7.84 (m, 1H), 8.16 (s, 1H), 8.42 (br t, 1H), 8.57-8.53 (m, 3H), 10.87 (br s, 1H); Mass spectrum MH+ 470.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=O)=O.[CH2:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)[CH3:22]>>[CH:24]1([N:23]([CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25]1
Reactant: CCNC1CC1
Reactant: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Product: CCN(CCCCNC(=O)OCc1ccccc1)C1CC1

Procedure:
Following the general procedure of Example 4, Step 2, and making non-critical variations but using 4-(benzyloxycarbonylamino)butyl methanesulfonate and commercially available N-ethylcyclopropanamine, benzyl 4-(cyclopropyl(ethyl)amino)butylcarbamate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[CH:29])[CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C>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.[Cu]I.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:29]#[C:28][CH2:27][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[S:18][C:11]=12)[NH2:5]
Reactant: C#CCN1CCN(C)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 60 °C
Yield: 84.1 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200 mg, 0.477 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (Example 17, Step A, 205.8 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium (0) (55.1 mg, 0.0477 mmol), copper(I) iodide (9.074 mg, 0.0477 mmol), N-ethyl-N-isopropylpropan-2-amine (2.49 ml, 14.3 mmol) and THF (25 mL). The reaction mixture was stirred at 60° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.159 g, 84.2%). LRMS (APCI pos): m/e 397 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, 1H), 7.58 (s, 1H), 7.01 (t, 1H), 6.43-6.58 (m, 3H), 3.90 (br s, 2H), 3.61 (s, 2H), 2.48-2.83 (m, 8H), 2.38 (s, 3H).