Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH2:10][NH2:11])[CH2:4][CH:3]=1.S(=O)(=O)(O)O.C#[N:19]>>[NH2:19][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]([CH:8]([CH2:9][CH2:10][NH2:11])[CH3:12])[CH2:4][CH2:3]1
Reactant: C#N
Reactant: CC1=CCC(C(C)CCN)CC1
Agent: O=S(=O)(O)O
Product: CC(CCN)C1CCC(C)(N)CC1
Temperature: 45 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
660 g of this amine were added dropwise to 1200 g of 70% sulphuric acid at 5 to 10° C. 170 ml of hydrocyanic acid were then added dropwise at 30 to 35° C., the mixture was stirred for a further 4 hours at 45° C. and the excess hydrocyanic acid was distilled off under vacuum. 300 ml of water were then added and the mixture was heated for 3 hours to reflux, rendered alkaline with 1400 ml of 45% sodium hydroxide solution and decanted from the precipitated salt. The phases were separated, the salts and the aqueous phase were extracted twice with toluene and the mixture was distilled under vacuum. 656 g (90%) of 1-amino-1-methyl-4-(4-aminobut-2-yl)cyclohexane, b.p.10 135 to 137° C. were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH2:13].CN1CCOCC1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br.C(O)(=O)C>C(COC)OC.CCOCC.CCCCCC.[Hg]>[NH2:13][C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:11])([F:12])[F:10])=[CH:8][C:3]=1[CH2:2][NH:1][CH2:26][C:25]1[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: NCc1cc(C(F)(F)F)ccc1N
Agent: [Hg]
Solvent: COCCOC
Solvent: CCOCC
Solvent: CCCCCC
Product: Nc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 24 %

Procedure:
In a 500-mL flask equipped with a septum inlet, magnetic stirring bar, and condenser leading to a mercury bubbler was placed 22.8 g (0.12 mol) of [2-(aminomethyl)-4-(trifluoromethyl)phenyl]amine in 218 mL dimethoxyethane. To this reaction flask with stirring was added 26 mL (0.24 mol) N-methylmorpholine and 24 mL (0.13 mol) 3,5-bis(trifluoromethyl)benzyl bromide. The contents were heated to and maintained at reflux under nitrogen for 12 hours. Afterwards, TLC analysis revealed a minor amount of starting material remaining. The contents were cooled to room temperature, diluted with ether and transferred to a separatory funnel and washed with water and brine, dried over magnesium sulfate, filtered and concentrated to afford an oil. The oil was dissolved in hexane, cooled in an ice bath and acetic acid was added slowly while stirring to precipitate solids. The solids were filtered, dissolved in ether, and cooled in an ice bath and stirred while saturated sodium bicarbonate was added slowly until basic. The contents were transferred to a separatory funnel and washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 12 g [2-amino-5-(trifluoromethyl)benzyl][3,5-bis(trifluoromethyl)benzyl]amine as an orange oil. In addition the hexane mother liquor contained significant amounts of product and byproducts. This liquor was concentrated to yield dark yellow oil that was used without further purification in the following step.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:27])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)(=O)C>[CH2:20]([N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[N:19]=2)[C:14](=[O:27])[C:15]([C:22]([OH:24])=[O:23])=[CH:16]1)[CH3:21]
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(C)=O)CC3)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CCNCC3)nc21
Temperature: 95 °C
Yield: 77 %

Procedure:
To 1.6 g of ethyl 7-(4-acetyl-1-piperazinyl)-1,4-dihydro-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylate was added 15 ml of a 10% aqueous solution of sodium hydroxide. The mixture was heated at 95° C for 1.5 hours, and neutralized, under cooling, with acetic acid to give a precipitate which was collected and recrystallized from water to yield 1.0 g of the product as colorless needles, m.p. 272° - 273° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.O>O1CCCC1.C(OCC)(=O)C>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:8]1
Reactant: c1ccc(C2CC2)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3(c4ccccc4)CC3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 13.4 %

Procedure:
A solution of 2.4 grams of phenylcyclopropane in 20 ml of tetrahydrofuran was added with 20 ml of 1M lithium diisopropylamide in tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for 30 minutes and room temperature for 20 minutes. This was then added with 3.0 grams of 4-chloro-6,7-dimethoxyquinazoline in 20 ml of tetrahydrofuran. The mixture was then stirred at room temperature overnight, poured into a mixture of cold water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was then purified on a silica gel column with dichloromethane and methanol as the solvent to provided 550 mg of 6,7-dimethoxy-4-(1phenylcyclopropyl)-quinazoline.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:22])[CH:8]=2)[N:3]=1.Cl.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:36][CH:35]=1)[CH:11]=[C:10]2[C:12]([NH:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13]
Reactant: O=C(NCCN1CCCC1)c1cc(Cl)nc2ccc(F)cc12
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCN1CCCC1)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2ccc(F)cc12
Reaction time: 0.5 h

Procedure:
In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4-(morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130° C. under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHCO3 saturated aqueous solution (2×100 ml). The organic layer was separated, dried over MgSO4 and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10% B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60-200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50° C. for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([CH2:6][CH:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][NH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CCC(C(=O)N2CCCC2)NC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC(CN2CCCC2)NC1
Yield: 81.2 %

Procedure:
By reducing 3.3 g (15.69 mmoles) of 2-(pyrrolidin-1-yl)carbonyl-5,5-dimethyl piperidine with 0.89 g (23.5 mmoles) of LiAlH4 in 80 ml of dry THF, using an alkaline work-up, 2.5 g of the title compound were obtained. The compound was sufficiently pure for the following step.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[OH:17])[C:12]#[N:13])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[S:25][C:24]=2[CH:32]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([OH:17])=[C:9]([CH:10]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:28]([C:26]2[S:25][C:24]3[CH:32]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[CH:27]=2)(=[O:30])=[O:29])[C:4]1=[O:18])#[N:13]
Reactant: N#Cc1ccc(O)c(CN2CCC(N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: N#Cc1ccc(O)c(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)cc4s3)C2=O)c1

Procedure:
The title compound is prepared from 3-[(3-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-hydroxy-benzonitrile hydrochloride as described in EXAMPLE 17, Part G substituting 6-chlorobenzo[b]thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].O.[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33]/[C:34](/[CH3:50])=[CH:35]/[CH2:36][C:37]1[C:42]([CH3:43])=[C:41]([O:44]C)[C:40]([CH3:46])=[C:39]([CH3:47])[C:38]=1[O:48]C.CCOC(C)=O>C(C#N)(C)=O.O>[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33]/[C:34](/[CH3:50])=[CH:35]/[CH2:36][C:37]1[C:38](=[O:48])[C:39]([CH3:47])=[C:40]([CH3:46])[C:41](=[O:44])[C:42]=1[CH3:43]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCCl)c1C
Agent: CC(=O)C#N
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C)C(=O)C(C/C=C(\C)CCCCCl)=C(C)C1=O
Temperature: 0 °C
Yield: 19 %

Procedure:
CAN (709 mg, 1.29 mmol) was dissolved into AcCN (7 mL) and water (3 mL) then cooled to 0° C. In a separate flask, (E)-1-(7-Chloro-3-methylhept-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (175 mg, 0.53 mmol) was dissolved into AcCN (2 mL) and 1 drop of H2O and transferred to the stirring CAN solution. Stirring was maintained for 1 h, after which time an additional charge of CAN (350 mg) was added and let stir for 1 h. Water (10 mL) and EtOAc (10 mL) were added, the layers separated and the combined organics washed H2O (2×5 mL). The combined aqueous phases were back extracted using EtOAc (2×5 mL) and the combined organics washed with brine (2×5 mL), dried over anhydrous Na2SO4 and concentrated to a yellow oil. Flash chromatography (SiO2) yielded 29.7 mg of (E)-2-(7-chloro-3-methylhept-2-enyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione as a yellow oil (18.7%). 1H NMR (400 MHz, CDCl3) δ4.95 (t, J=6.8 Hz, 1H), 3.50 (t, J=6.8 Hz, 2H), 3.19 (d, J=6.8 Hz, 2H), 2.00 (m, 11H), 1.71 (m, 5H), 1.51 (m, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=2)=[O:9])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1nn(CCc2ccccc2)cc1C(=O)O
Product: Cc1nn(CCc2ccccc2)cc1C(=O)Nc1ccc(N2CCC(N3CCOCC3)CC2)c(C#N)c1
Yield: 57.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 3-methyl-1-(2-phenylethyl)pyrazole-4-carboxylic acid (0.64 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.8 g), the title compound (0.8 g) was obtained, melting point: 188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:32])=[O:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)c1ncccc1Br
Product: CC(C)S(=O)(=O)c1ncccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 3-bromo-2-(isopropylsulfonyl)pyridine yielding 52 mg (88%) of the title compound. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 373.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.6, 1.7, 1H), 8.60 (dd, J=2.1, 1.5, 1H), 8.10 (d, J=1.5, 1H), 8.08-7.98 (m, 1H), 7.81 (dd, J=7.8, 1.6, 1H), 7.58 (dd, J=7.8, 4.6, 1H), 7.38 (dd, J=8.0, 1.8, 1H), 7.32 (dd, J=11.7, 1.7, 1H), 4.71 (s, 2H), 4.19 (hept, J=6.8, 1H), 1.31 (d, J=6.9, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Product: O=C(Cc1cccc([N+](=O)[O-])c1)NCCC(=O)OCc1ccccc1

Procedure:
coupling m-nitrophenylacetic acid and β-alanine benzyl ester to give N-[(m-nitrophenyl)acetyl]-β-alanine benzyl ester, MS: 236 (6, M--C6H5 --CH2O),
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:10]=1.C(P(CCCC)CCCC)CCC.[CH2:37]([N:44]1[CH:48]=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:46](O)=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:37]([N:44]1[CH:48]=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:46]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:23])=[CH:14][C:15]=2[O:21][CH3:22])=[N:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1OC
Reaction time: 15 h
Yield: 22.9 %

Procedure:
To a mixture of (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxyphenyl)methanol (1.04 g), tributylphosphine (1.34 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (0.81 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.67 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate as crystals (0.41 g, yield 23%) from a fraction eluted with tetrahydrofuran-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](SC)[N:5]2[CH:10]=[N:11][N:12]=[C:4]2[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O1CCOCC1>O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:12]2[N:11]=[CH:10][N:5]=[C:4]2[CH:3]=1
Reactant: CSc1nc(C)cc2nncn12
Reactant: C1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2ncnn2c(N2CCNCC2)n1

Procedure:
A mixture of 6.00 g (33.3 mmole) of 7-methyl-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, 30.0 g (0.35 mmole) of piperazine and 250 ml of dioxane was refluxed under nitrogen for six days. The mixture was cooled and concentrated in vacuo. The residue obtained was dissolved in 150 ml of water, and the solution was extracted four times with 150 ml portions of chloroform. The extracts were washed thrice with 150 ml portions of water and twice with 150 ml portions of sodium chloride solution and were dried over magnesium sulfate. Evaporation provided a yellow solid which was taken up in 150 ml of chloroform, filtered and chromatographed on a high pressure liquid chromatograph, eluting with methanol-ethyl acetate (1:1). Infrared and nuclear magnetic resonance spectral analyses showed fractions 2 and 3 to be 7-methyl-5-(1-piperazino)-1,2,4-triazolo-[1,5-c]pyrimidine, m.p. 92-95 C. Analysis: Calculated for C10H14N6 : %C, 55.0; %H, 6.5; %N, 38.5; Found: %C, 54.8; %H, 6.4; %N, 38.3. Fraction 4 contained about 15% of 7-methyl-5-(1-piperazino)-1,2,4-triazolo[4,3-c]pyrimidine.
Reaction SMILES: O=O.[C:3]([OH:6])(=[S:5])[CH3:4].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)(=O)C.C([O-])(O)=O.[Na+]>O>[C:3]([S:5][CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)(=[O:6])[CH3:4]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: CC(O)=S
Agent: O=C([O-])O
Agent: O=O
Agent: [Na+]
Solvent: O
Product: CC(=O)SC1CC(=O)N1
Reaction time: 2.75 h

Procedure:
To a cold (0°-5°) oxygen-free 1 N NaOH solution (803 ml.) was added over 20 minutes thioacetic acid (57) ml., 61 g., 0.803 mole). The resulting solution was added in ca 20 minutes to a cold (10°) oxygen-free solution of 4-acetoxyazetidinone (94 g., 0.730 mole) in water (300 ml.). The pH of the resulting solution was immediately adjusted to 7.4 with solid NaHCO3. The cooling bath was removed and the solution was stirred for 2.75 hours. The mixture was then extracted with chloroform, the combined organic extracts washed with water (150 ml.) and dried over sodium sulfate. Concentration on a rotary evaporator left a yellow oil (95.3 g., 90%) which solidified to a yellow solid on cooling and seeding. This solid was found identical by IR, NMR and TLC) to the product obtained in Preparation 1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[F:12][C:13]([F:22])([F:21])[C:14]1[C:19](O)=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:15][CH:16]=1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O[C@@H](CCCl)c1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(O[C@H](CCCl)c2ccccc2)cc1

Procedure:
The title compound was prepared by the method of example 55 using [S]-3-chloro-1-phenylpropanol (2.57g, 15 mmol), α,α,α-trifluoro-cresol (2.4 g, 15 mmol) in THF (40 ml) at room temperature. Workup provided the optically pure title compound as a thick liquid, bp 180°-200° C./0/5 mm. [α]D +2.3° (c 10, CHCl3 ; 13C NMR (CDCl3): 140.50, 129.39, 128.66, 127,56, 127.38, 127.19, 127.01, 126.34, 116.45, 77.82, 41.69, 41.38. Mass spectrum (EI): 153/155 (45), 91 (100). (CI): 314/316, (1, M+), 153/155 (100). Anal. Calcd. for C16H14ClNO: C, 61.05; H, 4.45; Cl, 11.29; F, 18.12. Found: C, 61.06; H, 4.51; Cl, 11.16; F, 18.22.
Reaction SMILES: [Na].[CH:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1>>[NH2:10][C:11]1[N:16]=[C:15]([O:9][CH2:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:12]=1
Reactant: Nc1nc(Cl)cc(NCc2ccccc2)n1
Reactant: OCC1CCCCC1
Agent: [Na]
Product: Nc1nc(NCc2ccccc2)cc(OCC2CCCCC2)n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a stirred solution of sodium (0.025 g, 1.09 mmol) in cyclohexylmethanol (5 ml, 43 mmol) under nitrogen at 100° C., was added 2-amino-6-benzylamino-4-chloropyrimidine (0.2 g, 0.86 mmol), and the mixture was stirred at 180° C. for 2 h. After removal of solvents, the residue was redissolved in methanol, filtered and the filtrate was evaporated to dryness. The crude product was purified by chromatography on silica, employing petrol: ethyl acetate (8:2) as eluent, to give the title product as a yellow solid (0.13 g, 49%); δH (200 MHz, d6-DMSO) 0.96-1.15 (5H, m, C6H11), 1.23-1.34 (6H, m, C6H11), 4.03 (2H, br s, OCH2), 4.51 (2H, d, C6H5CH2, J=5.31 Hz), 5.12 (1H, s, C(5)H), 6.56 (2H, br s, NH2), 7.20 (1H, br s, NH), 7.28-7.39 (5H, m, C6H5); m/z (+EI) 312 (M+, 100%), 229 (M+-C6H11, 45), 216 (MH+-C6H11CH2, 53), 91 (72).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[NH:29]1[CH2:34][CH:33]=[CH:32][CH2:31][CH2:30]1>C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([N:29]3[CH2:30][CH:31]=[CH:32][CH2:33][CH2:34]3)[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: C1=CCNCC1
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Solvent: CCO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CC=CCC3)n2)cc1OC

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (2.08 g) in ethanol (20 ml) was added 1,2,3,6-tetrahydropyridine (1.38 ml), and refluxed for 1.5 hours. The resulting precipitates were collected, dissolved in chloroform, washed with aqueous sodium bicarbonate solution, and dried over magnesium sulfate. After evaporated, the residue was triturated with diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(1,2,3,6-tetrahydropyridin-1-yl)-4-(2,4,6-trimethylphenylimino)pyrimidine (1.95 g).
Reaction SMILES: COC(=O)[C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Br:18])[C:12]=2[CH3:19])=[O:9])=[C:6](F)[CH:5]=1.[CH3:24][N:25](C)[C:26]1C=CC(C(Cl)=O)=CC=1>>[Br:18][C:13]1[C:12]([CH3:19])=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:20]=[CH:21][C:4]([N:25]([CH3:26])[CH3:24])=[CH:5][CH:6]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2cc(F)cc(Br)c2C)c(F)c1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Product: Cc1c(Br)cc(F)cc1NC(=O)c1ccc(N(C)C)cc1

Procedure:
Intermediate 46 was prepared analogue to Intermediate 34 by replacing Intermediate 33 with 4-dimethylamino-benzoyl chloride.
Reaction SMILES: C(O)(=O)[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>O>[CH:5]1[C:4]([C:5]([OH:7])=[O:6])=[CH:2][O:3][C:2](=[O:3])[CH:4]=1
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=C(O)c1ccc(=O)oc1
Temperature: 100 °C

Procedure:
To 200 g of malic acid was added 175 cc of concentrated sulfuric acid and 1 g of 65% oleum. The mixture was heated to 100° C. for two hours, cooled to 30° C. and diluted with 300 cc of water. The reaction mixture was cooled to 25° C. and filtered to give coumalic acid.