Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](\[Cl:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Cl:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+21.5°±2.5° (c=0.3% in chloroform).
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:4][CH2:3][CH:2]([OH:1])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(O)COc1cccc(CN2CCCCC2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(O)COc1cccc(CN2CCCCC2)c1

Procedure:
A solution of 2-[2-hydroxy-3-[3-(1-piperidinylmethyl) phenoxy]propyl]-1H-isoindole-1,3-(2H) dione (17.6 g) and hydrazine hydrate (2.5 g) in ethanol (60 ml) was heated under reflux for 3 h. The resulting mixture was evaporated to a solid residue which was suspended in 1N hydrochloric acid (30 ml) and filtered. The filtrate was basified with an excess of potassium carbonate and extracted with isopropanol (3×40 ml). The isopropanol extracts were dried (Na2CO3) and evaporated to a gum which was chromatographed using System A. Crystallisation of the product from n-hexane:ether (20:1) gave the title compound as colourless grains (7.7 g), m.p. 74°-76.5°.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][C:9]1[C:10]([Cl:16])=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1>C(O)=O>[Cl:15][C:12]1[N:11]=[C:10]([Cl:16])[C:9]([NH:8][CH:5]=[O:7])=[CH:14][N:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: O=CO
Product: O=CNc1cnc(Cl)nc1Cl
Temperature: 20 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (12 ml) was added to a mixture of 5-amino-2,4-dichloropyrimidine (2.34 g, 14.4 mmol) and formic acid (30 ml) at 0° C. The mixture was stirred at 20° C. for 4 hours, evaporated to dryness and co-evaporated with toluene. The crystalline product was homogeneous on t.l.c. (chloroform-methanol, 15.1) and used without further purification. (2.74 g, 100%). IR: υmax (KBr) 3445, 3350, 3240, 1635, 1570, 1515, 1415 cm-1. 1H NMR δH [(CD3)2SO] 8.45 (1H,s,H.2), 9.40 (1H,s,CH), 10.40 (1H,br.s, NH).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>CCO.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Brc1ccncc1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(c2ccncc2)CC1
Yield: 53.2 %

Procedure:
A solution of 4-hydroxypiperidine (7.80 g, 77 mmol), 4-bromopyridine (15.0 g, 77 mmol), and triethylamine (32 mL, 231 mmol) in 90 mL of EtOH and 30 mL of H2O was heated at 150° C. in a sealed tube for 4 days. The mixture was concentrated and the residue partitioned between CH2C2 and H2O. The organic layer was washed with 1 N NaOH (2×), diluted with EtOAc and the resulting solid collected by filtration affording 7.30 g (53%) of the title compound.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:16][C:17]([O:21][CH:22](Cl)[CH3:23])([CH3:20])[C:18]#[CH:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[N:12]([CH3:13])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH:22]([O:21][C:17]([CH3:20])([CH3:16])[C:18]#[CH:19])[CH3:23]
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Reactant: C#CC(C)(C)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CC(C)(C)OC(C)Oc1ccc(NC(=O)N(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a well-stirred suspension of the potassium salt of 3-chloro-4-hydroxyphenyl-1,1-dimethylurea (0.04 mole) in dry acetone (150 ml.) is added dropwise 1-chloroethyl 1,1-dimethyl-2-propynyl ether (5.9 grams, 0.04 mole). During the addition, an exotherm to 35° C. is observed; the reaction is stirred at room temperature overnight, then poured into an aqueous 10% sodium carbonate solution containing 200 grams of ice, and the mixture stirred vigorously for 30 minutes. The resulting solid is filtered off, water-washed and dried to give 8.5 grams, melting point 99° to 101° C., crystallization from hexane-cyclohexane-benzene gave 4.69 grams (36%), melting point 101° to 103° C.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([CH2:53][OH:54])[CH:49]=[C:50]([NH2:52])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:51]=[C:50]([NH:52][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:49]=[C:48]([CH2:53][OH:54])[CH:47]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 68.8 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-difluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24]OS(C)(=O)=O)[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30]1([C:36]2([OH:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:39]2[CH2:40][CH2:41][C:36]([OH:42])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:37][CH2:38]2)[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(N(C)C(=O)CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)C(=O)CC(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Yield: 12.4 %

Procedure:
3,4-Dichloro-beta-(2-methanesulfonyloxyethyl)-N-methyl-N-(4-methoxyphenyl)benzene propanamide (4.2 g) in DMF (20 mL) was treated with 4-phenyl-4-hydroxypiperidine (1.53 g) and K2CO3 (1.19 g). The mixture was heated at 60° C. for 18 hours. The cooled reaction mixture was diluted the EtOAc (200 mL) and washed with H2O (3×150 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 90:10 (CH2Cl2 :MeOH) gave the title compound (0.58 g). Mass spectrum (CI): 541.
Reaction SMILES: [F:1][C@H:2]1[CH2:18][C@@H:17]2[C@:9]([F:25])([C@@H:10]([OH:24])[CH2:11][C@@:12]3([CH3:23])[C@H:16]2[CH2:15][CH:14]=[C:13]3[C:19](=[O:22])[CH2:20]O)[C@:8]2([CH3:26])[C:3]1=[CH:4][C:5](=[O:27])[CH:6]=[CH:7]2.CCN(C(C)C)C(C)C.[F-:37].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C>[F:1][C@H:2]1[CH2:18][C@@H:17]2[C@:9]([F:25])([C@@H:10]([OH:24])[CH2:11][C@@:12]3([CH3:23])[C@H:16]2[CH2:15][CH:14]=[C:13]3[C:19](=[O:22])[CH2:20][F:37])[C@:8]2([CH3:26])[C:3]1=[CH:4][C:5](=[O:27])[CH:6]=[CH:7]2
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3CC=C(C(=O)CF)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
In a nitrogen atmosphere, intermediate 3 (100 mg, 0.264 mmol) was dissolved in acetonitrile (4 ml), and Mesyl-Cl (32 μl, 0.411 mmol) and DIPEA (78 μl, 0.447 mmol) were added. The mixture was stirred at RT for 30 minutes. Potassium fluoride (154 mg, 2.64 mmol) was added, and the mixture was stirred for 1 h at 60° C. TBAF 1M in THF (529 μl, 0.529 mmol) was added, and the mixture is stirred at 60° C. for 4 hours. The reaction mixture was partitioned between water and AcOEt, the organic layer was separated, dried over Na2SO4 and concentrated. The crude was purified by silica gel flash chromatography (eluent DCM/AcOEt=1:1) to yield intermediate 28 (62 mg, 61.7% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]#[CH:5])=[CH2:3].[Li]CCCC.[CH3:11][C:12](=[O:15])[CH:13]=[CH2:14]>>[CH3:11][C:12]([OH:15])([C:5]#[C:4][C:2]([CH3:3])=[CH2:1])[CH:13]=[CH2:14]
Reactant: C=CC(C)=O
Reactant: C#CC(=C)C
Agent: [Li]CCCC
Product: C=CC(C)(O)C#CC(=C)C

Procedure:
The title compound was prepared according to the general method above by using 2-methylbut-1-en-3-yne (1.725 g, 26.09 mmol), nBuLi (18.0 mL, 28.8 mmol) and but-3-en-2-one (2.194 g, 31.30 mmol). Crude product was purified by flash chromatography (2.229 g, 16.37 mmol, 62.7%): Rf 0.28 (hexanes/Et2O, 4:1); 1H NMR (300 MHz, CDCl3) δ 6.00 (dd, J=17.1, 10.2 Hz, 1H, H-2), 5.49 (dd, J=17.1, 0.7 Hz, 1H, H-1trans), 5.25-5.32 (m, 1H, H-7), 5.18-5.25 (m, 1H, H-7), 5.11 (dd, J=10.2, 0.7 Hz, 1H, H-1 cis), 2.24 (s, 1H, —OH), 1.88 (as, 3H, H-8), 1.56 (s, 3H, H-9); 13C NMR (300 MHz, CDCl3) δ 142.0 (C-2), 126.2 (C-6), 122.1 (C-7), 113.5 (C-1), 89.9 (C-4/5), 85.9 (C-4/5), 68.5 (C-3), 29.9 (C-9), 23.4 (C-8); HRMS calcd for C9H13O (M+H)+ 137.0966. found 137.0984.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1.Cl.[N:28]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][N:30]=[N:29]1.C1CCN2C(=NCCC2)CC1>CC#N.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:35]3[CH2:36][CH2:37][CH:33]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[CH2:34]3)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-(2,4-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (91 mg, 0.5 mmol), 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (259 mg, 1.5 mmol), and DBU (380 mg, 2.5 mmol) in CH3CN (20 ml) was heated under reflux for 2 h, cooled to r.t. and stirred further for 18 h, diluted with water. Unreacted starting materials were removed by extraction with chloroform. The water layer was concentrated to give a yellow oil. Yield: 150 mg, 62%. 1H NMR (CDCl3) δ: 1.3 (t, 3H), 2.5 (m, 2H), 3.9 (m, 4H), 4.4 (q, 2H), 5.3 (m, 1H), 7.3 (m, 4H), 7.8 (d, 1H), 8.0 (d, 1H), 8.4 (s, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:23][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][C:11]([C:20](=[O:21])[C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=4)=[CH:10][C:8]=3[C:9]=2[CH:1]=1)=[O:21]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cccc(C(=O)c2ccc3oc4ccc(C(=O)c5cccc(C)c5)cc4c3c2)c1

Procedure:
2,8-Bis(3-methylbenzoyl)dibenzofuran is prepared according to the procedure of Step 1, Example 1. Dibenzofuran (42 g, 0.25 mole), m-toluoyl chloride (82 g, 0.53 mole), and anhydrous aluminum chloride (73 g, 0.55 mole) are reacted in carbon disulfide (250 ml) for 24 hours at 20°. The desired compound is obtained after recrystallization of the crude product from toluene, yield 22 g (23% of theory), mp 180°-1°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](C#N)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-:19].[K+].[K+].O>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccc(F)cc1)c1ccc(Cl)cn1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(Cl)cn1
Yield: 93.2 %

Procedure:
Under oxygen atmosphere, a mixed solution of 5-chloro-2-(α-cyano-4-fluorobenzyl)pyridine (16.14 g) and potassium carbonate (10.85 g) in DMSO-water (330-66 ml) was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 5-chloro-2-(4-fluorobenzoyl)pyridine (14.37 g) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[O:38])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: O=C=NC(=O)Cc1ccccc1F
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 308 (320 mg, 0.90 mmol) and (2-fluoro-phenyl)-acetyl isocyanate (600 mg, 3.35 mmoL) [A. J. Hill, et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to MeOH/EtOAc(20:80), to afford the title compound 309b in 42% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.10(s, 1H), 10.58(s, 1H), 8.42(d, 1H, J=5.5 Hz), 7.94(d, 1H, J=1.1 Hz), 7.82-7.77(m, 2H), 7.65(s, 1H), 7.45-7.30(m, 4H), 7.19-7.16(m, 2H), 6.54(dd, 1H, J1=0.7 Hz, J2=5.4 Hz), 4.04(q, 2H), 3.83(s, 2H), 1.38(t, 3H). MS (m/z): 534.1(M+H) (found).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.CN(C)C=O.Cl.[CH2:26]([O:28][C:29](=[O:33])[CH:30]([NH2:32])[CH3:31])[CH3:27]>O>[NH2:12][C:4]1[N:3]=[C:2]([NH:32][CH:30]([CH3:31])[C:29]([O:28][CH2:26][CH3:27])=[O:33])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Reactant: CCOC(=O)C(C)N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Nc1nc(N)nc2c1CCCC2
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 29.2 %

Procedure:
To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and dimethylformamide (4 ml) was added 2-aminopropionic acid ethyl ester hydrochloride (167 mg, 1.09 mmol) at room temperature. After the mixture was stirred for 2.5 hours at 100° C., the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo. The residue was purified by silica gel chromatography (5% MeOH/CHCl3) to give the object compound (42.1 mg, 29.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8].I[CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]([CH3:32])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(Cl)c4)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4cccc(Cl)c4)cc3)c2)o1

Procedure:
N-(3-Chlorobenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(3-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, b), 7.59-7.33,(8H, m), 7.23,(1H, b), 4.70-4.55,(2H, m), 2.92,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.58 min, MH+ 432/434.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.[CH2:23]1[O:33][C:32]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=2[O:24]1>>[O:33]1[C:32]2[CH:31]=[CH:30][C:27](/[CH:28]=[C:20](/[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:19][CH:18]=3)\[C:21]#[N:22])=[CH:26][C:25]=2[O:24][CH2:23]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: N#CCc1ccc(OCCCCCCCCCCCO)cc1
Product: N#C/C(=C\c1ccc2c(c1)OCO2)c1ccc(OCCCCCCCCCCCO)cc1
Yield: 85 %

Procedure:
(2Z)-3-(1,3-benzodioxol-5-yl)-2-{4-[(11-hydroxyundecyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 4-[(11-hydroxyundecyl)oxy]-benzeneacetonitrile and commercial 3,4-(methylenedioxy)benzaldehyde according the same procedure following for example 1 in 85% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.[H][H]>C(O)C.[Rh]>[CH2:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1
Reactant: COC(=O)C1Cc2ccccc2CN1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: COC(=O)C1CC2CCCCC2CN1
Yield: 101.4 %

Procedure:
Methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (2.3 g, 10 mmol) in 200 ml absolute ethanol is hydrogenated at 50 psi, room temperature, using 0.6 g 5% Rh/C catalyst. After the theoretical amount of hydrogen is taken up (36 hours), the catalyst is filtered and the filtrate is evaporated to dryness. The residue is dissolved in methylene chloride and washed with a saturated solution of sodium carbonate. The organic phase is dried (Na2SO4) and acidified with ethanolic HCl. Evaporation of the solvent yields 2.0 g of the product as a diastereomeric mixture which is used without further separation.
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
At 0° C. to the solution of 550 mg (0.80 mmol) of Boc-Ala-Arg(Tos)-Pro-OBzl in 10 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 20:1) indicated complete disappearance of Boc-Ala-Arg(Tos)-Pro-OBzl. The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 130 mg (27%) of the title compound as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>C(#N)C>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCCN1CCCC1=O
Yield: 52.5 %

Procedure:
250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser, and a CaCL2 drying tube. 452 mg (3.18 mmol) 1-(3-aminopropyl)-2-pyrrolidinone and 1 ml acetonitrile were added. The solution was heated to reflux for 17 hours at which time all of the acetonitrile was evaporated leaving a dark viscous oil. The oil was chromatographed on 15 g silica gel, eluting with 40% methanol/60% ethyl acetate. This procedure gave 185 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(2-oxopyrrolidin-1-yl)propyl]propanamide (AIT-0034) as a pure white solid. Yield: 53%
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Br:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH2:20].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(Sc2ccccc2)cc1Br
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
Oxalyl chloride (0.052 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.095 g) in dichloromethane (3 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 2 hours and was then added to a solution of 2-bromo-4-phenylthioaniline (Method 17) (0.135 g) and 2,6-di-tert-butylpyridine (0.14 ml) in dichloromethane (5 ml) and stirred a further 3 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-30% ethyl acetate/hexane to give the title compound (0.061 g) as a waxy solid. NMR: 1.59 (s, 3H), 7.25-7.50 (bm, 6H), 7.59 (s, 1H), 7.82 (bs, 1H), 7.98 (d,1H), 9.79 (s, 1H); MS: 420 (M−H)−.