Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.N=C=N.[C:14]1([C:20]2[CH:24]=[C:23]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)C1C=CC=CC=1.C([NH+](CC)CC)C.C(=O)([O-])[O-]>ClC(Cl)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:33][CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:23]3[O:22][N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:24]=3)[CH2:31][CH2:30]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: CC[NH+](CC)CC
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=Cc1ccccc1
Product: O=C(NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1)c1ccc(Cl)cn1
Reaction time: 0.75 h
Yield: 39.6 %

Procedure:
A mixture of 5-chloropicolinic acid (43 mg) and N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene resin (PS-Carbodiimide: Argonaut Technologies catalog number 80,037-1; 354 mg) in dichloroethane (4 mL) was shaken for 45 minutes. The reaction was shaken for 45 minutes more after the addition of N,N-dimethylformamide (0.1 mL). The compound prepared in Example 9 (50 mg) was added and the mixture was shaken overnight. Benzaldehyde polystyrene resin (PS-benzaldehyde: Argonaut Technologies catalog number 80,036-2; 184 mg) was then added and the reaction was shaken for 3.5 hours. Macroporous triethylammonium methylpolystyrene carbonate (MP-carbonate: Argonaut Technologies catalog number 80,026-9; 202 mg) was added and the reaction was shaken for 1.5 hours more. The mixture was then filtered and concentrated to obtain the title compound (30 mg) having the following physical data.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[C:7]([O-:10])([O-])=[O:8].[K+].[K+].[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22]C=C(C)C)[N:15]=1>O.C(O)(C)(C)C>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22][C:7]([OH:10])=[O:8])[N:15]=1
Reactant: CC(C)=CCCc1cc(Cl)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)CCc1cc(Cl)nc(Cl)n1
Reaction time: 16 h
Yield: 49.8 %

Procedure:
The above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at −78° C. was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added. The organic layer was separated, the solvent was removed in vacuo, and the residue was chromatographed (ethyl acetate/hexane, 1/19) to give 2.06 g (74%) of 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (1H NMR (CDCl3) δ 7.15 (s, 1), 5.10 (t, 1), 2.80 (t, 2), 2.45 (m, 2), 1.70 (s, 3), 1.55 (s, 3). To a solution of NaIO4 (17 g, 81 mmol) and KMnO4 (251 mg, 1.59 mmol) in water was added K2CO3 (1.29 g, 9.38 mmol) and 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (2.06 g, 8.9 mmol) in t-butanol. After stirring for 16 hours, the reaction was acidified to pH 3 and extracted with ethyl acetate. The organic layer was extracted with aqueous NaHCO3. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to give 980 mg of 3-(2,4-dichloropyrimidin-6-yl)propionic acid (the compound of formula (XIX)), 1H NMR (CDCl3) δ 7.30 (s, 1), 3.05 (t, 2), 2.90 (t, 2). The acid was coupled to piperonylamine under standard conditions with isobutyl chloroformate and N-methylmorpholine to give the compound of formula (XX). Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60° C.) to give N-[(1,3-benzodioxol-5-yl)ethyl]-6-chloro-2-(1H-imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[K+].[Br-].[NH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=[O:21].[N-:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:16]([C:17]2[CH:18]=[C:19]([C:20]#[N:15])[C:1](=[O:2])[NH:8][C:12]=2[CH3:11])=[O:21])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: O=c1cccc[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1c[n-]cn1
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1C(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To 0.20 g (1.1 mmol) of 11 in 10 ml DMF was added carbonyldiimidazole (0.223 g, 1.4 mmol). The solution was stirred for 24 hours at room temperature. Dimethylformamide was stripped off under reduced pressure giving an oil which crystallized upon further drying. The solid was washed with water and dried in the vacuum dessicator. Yellow solids were obtained: 0.11 g, 40% yield; mp=237°-238° C. with decomposition; NMR (DMSO-d6) δ 2.5 (s, 3H), 7.2 (d, 1H), 7.8 (d, 1H), 8.4 (2s, 2H); IR (KBr) 1670 cm-1 (C=O of pyridone), 1710 cm-1 (C=O of imidazolide).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].P(C#N)(OCC)(OCC)=O.[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[OH:4][CH2:3][CH2:2][NH:1][C:27](=[O:28])[C@@H:26]([NH:25][C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:33][CH:32]=1
Reactant: NCCO
Reactant: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)OCc1ccccc1
Reaction time: 0.75 h
Yield: 90 %

Procedure:
2-Aminoethanol (1.62 mL, 26.9 mmol) and diethyl cyanophosphate (4.37 mL, 26.9 mmol) were added to a DMF (82 mL) solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (9.37 g, 24.4 mmol) prepared in Reference Example 6 (6a), at room temperature. Then, to the resulting mixture was dropwise added a DMF (10 mL) solution of triethylamine (3.75 mL, 26.9 mmol) under ice-cooling with stirring over 45 minutes. The mixture was stirred at room temperature for 3 hours, and ethyl acetate (480 mL) was added to this reaction solution. The mixture was sequentially washed with water (480 mL, four times), 1 N sodium hydroxide, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give 9.36 g of the title compound (white powder, yield: 90%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]C)=O)[NH:6]2.CC(C)([O-])C.[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].Cl>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:12](=[O:14])[CH:23]([C:22]([O:26][CH3:27])=[O:25])[CH2:24][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1Cn2c(cc3c(Br)cc(F)cc32)C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 81.8 %

Procedure:
To a suspension of the indole of Step 4 (4 g, 15 mmol) in a mixture of 10:1 toluene/THF (100 mL) at r.t. was added potassium t-butoxide (15 mL of a 1M solution in THF). The reaction mixture was stirred for 2 minutes and methyl acrylate (2.5 g, 30 mmol) was added. The mixture was stirred at reflux for 5 hours and cooled to r.t. Then 1N HCl was added to acidify to pH 3 and the reaction mixture was extracted with EtOAc and the combined organic layers were concentrated. The residue was swished in EtOAc/Hexanes to give 4 g of the desired compound as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl[CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][N:1]2[CH2:26][CH2:27][CH2:28][CH2:29][C:30]2=[O:31])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(Cl)CCCCCl
Product: Cl
Product: O=C1CCCCN1C[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 5-chloropentanoyl chloride, and by a method similar to that of Example 363, steps A and B and Example 39, step B, the title compound was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:9]([NH2:10])=[C:8]([NH2:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1.[C:14](O)(=O)[CH3:15]>>[CH:1]1([N:4]2[C:9]3[N:10]=[C:14]([CH3:15])[NH:11][C:8]=3[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: Nc1c(N)n(C2CC2)c(=O)[nH]c1=O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C1CC1
Reaction time: 1 h

Procedure:
A solution of 6.4 g of 1-cyclopropyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (IV) in 20 ml of acetic acid was refluxed for 2 hours. The solution was evaporated. The received oil was refluxed in 40 ml of 2N NaOH and 10 ml of 5N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off. Yield 1.85 g (26%) (XXXVI) NMR (see Table I).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=[CH:8][CH3:9])[OH:3].C(OC(=O)C)(=[O:15])C.C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:9][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:2]([OH:3])=[C:1]([O:11][CH3:12])[CH:10]=1)=[O:15]
Reactant: CC=Cc1ccc(O)c(OC)c1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(CC(C)=O)ccc1O
Temperature: 20 °C
Yield: 85.3 %

Procedure:
A mixture of isoeugenol (8.21 g., 50 mm.), acetic anhydride (5.62 g., 55 mm.) and anhydrous sodium acetate (0.41 g., 5 mm.) is heated at 100° C.-105° C. under nitrogen atmosphere for 2.5 hours. The reaction mixture is cooled and diluted with 65 ml. of toluene before a solution (11 ml.) of 38.6% peracetic and 0.85 g. of sodium acetate in acetic acid is added slowly. After heating at 50° C.-60° C. for 2-3 hours, the reaction mixture is cooled to 20° C. and treated with aqueous sodium bisulfite (2.8 g.) to destroy excess peracetic acid. The entire mixture is mixed with 8 ml. of toluene, 50 ml. of 14% aqueous sulfuric acid, and is heated with stirring to reflux for 12.5 hours. After cooling to ambient temperature, the toluene layer is separated, and the aqueous layer extracted 3×20 ml. of toluene. The toluene layers are combined, washed with saturated aqueous sodium sulfate, dried over anhydrous magnesium sulfate and concentrated in vacuo to give methylvanillyl ketone in 85.3% yield.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[BrH:26].O1CC[CH2:30]OO1>C(Cl)Cl>[Br:26][CH2:30][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1
Reactant: Br
Reactant: C1COOOC1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1cccc2ccccc12
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2ccccc12
Reaction time: 2 h

Procedure:
0.494 g of 5-Methyl-4-[2-(naphthalen-1-yloxy)-ethyl]-2-phenyl-oxazole (1.50 mmol) was dissolved under argon atmosphere in 6 ml of CH2Cl2 and cooled down to 0°. 0.455 ml of 62% aq. HBr was added, followed by 58 mg of trioxane (0.644 mmol, 1.29 eq.). After 2 h, additional 0.455 ml of 62% aq. HBr was added and stirring continued for totally 5 h under strict temperature control. The reaction mixture was then diluted with CH2Cl2, washed with sat. NaHCO3-sol., the aqueous layer extracted once more with CH2Cl2, the combined organic phases dried over sodium sulfate and evaporated to dryness. This left 0.70 g of the crude title compound which was used as such for the next step. The product is quite unstable and can not be purified by column chromatography on SiO2; it also decomposes readily on TLC-plates.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][C:19](=[O:26])[C:20]5[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=5)=[CH:8][C:6]=4[N:7]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(Cl)c1cccnc1
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C(NCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)c1cccnc1

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 was acylated with nicotinoyl chloride following General Procedure K and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (34 mg) following General Procedure A to give 288. MS (Q1) 472 (M)+
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].Cl[C:11](=[CH2:14])[C:12]#[N:13]>O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:1]1[CH:14]=[C:11]([C:12]#[N:13])[N:3]=[N:2]1)[CH3:9]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C=C(Cl)C#N
Solvent: O
Product: CCOC(=O)Cn1cc(C#N)nn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-azidoacetate (1.29 g) and 2-chloroacrylonitrile (1.75 g) in water (10 ml) is stirred at about 80° C. for 16 hours. After cooling, the product is extracted with dichloromethane and the concentrated extract is purified by means of column chromatography on silica gel 60 (6 g; eluent toluenelethyl acetate=4:1). The purified product (yield 1.21 g; 67% of theory) of m.p. 47-48° C. (recrystallization from toluene/hexane) is obtained after concentrating the eluate and drying.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][CH2:11][O-:12].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>C(O)C.O1CCCC1>[C:3]([C:2]([C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH3:14])[CH:17]=1)([C:11]([CH3:10])=[O:12])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CC[O-]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)(C(C)=O)C(=O)c1ccc(OC)c(OC)c1

Procedure:
32 ml of ethyl acetoacetate were added dropwise with ice cooling to 100 ml of 21% strength sodium ethylate solution in ethanol (=solution I). After 20 minutes 75 ml of a solution of 50 g of 3,4-dimethoxybenzoyl chloride in 150 ml of tetrahydrofuran (=solution II) were added dropwise to the reaction mixture. Subsequently further quanities of solutions I and II were added dropwise to the reaction mixture alternately, each at intervals of 20 minutes, until the reaction mixture contained a total of 190 ml of solution I and 176 ml of solution II. After 16 hours the precipitated salts were filtered out, washed with tetrahydrofuran and then suspended in water. The aqueous mixture was acidified to pH 1 with ice cooling and was extracted with methyl tert-butyl ether. The extract was evaporated to dryness, and 45 g of ethyl 2-acetyl-2-(3,4-dimethoxybenzoyl)-acetoacetate were obtained as a yellow oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[F:12][C:13]([F:18])([F:17])[C:14]([CH3:16])=[O:15].[NH4+].[Cl-]>CCOCC>[F:12][C:13]([F:18])([F:17])[C:14]([CH3:16])([OH:15])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)(C#C[Si](C)(C)C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of (trimethylsilyl)acetylene (2.80 mL, 20.2 mmol) in Et2O (25 mL) at −78° C., was added n-BuLi (2.5 M in hexane, 8.10 mL, 20.2 mmol), while maintaining internal temperature below −70° C. After 30 min., a solution of 1,1,1-trifluoroacetone (3.62 mL, 40.5 mmol) in Et2O (10 mL) was added rapidly, keeping the internal temperature below −45° C. After 2 h at −78° C., a saturated solution of NH4Cl was added. The aqueous layer was extracted with Et2O, and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated under vacuum, at 25° C., affording the title compound a liquid containing Et2O (7.25 g). The crude product was used as such in Step 2. 1H NMR (400 MHz, acetone-d6): 5.92 (br s, 1H), 1.59 (s, 3H), 0.18 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O[N:19]=[C:20]([C:22]1[CH:30]=[CH:29][C:25]2[NH:26][CH:27]=[N:28][C:24]=2[CH:23]=1)[NH2:21]>>[CH3:1][C:2]1[CH:10]=[C:6]([C:7]2[O:9][N:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]4[NH:26][CH:27]=[N:28][C:24]=4[CH:23]=3)[N:21]=2)[CH:5]=[N:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH3:17]
Reactant: Cc1cc(C(=O)O)cnc1N1CCCCC1C
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: Cc1cc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cnc1N1CCCCC1C

Procedure:
Title compound was prepared following general procedure 1 starting from Intermediate 13 (120 mg; 0.51 mmol) and Intermediate 1 (90 mg; 0.51 mmol). Reaction mixture was filtered over a SPE-NH2 column, washed with THF followed by evaporation of the solvent under reduced pressure. Purification by silica column chromatography (EtOAc/c-Hex, 30/70 to 100/0) afforded the title compound as a brown powder. 1H NMR (DMSO, d6): δ 12.78 (s, 1H), 8.39-8.37 (m, 2H), 8.31 (s, 1H), 8.24 (dd, J=8.8, 2.2 Hz, 1H), 7.95-7.92 (m, 1H), 7.78-7.75 (m, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.23-4.22 (m, 1H), 3.38-3.35 (m, 2H), 1.82-1.57 (m, 6H), 1.17 (d, 6.6 Hz, 3H). HPLC (Method A) Rt 2.71 min (Purity: 86.6%). LC/MS (method B): 358.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH:13]([CH3:17])[CH2:12]1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([Cl:25])=[O:24]>C1C=CC=CC=1>[ClH:25].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:23]([C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[CH:13]([CH3:17])[CH2:12]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccccc1CCCN1CCNC(C)C1
Solvent: c1ccccc1
Product: Cc1ccccc1CCCN1CCN(C(=O)c2ccco2)C(C)C1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of 1-[3-(o-methylphenyl)propyl]-3-methylpiperazine [b.p. 120° - 125°C (2 mmHg), dipicrate, m.p. 245° - 250°C], 2-furoyl chloride and benzene.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][NH2:44])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][N:44]2[C:7](=[O:9])[C:6]3[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=3[NH:1][C:14]2=[O:16])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CCN)cc1OC
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCc3ccc(OC)c(OC)c3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-(3,4-dimethoxyphenyl)ethanamine (1.36 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (28% methanol solution, 1.3 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.92 g, 95%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24]Br)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1.[C-:26]#[N:27].[Na+].O>CN(C=O)C.O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24][C:26]#[N:27])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1
Reactant: [C-]#N
Reactant: N#Cc1cccc(-c2cc(-c3nc4ccccc4o3)ccc2CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5′-(1,3-benzoxazol-2-yl)-2′-(bromomethyl)-1,1′-biphenyl-3-carbonitrile (183 mg, 0.47 mmol) and sodium cyanide (46 mg, 0.94 mmol) in DMF:H2O (5:1, 18 mL) and DMF (20 mL) was stirred at rt for 3 h. H2O was added to the reaction mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine (2×), dried over Na2SO4, and evaporated to dryness to give an orange oil. The crude was purified by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30 min: 0 to 20% EtOAc) to afford the desired 5′-(1,3-benzoxazol-2-yl)-2′-(cyanomethyl)-1,1′-biphenyl-3-carbonitrile as a colorless solid (M.p. 175–176° C.). 1H NMR (CDCl3, 300 MHz) δ 8.34 (dd, 1H), 8.18 (s, 1H), 7.77 (m, 3H), 7.67 (m, 3H), 7.60 (m, 1H), 7.40 (m, 2H), 3.69 (s, 2H). MS (ESI) 336 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:18][CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH2:21][CH2:20]1.[CH3:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@@H](C)CC3)CC2)cc1
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@H](C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To an ice-cooled solution of ethyl 4-(piperazin-1-yl)benzoate (2.00 g) and 4-methylcyclohexanone (1.05 ml) in a mixed solvent of methanol (40 ml) and acetic acid (1.47 ml) was added sodium cyanoborohydride (0.59 g) in a stream of nitrogen. The mixture was stirred at this temperature for 1 hour and at room temperature for 17 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a mixture of cis and trans products. This mixture was separated by column chromatography on silica gel eluting with a mixed solvent of methylene chloride-methanol (from 0% to 2% gradient solution) to give ethyl 4-[4-(cis-4-methylcyclohexyl)piperazin-1-yl]benzoate (0.80 g) as a pale green solid and ethyl 4-[4-(trans-4-methylcyclohexyl)piperazin-1-yl]benzoate (0.64 g) as a pale green solid. Trans-product was confirmed by X-ray crystal analysis.