Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[C:36](=[O:49])([O:41][CH:42]([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[O:37][CH:38](I)[CH3:39].C(OCC)(=O)C.[Cl-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:38]([O:37][C:36]([O:41][CH:42]([CH:43]([CH3:44])[CH3:45])[CH:46]([CH3:48])[CH3:47])=[O:49])[CH3:39])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)OC(C(C)C)C(C)C
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(OC(=O)OC(C(C)C)C(C)C)OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12
Temperature: 0 °C

Procedure:
A mixture of 1.78 g of 1-chloroethyl 2,4-dimethyl-3-pentyl carbonate and 5 g of sodium iodide is stirred in 30 ml of acetonitrile at 70° C. for 4 hours and concentrated. The residue is extracted with ether and concentrated to give crude 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate. In 30 ml of dimethylformamide is dissolved 3.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and with ice-cooling and stirring, the above 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate is added thereto at one stroke, followed by stirring for 5 minutes. The reaction mixture is poured into a mixture of 150 ml of ethyl acetate and 150 ml of ice-cooled 20% aqueous sodium chloride. The organic layer is separated, washed with two 150-ml portions of saturated aqueous sodium chloride and extracted with 40 ml of 1N hydrochloric acid. The extract is subjected to column chromatography using Diaion MCI® GEL CHP-20P (Mitsubishi Chemical Industries Limited, Japan), elution being carried out with acetonitrile-0.01N hydrochloric acid. The fractions containing the desired product are combined and lyophilized to give 940 mg of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][OH:20])#[N:15]>>[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:20][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:3]=1)#[N:15]
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: N#Cc1cccc(CO)c1
Product: N#Cc1cccc(COc2cncc(N3CCNCC3)n2)c1

Procedure:
Starting materials, 2-chloro-6-(1-piperazinyl)pyrazine and 3-cyanobenzyl alcohol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:29][C:30]([F:35])([F:34])[C:31]([CH3:33])=[O:32]>O1CCCC1>[C:13]([C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:31]([OH:32])([CH3:33])[C:30]([F:35])([F:34])[F:29])=[CH:25][CH:26]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(C(=O)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(C(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (99 mL, 0.87 mmol) in freshly distilled tetrahydrofuran (5 mL) was added a solution of n-butyllithium (326 mL of a 2.5M solution in hexanes, 0.81 mmol). The solution was stirred at -78° C. for 25 minutes before a tetrahydrofuran solution of 4-benzoylphenylethyne (120 mg, 0.58 mmol) was added. The reaction was kept at -78° C. for an additional 20 minutes before 1,1,1-trifluoroacetone (521 mL, 5.8 mmol) was added in one portion. After stirring at -78° C. for 15 minutes the reaction was quenched by pouring into a saturated NH4C1 solution. The product was extracted into diethyl ether. The combined ethers were dried and evaporated. The crude product was adsorbed onto silica gel and purified by chromatography, with ethyl acetate:hexanes as the eluent (gradient 1:9 to 1:3), to yield the title compound as a white solid after trituration with hexanes (80 mg, 43%); mp 94.5°-96.0° C.; 250 MHz NMR (CDCl3): 1.76 (s,3, CH3), 2.88 (s,1, OH), 7.46-7.64 (m,5, Ar), 7.77-7.79 (m,4, Ar); MS: m/z=319(M+ 1). Analysis for C18H13F3O2 : Calculated: C, 67.92; H, 4.14; Found: C, 68.16; H, 4.15.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:21]/[CH:22]=[O:23])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc2cccnc2c1
Product: O=C/C=C/c1ccc2cccnc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 7-quinolinecarboxaldehyde (prepared as described in J. Med. Chem. 1993, 36, 3308) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:53])[CH2:19][O:18][C:17]2([CH2:24][CH2:23][CH:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:21][CH2:20]2)[O:16][CH2:15]1>C(OCC)(=O)C>[CH3:53][C:14]1([CH3:13])[CH2:19][O:18][C:17]2([CH2:24][CH2:23][CH:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:21][CH2:20]2)[O:16][CH2:15]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)CO3)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)CO3)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.35 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.13 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CN(C=O)C>O>[CH2:31]([N:12]1[C:11](=[O:23])[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:13]1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCI
Reactant: COc1ccc(-c2n[nH]c(=O)nc2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nc1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
A mixture of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-one (2.14 g, 6.9 mmol), freshly ground potassium carbonate (1.45 g, 10.5 mmol), 1.43 g of iodopentane (7.2 mmol) and 11 mL of DMF were stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and stripped. Column chromatography gave 0.4 g of Compound 8.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:50])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:50])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:46][C:39]2[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:36]=[CH:37][CH:38]=2)[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccnc2ccccc12
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(Cc2ccnc3ccccc23)C[C@@H]1CCCB(O)O
Reaction time: 2 h
Yield: 27.4 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and quinoline-4-carboxaldehyde (110 mg, 0.7 mmol), stirred for 2 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 16 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(quinolin-4-ylmethyl)pyrrolidine-3-carboxylic acid (49 mg, 23%) as a pale amber solid. NMR (D2O) δ 9.12 (d, J=5.5 Hz, 1 H), 8.41 (d, J=8.5 Hz, 1 H), 8.23 (d, J=8.5 Hz, 1 H), 8.10-8.20 (m, 2 H), 8.00 (t, J=8.5 Hz, 1 H), 5.30 (m, 2 H), 4.06 (d, J=12.5 Hz, 1 H), 3.83 (m, 2 H), 3.51 (t, J=11.5 Hz, 1 H), 2.50-2.70 (m, 1 H), 1.60 (m, 1 H), 1.15-1.30 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m−H2O+1): 340.3; MS (m−2H2O+1): 322.1.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][OH:58].CCN(C(C)C)C(C)C>C(Cl)Cl.CS(C)=O>[O:58]=[CH:57][CH2:56][CH2:55][CH2:54][CH2:53][NH:52][C:19]([CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)=[O:21]
Reactant: NCCCCCO
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=CCCCCNC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A mixture of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (5 g, 13.5 mmol; prepared as described in Preparation 10), HATU (10.3 g, 27 mmol), 5-amino-1-pentanol (1.67 g, 16.2 mmol) and DIPEA (7.04 mL, 40.5 mmol) in 100 mL of DCM was stirred at room temperature for 1 hour. The reaction mixture was then washed with brine (100 mL), water (100 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in DCM (100 mL) and cooled down to −5° C. in an ice/brine bath. DIPEA (7.04 mL, 40.5 mmol) and DMSO (10 mL) were added to the solution, followed by sulfur trioxide pyridine complex (6.45 g, 40.5 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then washed with water (100 mL) and brine (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 4.88 g of the title intermediate (80% yield) as a semi-solid.
Reaction SMILES: [CH:1]([CH:3]([C:8]1[N:9]([CH3:18])[C:10]([CH3:17])=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:4]([O:6][CH3:7])=[O:5])=O.C([O-])(=O)C.[NH4+:23]>CO>[NH2:23][CH:1]=[C:3]([C:8]1[N:9]([CH3:18])[C:10]([CH3:17])=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(C)n(C)c1C(C=O)C(=O)OC
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C(=CN)c1c(C(=O)OC)cc(C)n1C
Yield: 96.9 %

Procedure:
A mixture of methyl 2-[1-formyl-2-(methyloxy)-2-oxoethyl]-1,5-dimethyl-1H-pyrrole-3-carboxylate (2.59 g), ammonium acetate (4.0 g) and methanol (50 ml) was heated under reflux for 4 hours. After cooling the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with 2 further portions of ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to afford the title compound 2.5 g, as a tautomeric mixture.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].C(O)(=O)/C=[CH:22]/[C:23]1[CH:30]=[CH:29][C:27](O)=[C:25](O)[CH:24]=1.P(Cl)(OCC)(OCC)=O.[Cl-].C([N:45](CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:22][C@H:23]1[CH2:30][CH2:29][C@H:27]([NH:45][C:10](=[O:12])[CH:9]=[CH:8][C:7]2[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:19])[CH3:18])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1OC(C)=O
Reactant: CCN(CC)CC
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC(C)=O

Procedure:
Using 3.4 g of 3,4-diacetoxycinnamic acid derived from caffeic acid by the acetylation thereof, 2.8 ml of diethyl chlorophosphate, 3.9 ml of triethylamine, 2 g of trans-4-methylcyclohexylammmonium chloride, 60 ml of methylene chloride, and 0.6 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. The product obtained was recrystallized from methylene chloride/hexane, yielding 3.19 g of N-(trans-4-methylcyclohexyl)-3,4-diacetoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:30][CH:27]4[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=CC1CC1
Reactant: N#Cc1ccc(S(=O)(=O)NC2CCC(C(=O)N3CCNCC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N3CCN(CC4CC4)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 0.1 g (0.26 mmol) 4-cyano-N-[4-(piperazine-1-carbonyl)-cyclohexyl]-benzenesulfonamide, 0.022 g (0.31 mmol) cyclopropanecarboxaldehyde (commercially available), 0.159 g (2.65 mmol) acetic acid and 0.073 g (0.34 mmol) sodium triacetoxyborohydride in 1 mL THF was stirred at 80° C. for 1 h. The mixture was subjected to purification on preparative HPLC eluting with a gradient formed from acetonitrile and water. Evaporation of the product fractions yielded 3 mg (2.6%) of the title compound. MS (m/e): 431.4 (MH+).
Reaction SMILES: [CH:1]1[C:2]([C:10]([OH:12])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.[CH3:13]N(C=O)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>CO.C(Cl)Cl>[CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C(O)c1cc2n(c1)CCCC2
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc2n(c1)CCCC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 5,6,7,8-tetrahydroindolizine-2-carboxylic acid (30.4 g, 184 mmol), DMF (1.00 g, 13.6 mmol) and methylene chloride (300 mL). The solution was cooled to 0° C. using an ice bath. Oxalyl chloride (28.0 g, 221 mmol) was added dropwise, and the reaction mixture was warmed to room temperature over 30 min and stirred for 5 h. After this time, the resulting solution was concentrated to afford a brown solid. This solid was dissolved in anhydrous methanol (400 mL), and the solution was cooled to 0° C. Triethylamine (57 g, 552 mmol) was added to the reaction mixture, and it was stirred for a further 2 h at room temperature. After this time, the reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with methylene chloride (300 mL) and washed with water (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was titrated with hexane (200 mL) to afford 118a in 58% yield (19.1 g) as a white solid: mp 72-74° C.; 1H NMR (300 MHz, DMSO-d6) d 7.13 (s, 1H), 6.23 (s, 1H), 3.93 (t, 2H, J=6.0 Hz), 3.77 (s, 3H), 2.75 (t, 2H, J=6.0 Hz), 1.93 (m, 2H), 1.80 (m, 2H); (APCI+) m/z 180.1 (M+H)
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C(#N)C>[CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][Br:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Solvent: CC#N
Solvent: O
Product: BrCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4′-(2-benzylbenzofuran-3-yl)biphenyl-4-methanol (5.01 g, 12.7 mmol) in anhydrous acetonitrile (75 mL) was added dibromotriphenylphosphorane (5.45 g, 12.7 mmol) as a solid portionwise over 15 mins. The reaction was stirred for 2 hours (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the title compound as an off-white solid (4.98 g, 87%): 1H NMR (CDCl3, 300 MHz): δ 7.70 (2H, m, Ar—H), 7.63 (4H, m, Ar—H), 7.50 (3H, m, Ar—H), 7.30 (4H, m, Ar—H), 7.25 (4H, m, Ar—H), 4.57 (2H, s, CH2Br), 4.26 (2H, PhCH2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH2:11][Br:12]>CC(C)=O>[Br-:12].[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH2:11][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON=C(CBr)c1ccc(C)cc1
Reactant: c1ccncc1
Solvent: CC(C)=O
Product: CON=C(C[n+]1ccccc1)c1ccc(C)cc1
Product: [Br-]
Yield: 84 %

Procedure:
A solution of pyridine (165 μl, 2.05 mmol) and (3) (543 mg, 2.24 mmol) in acetone (3 mL) was refluxed for a day. The solid formed was isolated by filtration and rinsed with Et2O in 84% yield: mp 106-109° C.; 1H NMR 400 MHz (DMSO-d6) δ 3.30 (s, 3H), 3.99 (s, 3H), 6.10 (s, 2H), 7.24 (d, 2H, J=5.6 Hz), 7.65 (d, 2H, J=5.9 Hz), 8.13 (m, 2H), 8.60 (m, 1H), 9.07 (s, 2H); FABHRMS: found M+, 241.1340 (calcd for C15H17ON2: M+, 241.1335).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:40])[NH:41][CH2:42][CH2:43][C:44]([N:29]1[CH2:28][CH2:27][CH:26]([C:24](=[O:25])[NH:23][C:10]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH:13]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)[CH2:31][CH2:30]1)=[O:45])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1ccc(Oc2cc(NC(=O)C3CCNCC3)cc(Oc3ccc(C#N)cc3)c2)cc1
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 68.3 %

Procedure:
Following the procedure of Example 9(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine 1.0 g (2.28 mmol) and 3-tert-butoxycarbonylamino-propionic acid (0.431 g, 2.28 mmol) were used to afford 0.95 g of the required product. 114 NMR (DMSO-d6): δ 1.4 (9H, s), 1.42 (4H, m), 2.31 (3H, m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (1H, m), 3.7 (1H, m), 6.76 (1H, s), 7.26 (6H, m), 7.86 (4H, d), 10.01 (1H, s).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][CH2:15][C:16]1[C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)=[N:18][C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:21]=1[CH3:22].C(Cl)(Cl)Cl>CC(C)=O.O>[C:5]([NH:3][C:2](=[S:1])[NH:14][CH2:15][C:16]1[C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)=[N:18][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:21]=1[CH3:22])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CNC(=S)NC(=O)c1ccccc1
Yield: 81 %

Procedure:
A mixture of ammonium thiocyanate (0.25 g) and benzoyl chloride (0.41 g) in acetone (20 ml) was refluxed for 2 hours, and 5-aminomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (0.9 g) in acetone (5 ml) was added thereto. After refluxing for 2 hours, the reaction mixture was poured into a mixture of chloroform (100 ml) and water (50 ml). The organic layer was separated, washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the resulting crystal was recrystallized from diisopropyl ether to give 5-(3-benzoylthioureidomethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.1 g).