Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH:42][C:13](=[O:15])[C:12]5[CH:11]=[CH:10][C:9]([CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[CH:17][CH:16]=5)=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Oc4ccc5c(c4)CCC(c4ccc(F)cc4)O5)nc3)cc2)CC1
Reaction time: 3 h

Procedure:
4-(4-Methylpiperazin-1-ylmethyl)benzoic acid (ca 0.19 g), 6-[2-(4-fluoro-phenyl)-chroman-6-yloxy]pyridin-3-ylamine (0.18 g) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.12 g) were added into dichloromethane (12 ml). The mixture was stirred at room temperature and after 4 hours more 4-(4-methylpiperazin-1-ylmethyl)-benzoic acid (ca 0.11 g) and 1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide hydrochloride (0.0.46 g) were added. Stirring was continued for additional 3 hours. Water and dichloromethane were added and organic and water phases were separated. Water phase was extracted with dichloromethane. The product was purified by column chromatography using dichloromethane-methanol (9:1) as an eluent to give N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}-4-(4-methylpiperazin-1-ylmethyl)benzamide. 1H NMR (300 MHz, d6-DMSO) δ: 1.90-2.08 (m, 1H), 2.11-2.21 (m, 1H), 2.18 (s, 3H), 2.38 (bs, 8H), 2.68-2.79 (m, 1H), 2.91-3.05 (m, 1H), 3.54 (s, 2H), 5.13 (dd, 1H, J 2.0, 10.1 Hz), 6.86 (d, 2H, J 1.2 Hz), 6.90 (s, 1H), 6.98 (d, 1H, J 8.8 Hz), 7.19-7.27 (m, 2H), 7.43-7.54 (m, 4H), 7.92 (d, 2H, J 8.2 Hz), 8.18 (dd, 1H, J 2.7, 8.9 Hz), 8.48 (d, 1H, J 2.7 Hz), 10.31 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][S:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][NH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][S:6]([C:7]1[NH:11][CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: CNc1ccccc1CSc1ncc[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1ccccc1CS(=O)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 900 mg (4.11 mmol) of 2-(2-methylaminobenzylthio)imidazole in a mixture of 40 ml of chloroform and 10 ml of methanol was portionwise added under chilling with ice 880 mg (4.11 mmol, purity 80%) of m-chloroperbenzoic acid. The mixture was then stirred for 30 min. To the stirred mixture was added a saturated aqueous sodium hydrogencarbonate. The resulting aqueous solution was subjected to extraction with 50 ml of chloroform. The chloroform portion was taken out and the subjected to extraction with three portions of 10 ml of 0.1N aqueous NaOH and one portion of 20 ml of 0.1N aqueous NaOH to transfer a product into the aqueous fractions. The last three aqueous fractions were combined and made ammonia-alkaline by addition of 20% aqueous ammonium chloride to precipitate a crystalline product. The product was collected, washed sufficiently with water and dried under reduced pressure at room temperature to give 637 mg of the desired compound as a pale yellow crystalline product, yield 66%.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([CH2:20][CH2:21][CH2:22][S:23][CH:24]([C:28](O)=[O:29])[C:25](O)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:29][C:28]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:25](=[O:26])[C:24]=1[S:23][CH2:22][CH2:21][CH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(SCCCc1ccccc1)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1SCCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 1-Phenyl-1-(trimethylsilyloxy)ethylene (0.922 g, 4.83 mmol) and diethyl ester of [(3-phenylpropyl)thio]propanedioic acid (1.00 g, 3.22 mmol). m.p. 114-116° C.; 1H NMR (400 MHz, DMSO-d6) δ1.74 (m, 2 H), 2.71 (m, 4 H), 6.82 (m, 1 H), 7.16 (m, 3 H), 7.25 (m, 2 H), 7.54 (m, 3 H), 7.81 (m, 2 H), 11.95 (bs, 1 H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 665.33 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:16])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([O:14]C)=[CH:12][CH:13]=1.I[CH3:18]>CC(OC)(C)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH3:18])[CH:9]=1
Reactant: COc1ccc(CC(=O)c2ccco2)cn1
Reactant: CI
Solvent: COC(C)(C)C
Product: Cn1cc(CC(=O)c2ccco2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 287.1 %

Procedure:
To a solution of 1-furan-2-yl-2-(6-methoxy-pyridin-3-yl)-ethanone (7) (800.0 g, content 625.6 g, 2.88 mol) obtained in Preparation Example 4 in N-methyl-2-pyrrolidine (NMP) (1.88 L) was added iodomethane (122.6 g, 0.86 mol), and the reaction mixture was stirred at 100° C. for 3 hours and then at room temperature for 17.5 hours. To the reaction mixture was added dropwise MTBE (6.6 L) over a period of 77 minutes, followed by stirring for 1 hour while cooling in an ice bath. The precipitated crystals were collected by filtration and washed with MTBE (2.0 L), and then dried under reduced pressure at 50° C. for 3 hours to give 692.0 g of a crude product of the title compound as a dark brown powder (content 536.4 g, yield 85.7%).
Reaction SMILES: C([O:5][C:6]([C:8]([CH3:58])([CH3:57])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[C@@H:16]([N:27]([CH2:40][C:41]2[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=2)[C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:55][CH3:56])=[O:12])=[O:7])(C)(C)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[C:6]([C:8]([CH3:57])([CH3:58])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)[C@@H:16]([N:27]([CH2:40][C:41]2[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=2)[C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:55][CH3:56])=[O:12])([OH:7])=[O:5]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound obtained in Example 10 above (178 mg) was dissolved in 4N—HCl/dioxane (2 ml) and stirred at room temperature for 2.5 hours. To the reaction mixture, were added a saturated sodium hydrogen carbonate aq. solution and ethyl acetate and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the titled compound (157 mg). MS (m/z): 777 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[OH:24])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:44]1[O:46][C@H:45]1[CH2:47]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:21]([C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:23])[C:4]([O:24][CH2:47][C@H:45]4[CH2:44][O:46]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:19]=[C:18]([CH3:20])[N:17]=1)[CH3:22]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cc(C)n1
Reactant: OC[C@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H]4CO4)c(CC)c3)no2)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.2 %

Procedure:
To a solution of 2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (150 mg, 0.464 mmol) in THF (10 mL), PPh3 (146 mg, 0.557 mmol) and (S)-glycidol (52 mg, 0.696 mmol) is added. The mixture is cooled to 0° C. before DEAD (303 mg, 0.696 mmol, 320 μL of a 40% solution in toluene) is added. The mixture is warmed to rt and stirred for 1 h. The solvent is evaporated and the residue is purified by chromatography on prep. TLC plates with heptane:EA 1:1 to give (R)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (201 mg) as a white solid; LC-MS*: tR=1.10* min; [M+1]+=380.42.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 38.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (1.01 g, 2.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.01 g, 4.29 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 15 & 25% EtOAc/hexane step gradient followed by crystallization from ether/pet ether gave 0.549 g (38%) of the title compound as a tan solid, mp 165-170° C. 1H NMR (DMSO-d6) δ 1.22-1.32 (m, 2 H), 1.46-1.58 (m, 2 H), 1.61-1.76 (m, 4 H), 1.78 (s, 3 H), 2.26 (s, 3 H), 2.97 (quintet, 1 H), 3.84 (s, 2 H), 6.94 (d, 2 H), 7.23 (d, 1 H), 7.34-7.40 (m, 4 H), 7.50 (dd, 1 H), 7.53 (d, 1 H), 8.00 (d, 1 H). IR (KBr) 3400, 2950, 1680, 1480, 1390 and 1190 cm-1. mass spectrum (-ESI) m/z 667 (M-H). Anal. Calcd. for C32H29BrO7S2 : C, 57.40; H, 4.37; N, 0.00. Found: C, 57.47; H, 4.24; N, 0.08.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
According to General Method 1A, 28 g (132 mmol) of methyl 5-bromonicotinate and 30 g (158 mmol, 1.2 eq.) of 4-trifluoromethylphenylboronic acid were reacted. Yield: 32 g (85% of theory)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1CCCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCC1CCCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(tetrahydro-2H-pyran-3-yl)-1-butanol (1.20 g) in dry dichloromethane (30.3 ml), cooled to 0° C., was added triethylamine (2.43 ml) and methanesulphonyl chloride (0.77 ml) to give a yellow solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (25 ml). The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to afford a yellow oil (1.80 g). The product was purified by silica chromatography using a gradient elution of 0-40% ethyl acetate/cyclohexane to afford the title compound as a yellow oil (1.58 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16]
Reactant: COC(=O)C1CCCCO1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
A solution of N,N-diisopropylamine (909 mg, 1.25 mL, 9 mmol) in tetrahydrofuran (4 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (3.6 mL, 9 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of tetrahydro-pyran-2-carboxylic acid methyl ester (864 mg, 6 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was stirred at −78° C. for 20 minutes. Acetaldehyde (792 mg, 1.0 mL, 18 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.28 g) as an oil and as a 2:1 mixture of diastereoisomers. LCMS (m/z) 189.3 [M+H], Tr=1.23 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([NH:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC(CN)n1nnnc1S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(CNC(=O)OC(C)(C)C)n1nnnc1S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 1-[1-(aminomethyl)ethyl-1H-tetrazole-5-thiol hydrochloride (17 g) and triethylamine (19.33 g) in 50% aqueous dioxane (80 ml) was added a solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (21.4 g) in dioxane (50 ml) under cooling in an ice bath. The mixture was stirred for 1.5 hours at ambient temperature and concentrated to third volume. The aqueous solution was washed with diethyl ether and the washings were reextracted with aqueous solution of potassium carbonate. The two aqueous solutions were combined, washed with diethyl ether and mixed with ethyl acetate. The mixture was acidified with 10% hydrochloric acid and the organic layer was separated out. The solution was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with n-hexane to give 1-[1-{(N-t-butoxycarbonylamino)methyl}ethyl]-1H-tetrazole-5-thiol (19.15 g), mp 156° to 158° C.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[N:23]([CH3:3])[C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (0.15 mL, 2.41 mmol) and potassium carbonate (0.19 g, 1.34 mmol) are added to a solution of methyl 3-[5-(2,4-dichlorophenoxy)-2-nitrophenyl]-tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.40 g, 0.83 mmol) in N,N-dimethylformamide. The reaction mixture is stirred overnight at room temperature and poured into a saturated ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and an ethyl acetate/hexanes (1:3) solution gives the title product as a yellow foam which is identified by NMR spectral analysis.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH:5]([CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[NH2:6].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:37](O)=[O:38])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[CH3:2][O:3][C:4](=[O:13])[CH:5]([CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[NH:6][C:37](=[O:38])[C@H:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[NH:24][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C(N)Cc1cccs1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 73.6 %

Procedure:
A mixed solution of 1.11 g (5 mmole) of 3-(2-thienyl)-DL-alanine methyl ester hydrochloride and 1.75 g (5 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine in 15 ml of dimethylformamide was cooled with ice water, and then 1.11 g (11 mmole) of triethylamine was added with stirring. After that, 0.83 g (5 mmole) of diethyl phosphorocyanidate was added, and the mixture was stirred for 3 hours at room temperature. Subsequently, the reaction product was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water, then dried, and finally purified by thin layer chromatography, yielding 1.9 g (73.6%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine methyl ester melting at 140°-141° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH:29]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].O1CCCC1>C(OCC)C>[O:34]([CH:29]([O:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)[C:30]([O:32][CH3:33])=[O:31])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: COC(=O)C(Br)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(Oc1ccccc1)Oc1nc(C)cc(C)n1
Reaction time: 48 h

Procedure:
Alternately, the tetrabutylammonium salt of 4,6-dimethyl-2-pyrimidinol was first prepared by placing 4,6-dimethyl-2-hydroxypyrimidine (13.0 g, 0.105 mol) in a flask, adding 65 g of 40 percent aqueous tetrabutylammonium hydroxide (0.10 mol), and removing the water by evaporation under reduced pressure at pressures down to about 10 mm Hg (1.33 kPa) at 40°-45° C. The residue amounted to 42.7 g and appeared to be a dihydrate of the desired salt. A 10.9 g portion of this (25 mmol) was placed in a 500 mL flask containing 25 mL of tetrahydrofuran. A cloudy solution formed. To this was added with stirring at ambient temperature 14 mL of a solution of methyl 2-bromo-2-phenoxyacetate in tetrahydrofuran (containing about 25 mmol). The resulting mixture was allowed to stir for 2 days. Analysis by gas-liquid chromatography indicated only one significant compound was present. A 250 mL portion of diethyl ether was added and the resulting mixture was extracted 5 times with 100 mL portions of water and then with brine. The ethereal solution was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound in crude form as a dark borwn oil. This was filtration chromatographed on silica gel eluting first with a 10:90 mixture of diethyl ether and hexane and then with a 15:85 mixture of ethyl acetate and hexane. The product containing eluate was concentrated by evaporation under reduced pressure to obtain 2.50 g (35 percent of theory) of the title compound as a pale yellow oil. This oil solidified on standing to a light orange solid melting at 50°-53° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][N:16]([CH3:34])[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])(O)=O.[Na+]>O.CC(N(C)C)=O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH:22]3[CH2:23][CH2:24][N:19]([C:17]([N:16]([CH3:15])[CH3:34])=[O:18])[CH2:20][CH2:21]3)=[CH:31][CH:30]=1)=[N:1]2
Reactant: CN(C)C(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC4CCN(C(=O)N(C)C)CC4)cc3)nc2c1
Temperature: 115 °C
Reaction time: 17 h

Procedure:
To a 100 mL round-bottom flask was added 2-amino-4,6-dimethoxybenzamide (196 mg, 1.00 mmol), 4-(4-formylphenoxy)-piperidine-1-carboxylic acid dimethylamide (300 mg, 1.10 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.10 mmol), sodium hydrogensulfite (216 mg, 1.20 mmol) and dimethylacetamide (5 mL). The mixture was stirred at 115° C. under N2 for 17 hours and cooled to room temperature. Water (20 mL) was added and stirred for 0.5 hours. The precipitate was filtered off, washed with water, and air dried. The crude product was purified by column chromatography (SiO2, neat ethyl acetate, then ethyl acetate/methanol=19:1, then CH2Cl2/methanol=19:1) to afford the title compound as a white solid. Yield: 110 mg (24%). MP 248-249° C. 1H NMR (400 MHz, DMSO-d6): δ 11.91 (s, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.72 (s, 1H), 6.51 (s, 1H), 4.71-4.69 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.44-3.39 (m, 2H), 3.06-2.99 (m, 2H), 2.74 (s, 6H), 2.00-1.96 (m, 2H), 1.64-1.59 (m, 2H).