Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[NH2:12])[CH2:3]1.CN1CCOCC1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([NH:12][S:36]([C:34]3[S:35][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[CH:32][CH:33]=3)(=[O:37])=[O:38])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)cc1N1C[C@@H](C)N[C@@H](C)C1
Reaction time: 18 h

Procedure:
3-(cis-3,5-Dimethyl-1-piperazinyl)-4-(methyloxy)aniline (D2) (100 mg, 0.42 mmol) in dichloromethane (10 ml) was stirred with morpholinomethyl-polystyrene HL resin (320 mg, 4 mmol/g loading, 1.28 mmol) at ambient temperature. 5-(2-Pyridinyl)-2-thiophenesulfonyl chloride (110 mg, 0.4 mmol) was added and the mixture stirred for 18 hours. Argopore-trisamine scavenger resin (100 mg, 4 mmol/g loading, 0.4 mmol) was then added and the mixture stirred for a further 30 minutes. The resin was removed by filtration, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography (1:19 2M ammonia in methanol: dichloromethane) to afford the title product (El). MS (ES+) 459 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:23](=[O:24])[NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2cc(O)ccc21
Reactant: O=C=Nc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2cc(OC(=O)Nc3ccccc3Cl)ccc21
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.326 g., 2 mmol) in dry dimethylformamide (5 ml) was added to a stirred suspension of sodium hydride (0.048 g., 2 mmol) in dry dimethylformamide (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 30 min. Then 2-chloro-phenyl isocyanate (0.329 g., 2 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (35° C.). The reaction mixture was quenched with water (0.2 ml), diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2o; yield: 0.50 g. (78.9%), m p. 120° C., C17H17ClN2O2; 1H NMR δ ppm (CDCl3); 1.95-2.01 (m, 2H), 2.77 (t, 2H), 2.88 (s, 3H), 3.21 (t, 2H), 6.54-6.58 (m, 1H), 6.81-7.05 (m, 31), 7.23-7.44 (m, 2H), 8.18-8.22 (m, 1H); IR vmax (KBr) (cm−1); 563, 670, 758, 1017, 1201, 1305, 1432, 1507, 1596, 1746, 2375, 2940, 3020, 3282, 3413, 3686, 3763.
Reaction SMILES: C([BH3-])#N.[F:4][C:5]1[CH:55]=[CH:54][C:8]([C:9]([N:11]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:52]=[CH:51][C:28]4[N:29]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:30]=[N:31][C:27]=4[CH:26]=3)[CH:22]=[CH:21][C:20]=2[F:53])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:7][CH:6]=1.C(O[C:59]1(O[Si](C)(C)C)[CH2:61][CH2:60]1)C.C(O)(=O)C>CO>[CH:59]1([N:15]2[CH2:16][CH2:17][CH:12]([N:11]([CH2:18][C:19]3[CH:24]=[C:23]([C:25]4[CH:52]=[CH:51][C:28]5[N:29]([C:32]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)[C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:30]=[N:31][C:27]=5[CH:26]=4)[CH:22]=[CH:21][C:20]=3[F:53])[C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:55][CH:54]=3)[CH2:13][CH2:14]2)[CH2:61][CH2:60]1
Reactant: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCN(C2CC2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Solid supported cyanoborohydride (2.5 mmol/g, 46 mg) was added to a solution of 4-fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-piperidin-4-yl-benzamide (20 mg, 0.029 mmol), (1-ethoxy-cyclopropoxy)-trimethylsilane (25 mg, 0.145 mmol) and acetic acid (1.74 mg, 0.029 mmol) in 1 mL of methanol. The mixture was stirred at 45° C. for 2 h and then at 75° C. overnight. The mixture was cooled and filtered and the filtrate concentrated in vacuo to provide the crude product. Chromatography provided 14 mg of product. LC/MS: Retention time, 3.20 min; (M+H)=730.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)CCc1cccc(Br)c1
Product: COC(=O)CCc1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 34, Step 1, using 3-(3-bromo-phenyl)-propionic acid and methanol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][S:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][S:30][CH2:31][CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: CSCCN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCSC)ccc21
Yield: 37.9 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methylsulfanyl-ethyl)-amide (67.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methylsulfanyl-ethylamine (45.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 481; and 1H NMR (DMSO-d6, 400 MHz): δ 8.59 (1H, br. s), 8.26 (1H, br. s), 8.11 (1H, br. s), 7.76-7.68 (2H, m), 7.56 (1H, m), 4.25 (2H, bs. s), 3.51-3.46 (2H, q), 3.32 (2H, s), 2.70-2.66 (2H, t), 2.12 (3H, s), 1.35-1.32 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:1]([C:4]1[C:9]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (15 g.), phenol (6.4 g.), anhydrous potassium carbonate (13 g.) and cupric oxide (4.5 g.) was stirred for 4 hours at 120° C. To the reaction mixture was added water and the mixture was extracted with diethyl ether. The extract was washed with a diluted aqueous solution of potassium carbonate and water, dried over magnesium sulfate and then evaporated under reduced pressure. The oily residue was distilled under reduced pressure to give ethyl 2-(2-nitro-3-phenoxypheny)acetate (5.2 g.) bp 160°-183° C./0.4 mmHg.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][OH:14].[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>CS(C)=O.C1C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][O:14][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2OCN1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=Cc1ccc(OCCN2COc3ccccc3C2=O)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.58 g (3.0 mM) of 2-(4-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-ethanol was dissolved in 5.0 ml of dimethyl sulfoxide. After the addition of 0.18 g (4.5 mM) of sodium hydride (oil) under ice cooling, the mixture was stirred for one hour while heating at 40° C. Then, 0.56 g (4.5 mM) of p-fluorobenzaldehyde in 5.0 ml of benzene was gradually added dropwise under ice cooling. After the addition, the mixture was allowed to stand room temperature while stirring for one hour. After the reaction, the reaction mixture was poured into ice water and extracted twice with ethyl acetate. The oil phase was combined and washed once with water, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified with a silica gel column (eluent, hexane:ethyl acetate=5:1) to obtain 0.56 g (yield 62%) of colorless crystals of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:17]CN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:17])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a cooled (0° C.) solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.095 g, max. 5.29 mmol) in extra dry MeOH (0.24 mL, 5.93 mmol) and DCM (5 mL) was added DMAP (0.066 g, 0.539 mmol). EDCI (1.239 g, 6.47 mmol) was added and the reaction mixture allowed to warm up to room temperature. The reaction mixture was washed with aqueous 0.5 N HCl (3×10 mL), and brine (25 mL). The organic phase was dried over Na2SO4, filtered, and evaporated in vacuo to afford the desired product (1.129 g, 98% over two steps) as a colourless oil.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1>C(#N)C.Br[Bi](Br)Br>[CH:33]1([CH2:36][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:16](=[O:25])[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]3=[O:24])[CH2:11][CH2:10]2)[CH2:35][CH2:34]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Reactant: O=CC1CC1
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 12B (750 mg, 2.086 mmol) in acetonitrile (10 mL) was treated with triethylsilane (0.432 mL, 2.71 mmol) and tribromobismuthine (94 mg, 0.209 mmol), followed by slow addition of cyclopropanecarbaldehyde (175 mg, 2.503 mmol) (dissolved in acetonitrile (0.5 mL)). The reaction mixture was stirred at room temperature overnight. The dark solid was removed by filtration, the filtrate was concentrated, and the residue was purified by ISCO silica column (24 g), gradient elution with ethyl acetate:hexane (0%-100% ethyl acetate over 15 min). Concentration of the desired fractions yielded 12C (630 mg, 2.104 mmol, >quantitative yield) as a white solid. MS (ES): m/z=322 [M+Na]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.56-7.65 (m, 2H); 7.46-7.53 (m, 2H); 3.89-3.99 (m, 1H); 3.13-3.22 (m, 1H); 3.12 (d, 2H, J=6.8 Hz); 2.04-2.16 (m, 2H); 1.92-2.00 (m, 2H); 1.52-1.61 (m, 2H); 1.14-1.27 (m, 2H); 0.80-0.92 (m, 1H); 0.30-0.39 (m, 2H); −0.02-0.05 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
Ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate (1.233 g, 4.54 mmol) was dissolved in dioxane (20 ml). Lithium hydroxide (0.120 g, 5.00 mmol) was added as a solid. Water (10 ml) was added. The solution was stirred 16 h at room temp. The solution was diluted with water (70 ml) and was extracted with tert-butylmethylether (2×100 ml). The aqueous phase was acidified with 1N sodium hydrogensulfate solution (pH =1) and was extracted with tert-butylmethylether (3×70 ml). These organic layers were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 1.05 g of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid. The crude product was used for further synthesis.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.S1C=CC(B(O)O)=C1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:29]4[CH:30]=[CH:31][O:27][CH:28]=4)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccoc1
Agent: OB(O)c1ccsc1
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccoc3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 17 using 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole and furan-3-boronic acid, instead of thiophen-3-boronic acid.
Reaction SMILES: [Na].[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH2:21]([C:25]1[C:26](=[O:34])[CH2:27][C:28]([CH3:33])([CH3:32])[CH2:29][C:30]=1[CH3:31])[CH2:22][CH2:23][CH3:24].C([O-])(=O)C.[NH4+]>C(O)C.C(OCC)(=O)C>[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:31][C:30]2[CH2:29][C:28]([CH3:32])([CH3:33])[CH2:27][C:26](=[O:34])[C:25]=2[CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: CCCCC1=C(C)CC(C)(C)CC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCC1=C(C=Cc2ccc(N(CCCC)CCCC)cc2OC)CC(C)(C)CC1=O
Temperature: 60 °C
Yield: 10.6 %

Procedure:
0.3 g (13.0 mmol) of sodium was dissolved in 15 ml of ethanol. Next, 2.63 g (10.0 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 2.22 g (11.0 mmol) of 2-butyl-3,5,5-trimethyl-2-cyclohexenone were dissolved in 5 ml of ethanol and added to the mixture. To this mixture, 0.36 g of ammonium acetate was added and the mixture was stirred with heating at 60° C. for 22 hours. To the mixture, 100 ml of ethyl acetate was added. Washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 465 mg of a dark red oily matter (yield: 10.6%).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([N:21]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]1=[O:27])(=[O:20])[NH2:19].O>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[C:25]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:26])/[CH:24]=[CH:23]\[C:22](=[O:27])[NH:21][C:18](=[O:20])[NH2:19]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: NC(=O)N1C(=O)C=CC1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)NC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A mixture of 49 g of hexadecanol (0.202 moles), 28 g of N-carbamylmaleimide (0.2 moles) and 270 mg of zinc chloride (0.002 moles) in 300 mL of p-dioxane was heated to reflux. After 24 hours, the mixture was cooled to room temperature and 200 mL of H2O was added. The resulting solid was filtered, washed with additional H2O and dried to afford 75 g (97% yield) of hexadecyl maleurate. M.P.: 106°-09° C. (dec.); 1H NMR (CDCl3): δ10.5 (br s, 1H), 8.2 (br s, 1H), 6.3 (m, 2H), 5.4 (br s, 1H), 4.2 (t, 2H), 1.6 (m, 2 H), 1.2 (m, 26H), 0.9 (t, 3H); HPLC (80% CH3CN/H2O, C18): Rt=6.9 minutes.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].ClC1C=CC=C2C=1C1C(=O)NC(NC(=O)C(C)(C)C)=[N:26][C:20]=1[NH:21]2.O.[OH-].[NH4+]>CS(C)(=O)=O>[NH2:21][C:20]1[NH:26][C:7](=[O:8])[C:6]2[C:5]3[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Agent: CS(C)(=O)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Temperature: 150 °C
Yield: 59.7 %

Procedure:
To a 50 mL flask was added 4 (225 mg, 1 mmol), 9 (452 mg, 4 mmol) in DMSO2 (500 mg) was heated at 150° C. for 2 h. The mixture was cooled to room temperature. 15 mL water was added and ammonium hydroxide was used to neutralize the suspension. The brown solid was obtained by filtration. Washed with water and dried. The solid was dissolved in methanol and silica gel was added. A dry silica gel plug obtained after evaporation. The plug was then loaded on the column and washed with 5% methanol in chloroform. The fractions containing the desired product (TLC) were pooled and evaporated to afford 132 mg (60%) of 10 as a white solid: 1H NMR (DMSO-d6) δ 1.71 (m, 4H), 2.60 (m, 2H), 2.72 (m, 2H), 6.38 (s, 2H), 10.72 (s, 1H). Anal. calcd for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99; 0, 7.23; S, 14.49. Found: C, 53.45; H, 5.06; N, 18.26; S, 14.02.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[F:9])=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1ccccc1F
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccccc1CNc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
In a round bottom flask, 5-bromo-pyridin-2-ylamine (38, 4.05 g g, 23.4 mmol) was combined with 70.0 mL of acetonitrile, 2-fluoro-benzaldehyde (39, 2.45 mL, 23.4 mmol), triethylsilane (20.0 mL, 125 mmol) and trifluoroacetic acid (10.0 mL, 130 mmol). The reaction was stirred at 80° C. for 3 hours. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-60% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (40, 5.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(NC(C)=O)nc2C)cc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A stirred solution of methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate (Description 7 in EP 97/17351, 300 mg, 1.2 mmole) and pyridine (0.16 ml, 2.0 mmole) in DCM (35 ml) at 0° C. under argon was treated with acetyl chloride (120 mg, 1.5 mmole) and allowed to warm to room temperature over 1 h. Additional acetyl chloride (120 mg) was added, the mixture maintained at room temperature for a further 1 h, then washed with 10% Na2CO3 solution, dried (Na2SO4) and concentrated under vacuum to afford the title compound as a white solid (344 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:19][OH:20])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(Cc1ccc(Cl)cc1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(Cc1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 110.7 %

Procedure:
A solution of 3-(p-Chlorophenyl)-1,1,1-trifluoro-2-propanone (10.0 g, 0.045 mol) and ethanol (60 mL) is treated with a solution of hydroxylamine hydrochloride (4.68 g, 0.067 mol) and water (20 mL) and then with a solution of sodium acetate (5.53 g, 0.067 mol) and water (20 mL). The reaction mixture is then refluxed for 2 hours, cooled to room temperature, diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a liquid which solidifies upon standing to give the title product as white needles (11.84 g). Identified by IR and NMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]([F:18])([F:17])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:17][CH:12]([F:18])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
4-Nitrophenol (0.14 g, 1.0 mmol, Aldrich), methyl chlorodifluoroacetate (0.29 g, 2.0 mmol, Aldrich) and potassium carbonate (0.29 g, 2.1 mmol) were combined in dry DMF (0.5 mL) under an argon atmosphere. After stirring at 95°-100° C. for 0.5 h, the mixture was cooled to RT, ethyl acetate (20 mL) was added and the organic layer was washed three times with 10% NaOH. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ether/hexanes) to provide the title compound as a white solid (0.12 g, 65%). mp 33°-35° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of commercially available (Aldrich) methyl 5-oxo-L-prolinate (20 g, 140 mmol) in DCM (200 ml) were added triethylamine (19.6 ml, 140 mmol), 4-(dimethylamino)pyridine (17.2 g, 140 mmol) and finally, dropwise, a solution of BOC2O (61 g, 280 mmol) in DCM (100 ml). The resulting red mixture was stirred at room temperature for 2 hours. Then the solvent was removed in vacuo and the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6) to afford (after trituration in hexane/diethylether 1:1) the title compound as a white solid (32.4 g, 96%); Rf (cyclohexanes:ethyl acetate=65:35): 0.21; 1H NMR (300 MHz, CDCl3) δ (ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H).