Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:6]1([NH:5][C:3](=[O:4])[CH2:2][N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
N-Chloroacetylaniline (0.5 g, 2.95 mmol), 1-(2-pyridinyl)piperazine (0.72 g, 4.42 mmol), and N,N-diisopropylethylamine (1.03 mL, 5.9 mmol) were combined in toluene and heated at reflux overnight. The mixture was allowed to cool to room temperature, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 60% ethyl acetate:hexanes) to provide 400 mg (46% yield) of the title compound as a hygroscopic white solid. 1H NMR (300 MHz, CDCl3) δ 2.60 (m, 4H), 3.18 (s, 2H), 3.55 (m, 4H), 6.65 (dd, 1H, J=12, 6 Hz), 6.85 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=6 Hz), 7.3 (t, 2H, J=9 Hz), 7.51 (ddd, 1H, J=9, 7.5, 3 Hz) 7.68 (d, 2H, J=9 Hz) 8.1 (dd, 1H, J=6, 3 Hz) 9.75 (br s, 1H); MS (DCI/NH3) m/e 297 (M+H)+; Anal. calcd for C17H20N4O: C, 68.89; H, 6.80; N, 18.90. Found: C, 68.97; H, 6.87; N, 19.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(F)cc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(F)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A mixture of methyl 3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylate (37 mg, 0.18 mmol), LiOH (27 mg, 1.1 mmol), water (2 mL) and THF (1 mL) was stirred at room temperature overnight and then partitioned between ether and water. The aqueous layer was extracted thrice with ether and then repeatedly with ethyl acetate. The combined organic solutions were dried over MgSO4 and the solvent was removed by evaporation. There was obtained 15 mg (43%) of 3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid as a white solid. 1H NMR (500 MHz, CD3CO CD3): 1.8 (m, 4H), 2.8 (m, 2H), 3.1 (m, 2H), 7.0 (m, 1H), 7.6 (m, 1H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][N:28]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][N:28]=3)=[CH:21][N:20]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COc1ccnc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Solvent: c1ccncc1
Product: COc1ccnc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)c1

Procedure:
2-(2-Guanidino-4-thiazolylmethylthio)ethylamine is heated under reflux in pyridine for 12 hours with 0.75 molar equivalents of 2-nitroamino-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone. When this product is boiled under reflux in 2N hydrogen bromide in ethanol 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(4-hydroxy-2-pyridylmethyl)-4-pyrimidone trihydrobromide is produced.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[CH:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:20][C:15]1([C:13]2[CH:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=2)[O:16][CH2:17][CH2:18][O:19]1
Reactant: CC1(c2csc(CO[Si](C)(C)C(C)(C)C)c2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2csc(CO)c2)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of tert-butyl-dimethyl-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethoxy]-silane (545 mg, 1.73 mmol) in dry THF (5.0 mL) was treated at 0° C. with TBAF (2.6 mL of a 1M solution in THF, 2.60 mmol). The reaction mixture was stirred at 0° C. for 2 h. The mixture was then diluted with EA (10 mL), washed with brine (3×20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:5 EA-Hept) gave the title compound as a colorless oil. TLC:rf (1:1 EA-Hept)=0.36. LC-MS-conditions 02: tR=0.70 min.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]([O:16][CH3:17])[CH:5]=1)#[N:2].[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[OH:11][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([C:13]([NH2:15])=[O:14])[CH:8]=2)[CH:3]=[C:1]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:2]=1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1C(N)=O
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(N)=O
Temperature: 130 °C
Yield: 85.9 %

Procedure:
A mixture of 6-Cyanomethyl-4-methoxy-isophthalamic acid (0.5 g, 2.34 mmol), 3-amino-5-methylpyrazol (0.45 g, 4.68 mmol), acetic acid (10 ml) were sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 1.5 ml MeOH. This solution was added dropwise to 30 ml water, and the formed solid was collected and purified by flash column chromatography to give product (0.63 g, 86%). LC-MS: m/e 314 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:21].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:23]1([C:22](=[N:35][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][C:3]=2[CH3:21])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1N=C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 46 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.7 g) and benzophenone imine (1.2 ml) in toluene (20 ml) was added sodium tert-butoxide (732 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (296 mg) and tris(dibenzylideneacetone)dipalladium(0) (131 mg) were added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was then cooled to room temperature, poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 75% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(diphenylmethyleneamino)-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.01 g, 46%) as a yellow foam. MS (ISP): 458.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC[CH:25]([O:28]C(CCl)CCl)CCl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:25]=[O:28])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: Cc1ccc(S(=O)(=O)N2CCC(c3ccccc3)CC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccc(C=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-methylphenylsulfonyl)-4-phenylpiperidine (1.0 g) and 1,1-dichloromethylmethylether (0.57 ml) in dichloromethane (5 ml) was added at 0° C. a solution of titanium tetrachloride (0.7 ml) in dichloromethane (5 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was added to stirred ice/water to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:→41:2) to give pale yellow crystals of 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]benzaldehyde (0.381 g). (469.4 mg of the starting materials were collected)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH2:28])=[O:27])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:52]CC1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH:28][OH:52])=[O:27])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: C1CCOC1
Reactant: NC(=O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NO)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a 25° C. solution of 3(S)-N-(tert-butyldiphenylsilyl)oxy-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxamide (35 mg) in 2 mL of THF was added 0.060 mL of 2M tetrabutylammonium fluoride in THF. After 30 minutes, the solution was partitioned between 1 M pH 7 phosphate buffer and ethyl acetate. The aqueous layer was extracted once with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was triturated with hexane and the resulting solid was collected by filtration to yield 3(S)-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-N-hydroxy-tetrahydro-2H-1,4-thiazine-3-carboxamide (22 mg). 1H NMR (CDCl3): δ 9.69 (bs, 1H), 7.24 (d, 2H, J=8.82 Hz), 7.51 (d, 2H, J=8.46 Hz), 7.05 (t, 4H, J=9.37 Hz), 6.69 (s, 1H), 4.57 (s, 1H), 4.02 (d, 1H, J=12.5 Hz), 3.28-3.12 (m, 2H), 2.50 (d, 1H, J=12.87 Hz), 1.61 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].[CH:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:20][CH:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C(O)Cc2nc(C)c(C)nc2C)cc1
Yield: 52.1 %

Procedure:
The reaction of 13.6 grams (0.1 mole) of tetramethylpyrazine with 13.6 grams (0.1 mole) of p-anisaldehyde was conducted in the manner described in Example II. Crystallization of the recovered crude product from ether yielded 14.2 grams (52%) of white crystals, m.p. 97°-98° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[CH3:19][NH2:20]>CO>[OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:20][CH3:19])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: O=Cc1c2ccccc2c(CO)c2ccccc12
Reactant: CN
Solvent: CO
Product: CN=Cc1c2ccccc2c(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10-(hydroxymethyl)-9-anthraldehyde (3.00 g, 12.7 mmol) was added to 50 mL of a saturated solution of methylamine in methanol and stirred at room temperature for 2 h. The solvent and excess methylamine was removed under reduced pressure to afford the imine as a bright yellow powder (quant); 1H NMR (300.13 MHz, DMSO-d6) δ 3.35 (s, 3H), 5.51 (s, 2H), 7.61 (m, 4H), 8.55 (m, 4H), 9.48 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:10][CH:12]1[CH2:13][O:14]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(F)c(F)c1
Product: Fc1ccc(OCC2CO2)cc1F

Procedure:
The title compound was prepared from 3,4-difluoro-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:21]([O-])([OH:23])=[O:22].[OH-].[K+]>C(O)(=O)C>[N+:21]([C:9]1[CH:8]=[CH:7][C:6]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)([O-:23])=[O:22]
Reactant: c1ccc(CCCc2ccncc2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CCCc2ccncc2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Into a solution consisting of 10.3 ml of pure acetic acid and 18.6 ml of 98% sulfuric acid, cooled to 5° C., are introduced slowly, drop by drop, 25 g of 4-(3-phenylpropyl) pyridine. When this addition has been completed, the solution obtained is cooled to -15° C. and a sulfonitric mixture consisting of 9 ml of nitric acid and 18.6 ml of 98% sulfuric acid is added drop by drop. During the whole of the addition the temperature of the reaction medium is maintained below +10° C. The addition is completed in one hour. The yellow solution obtained is poured into 600 g of a water+ice mixture. The pH is adjusted to 11 by the addition of an aqueous potassium hydroxide solution and the mixture is extracted twice with 200 ml of ether. The ethereal phases are collected and washed with water, dried over magnesium sulfate and concentrated. 29.7 g of 4-[3-(4-nitrophenyl)propyl]pyridine are obtained.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32])([O-:23])=[O:22]>ClCCl.N1C=CC=CC=1>[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[C:25]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:13])=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34])([O-:23])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 6.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-nitro-3-(trifluoromethyl)aniline (2.39 g, 11.6 mmol) in 19 mL of pyridine. The crude product was recrystallized from ethyl ether to yield 0.25 g of the title compound, mp 167-169° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:17]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[F:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C@H:17]1[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CNCC[C@@H]1c1cc(F)c(F)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step D was dissolved into 40 ml of 1:1 dichloromethane/trifluoroacetic acid and stirred at ambient temperature for 60 min. The solution was then concentrated and taken up in 250 mL of 3:1 chloroform/isopropyl alcohol then washed with saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound as a colorless crystalline solid which was used without further purification. LC/MS 365.4 (M+1).
Reaction SMILES: O.[Li+].[C:3]([O-:13])(=[O:12])[C:4]1[NH:11][C:9](=[O:10])[NH:8][C:6](=[O:7])[CH:5]=1.Cl>CN(C=O)C>[OH:10][C:9]1[N:11]=[C:4]([C:3]([OH:13])=[O:12])[CH:5]=[C:6]([OH:7])[N:8]=1
Reactant: O=C([O-])c1cc(=O)[nH]c(=O)[nH]1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(O)nc(O)n1
Temperature: 70 °C

Procedure:
23.00 g (127.74 mmol) orotic acid lithium salt monohydrate in 400 mL DMF were heated to 70° C. and at this temperature hydrochloric acid was added batchwise within 2 h. The reaction mixture was stirred for a further hour at 70° C. and then evaporated down in vacuo. The residue was stirred with water, suction filtered and dried at 50° C. in the CAD.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([CH3:19])[CH2:10]2)=[C:4]([N+:20]([O-])=O)[CH:3]=1.[H][H]>[Ni].O1CCCC1>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([CH3:19])[CH2:10]1
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1C
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1C

Procedure:
A mixture of 39.6 parts of methyl 4-(4-chloro-2-nitrophenylamino)-2-methyl-1-piperidinecarboxylate and 450 parts of tetrahydrofuran is hydrogenated at 40 lbs./sq. inch and at room temperature with 2 parts of raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off. The filtrate is evaporated, yielding methyl 4-(2-amino-4-chlorophenylamino)-2-methyl-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][O:27][CH2:28][CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][N:30]1[CH3:35].C(N(C(C)C)CC)(C)C>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]4[CH2:32][CH2:31][N:30]([CH3:35])[CH:29]([CH2:28][O:27][CH3:26])[CH2:34]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: COCC1CNCCN1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)CCN1C

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3, step A) (70 mg, 0.197 mmol), commercially available rac-2-methoxymethyl-1-methyl-piperazine (CAS no. 734507-92-7) (28.5 mg, 0.197 mmol) and diisopropylethyl amine (167 ul, 0.984 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a light yellow (50 mg, 55%), MS (ISP) m/e=464.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH3:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CS[C:21]1[NH:22][CH:23]=[C:24]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[C:25](=[O:27])[N:26]=1>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH3:16])[C:21]3[NH:22][CH:23]=[C:24]([CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[C:25](=[O:27])[N:26]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CNCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: CN(CCc1ccc(Oc2ccc(F)cc2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 125 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl-methyl amine (0.204 mmol, 1 eq) and 2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.082 mmol, 0.4 eq) were dissolved in dry ethanol (200 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-10% in 30CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-fluoro-phenoxy)phenyl]-ethyl-methyl-amino}-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.042 mmol, yield: 20%, HPLC-MS/UV: [M+H]+=432.14; rt: 10.14 mins; purity: 97%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.89 (t, J=7.17, 2H), 3.59 (s, 2H), 3.69-3.77 (m, 2H), 6.86-7.05 (m, 5H), 7.10-7.18 (m, 2H), 7.23-7.30 (m, 2H), 7.69 (s, 1H), 8.61 (s, 1H), 9.02-9.05 (m, 1H), 9.95 (br.s., 1H)
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](Cl)(C)C.[Cl:25][CH:26]([O:30][C:31](Cl)=[O:32])[CH2:27][CH2:28][CH3:29]>ClCCl>[Cl:25][CH:26]([O:30][C:31]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:32])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(Cl)OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
To a suspension of gabapentin (8.55 g, 50 mmol) in dichloromethane at 0° C. was added triethylamine (21 mL, 150 mmol) and TMSCl (6.4 mL, 50 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then a solution of chloroformate (132) (8.55 g, 50 mmol) in dichloromethane was added. The reaction was stirred for another hour at room temperature, then quenched with citric acid and extracted with dichloromethane. The combined organic phase was washed with water and brine and dried over Na2SO4. Filtration and evaporation gave 9.5 g of crude product (133), which was used directly in the subsequent step.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([O-:14])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.N12CCCN=C1CCCCC2.[CH3:28][C:29]([CH3:37])([CH2:35][CH3:36])[C:30]([O:32][CH2:33]I)=[O:31]>C(Cl)Cl>[NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([O:14][CH2:33][O:32][C:30](=[O:31])[C:29]([CH3:37])([CH3:28])[CH2:35][CH3:36])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Reactant: CCC(C)(C)C(=O)OCI
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C)(C)C(=O)OCOC(=O)C1=C(COC)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
1.46 g (6 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylate were suspended in 30 ml of methylene chloride, and 0.92 ml (6 mmol) of 1,8-diazabicyclo-(5,4,0)-undec-7-ene (DBU) was added at 0° C. After 30 minutes, 1.66 g (6.5 mmol) of iodomethyl 2,2-dimethyl-butyrate (compare preparation example 4) were added, while cooling with ice, and the mixture was subsequently stirred at room temperature for 2 hours. The precipitate which had separated out was filtered off with suction and the crude product was chromatographed (SiO2 ; toluene/ethyl acetate=1:1). 1.2 g (53%) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1Br.[CH3:12][C:13]1([CH3:28])[CH2:18][CH2:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH2:14]1>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13]([CH3:28])([CH3:12])[CH2:14][CH:15]=1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: NC(=O)c1ccc(N)c(Br)c1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2N)CC1
Yield: 77.9 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 4-amino-3-bromo-benzamide (as prepared in Example 16, step (a), 62.4 mg, 0.289 mmol), and 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (75.0 mg, 0.318 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (55 mg, 78%) as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C15H20N2O, 245.2 (M+H), found 245.2.