Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH:5]([O:26][CH3:27])[O:6][C@@H:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][C@H:9]([OH:20])[C@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([OH:13])=O)(=[O:3])[NH2:2].C(N(CC)CC)C.CN(C(ON1N=N[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(#N)C>[CH2:14]([C@@H:10]1[C:11](=[O:13])[O:20][C@H:9]1[CH2:8][C@@H:7]([O:6][CH:5]([O:26][CH3:27])[CH2:4][C:1]([NH2:2])=[O:3])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:48][CH2:49][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCCCCC[C@H](C(=O)O)[C@@H](O)C[C@H](CCCCC)OC(CC(N)=O)OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(CC(N)=O)OC
Yield: 42.2 %

Procedure:
A solution of 42.5 mg of (2S,3S,5S)-5-[(R/S)-2-carbamoyl-1-methoxyethoxy]-2-hexyl-3-hydroxydecanoic acid (Example Kd)) in 10 ml of methylene chloride/acetonitrile (1:1) was treated with 1g of molecular sieve (4Å), 0.1 ml of triethylamine and 50 mg of HBTU. After stirring the reaction mixture was filtered and concentrated and the residue was partitioned between hexane and methanol/water (1:1); the aqueous methanolic phase was extracted with hexane, the hexane phase was dried and concentrated; the residue was subsequently chromatographed on silica gel with 5 percent methanol in methylene chloride. There were obtained 21 mg of (R/S)-3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-3-methoxypropionamide (epimers 3:1), m.p. 54°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[N:14]=1.FC(F)(F)C1C=CC=NC=1>>[Cl:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N:3]=1.[Cl:12][C:13]1[C:18]([Cl:1])=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[C:15]([Cl:23])[N:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Agent: FC(F)(F)c1cccnc1
Product: FC(F)(F)c1cc(Cl)c(Cl)nc1Cl
Product: FC(F)(F)c1cnc(Cl)c(Cl)c1

Procedure:
The process according to claim 1 wherein 2-chloro-5-trifluoromethylpyridine or 2,6-dichloro-5-trifluoromethylpyridine is used as the 5-trifluoromethylpyridine derivative to produce 2,3-dichloro-5-trifluoromethylpyridine or 2,3,6-trichloro-5-trifluoromethylpyridine, respectively, as the 3-chloro-5-trifluoromethylpyridine derivative.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:20])[NH:18][OH:19].[C:21](Cl)(=[O:23])[CH3:22].C(N(CC)CC)C.[OH-].[Li+]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([N:18]([OH:19])[C:21](=[O:23])[CH3:22])[CH3:20]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(C)NO)c1Cl
Reactant: CC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(=O)N(O)C(C)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 44.7 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxy-α-methylbenzenemethanamine (1.2 g, 3.8 mmol) is reacted with acetyl chloride (0.66 g, 8.5 mmol), triethylamine (1.2 g, 11.6 mmol), and lithium hydroxide (0.46 g, 19.3 mmol) according to the procedure of Example 48 to give N-[1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethyl]-N-hydroxyacetamide (0.6 g, 45% yield); mp 185°-187° C.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[C:13]2[CH2:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:34].[CH3:35]C(O)=O>>[CH3:2][O:3][C:4]1[C:5]([O:34][CH3:35])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH2:11][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]2[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1
Reactant: COc1c(O)ccc2c1CCC(c1ccccc1)C2c1ccc(OCCN2CCCC2)cc1
Reactant: CC(=O)O
Agent: Br
Product: COc1ccc2c(c1OC)CCC(c1ccccc1)C2c1ccc(OCCN2CCCC2)cc1

Procedure:
Using a procedure analogous to Example 5, from 2.3 g (0.005 mole) of 1-{2-[4-(5,6-dimethoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine, 80 ml of HOAc and 80 ml of 48% aqueous HBr, was obtained 650 mg of a mixture of 2-methoxy-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ehtoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-1-ol and 1-methoxy-6-phenyl-5-[4-(2-pyrroldin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([CH:21]([CH3:23])[CH3:22])[N:9]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([CH:21]([CH3:23])[CH3:22])[N:9]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3Cl)nn(C(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1nc(-c2ccccc2Cl)c2ccc(C(=O)O)cc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of methyl 3-(2-chlorophenyl)-1-isopropyl-1H-indazole-6-carboxylate (57.7 mg, 0.18 mmol) in methanol (1.1 mL) and tetrahydrofuran (0.7 mL) was added sodium hydroxide (1.0 M, 1.10 mL, 1.10 mmol). The mixture was heated to 50° C. and stirred for 18 h. The mixture was cooled to ambient temperature and 1.0 M hydrochloric acid (ca 1.1 mL) was added until pH<3. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride (1×7 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (55.0 mg): LC-MS [M+1]=315.0.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:20]([CH3:34])[CH2:21][CH2:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:23][CH2:22][CH2:21][CH:20]([N:16]1[CH2:17][CH2:18][CH:13]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])[CH2:14][CH2:15]1)[CH3:34]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: O=C1OC[C@@H](c2ccccc2)N1C1CCNCC1
Product: CC(CCN)N1CCC(N2C(=O)OC[C@H]2c2ccccc2)CC1
Yield: 62.2 %

Procedure:
Using general procedure B with the above amine (101 mg, 0.41 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (179 mg, 0.82 mmol) followed by general procedure D gave (R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-oxazolidin-2-one (81 mg, 62% over 2 steps).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(O[CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=O)C>C1(C)C=CC=CC=1>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH:15]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[O:22][C:23]4[C:28]3=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: NC1CCN(C2CC2)CC1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NC1CCN(C2CC2)CC1

Procedure:
Refluxing 4-amino-1-cyclopropylpiperidine and 9-acetoxyxanthene in dry toluene for 24 hours, then working up as in Example 1 gives N-(N-cyclopropyl-4-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([I:16])[CH:15]=[C:10]3[N:9]=[C:8]2[NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:4][C:3]=1[O:25][CH3:26].[OH-].[Na+].Cl[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[I:16][C:14]1[CH:15]=[C:10]2[N:9]=[C:8]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([O:1][CH2:30][C:31]4[CH:36]=[N:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[C:3]([O:25][CH3:26])[CH:4]=3)[C:11]2=[N:12][CH:13]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Reactant: COc1ccc(CCl)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirred solution of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate ( ) (1.30 g, 2.78 mmol) and 5M aqueous sodium hydroxide solution (0.8 mL, 4.00 mmol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL) was added 5-(chloromethyl)-2-methoxypyridine (0.567 g, 3.60 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was diluted with brine (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to provide 1.10 g (71%) of ethyl (6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.
Reaction SMILES: [N:1]([N:3](C)[C:4](N)=O)=O.[OH-].[K+].[CH3:10][O:11][C:12]([O:14][C@@H:15]1[C@@:36]2([CH3:37])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[CH:27]([C:29]([OH:31])=[O:30])[CH3:28])[CH2:18][C@@H:17]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:16]1)=[O:13].[N+](=[CH2:46])=[N-]>C(OCC)C.C(O)(=O)C>[N+:3](=[CH2:4])=[N-:1].[CH3:10][O:11][C:12]([O:14][C@@H:15]1[C@@:36]2([CH3:37])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[CH:27]([C:29]([O:31][CH3:46])=[O:30])[CH3:28])[CH2:18][C@@H:17]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:16]1)=[O:13]
Reactant: CN(N=O)C(N)=O
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)OC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1

Procedure:
A solution of diazomethane in diethyl ether was prepared by adding N-nitroso-N-methylurea to a mixture of 50% aqueous potassium hydroxide solution and diethyl ether in accordance with the method described in Organic Syntheses Collective Volume 2, p. 165 (1943) and this solution was added to a solution of 85 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylic acid (prepared in Example 6 above) in 5 ml of diethyl ether until the yellow color of diazomethane would be persistent. After the excess diazomethane was decomposed by addition of acetic acid, the reaction mixture was washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 79 mg of methyl 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylate.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>CO.C(O)(=O)C>[C:16]([O:15][C:11]([NH:12][N:13]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCc2ccccc21

Procedure:
A solution of indan-1-one (5.0 g) and tert-butyl carbazate (5.0 g) in methanol (20 ml) containing glacial acetic acid (1 drop) was boiled and stirred under reflux for 1.5 hours. The mixture was cooled and evaporated under reduced pressure. The residue was recrystallized from ethanol to give indan-1-one tert-butyloxycarbonyl-hydrazone.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[C:40]([CH:41]=[O:42])=[CH:39][N:38]=[CH:37]1.[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:41]([C:40]2[S:36][CH:37]=[N:38][CH:39]=2)[OH:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cncs1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3cncs3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1,3-thiazole-5-carbaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: [CH2:1]([Cl:3])[Cl:2].[Li]CCCC.[B:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])OCC.Cl.[C:20]12(O)[CH2:28][CH:24]([C:25]1([CH3:27])[CH3:26])CCC2(O)C>C1COCC1.C(OCC)C>[Cl:2][CH:1]([Cl:3])[B:9]1[O:13][CH:14]2[CH2:15][C@@H:24]3[CH2:28][C@H:20]([C@:17]2([CH3:18])[O:16]1)[C:25]3([CH3:27])[CH3:26]
Reactant: ClCCl
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)[C@@H]2CC3OB(C(Cl)Cl)O[C@@]3(C)[C@H]1C2
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
To a solution of DCM (80 mL, 1.2 mol) in THF (800 mL) at −80° C. to −90° C. was added n-BuLi (2.5 M in hexane, 480 mL, 1.2 mol) under N2, and the reaction mixture was stirred for 1.5 h below −80° C. B(OEt)3 (200 mL, 1.2 mol) was added in one portion and the mixture was stirred for 1 h at −45° C. to −30° C. Aqueous HCl (5 M, 240 mL, 1.2 mol) was then added dropwise while maintaining the temperature below −20° C. and the resulting mixture was stirred at −20° C. for 4 h. The organic layer was separated, and the water layer was extracted with diethyl ether (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give an intermediate. The intermediate was re-dissolved in diethyl ether (800 mL) and pinanediol (188 g, 1.1 mol) was added to the solution. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 10:1 to 1:1) to afford Intermediate 1 (190 g, 60% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>ClCCl>[CH2:30]([O:29][C:27]([O:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:28])[CH3:31]
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1c(Cc2ccccc2)ccc2ccccc12
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of 2-phenylmethyl-1-naphthol (5.00 g, 0.021 mol) and triethylamine (2.53 g, 0.025 mol) in dichloromethane (65 mL) was stirred at 0°. Ethyl chloroformate (2.73 g, 0.025 mol) was added and the mixture stirred for one hour at 0°, then for two hours at room temperature. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated. The residue was flash chromatographed (5% ethyl acetate/hexane) to provide the title compound (6.50 g, 100%) as a viscous oil: NMR (CDCl3) 7.84 (t, J=8 Hz, 2H), 7.68 (d, J=7 Hz, IH), 7.50 (m, 2H), 7.25 (m, 6H), 4.30 (q, J=7 Hz, 2H), 4.IO (s, 2H), 1.36 (t, J=7 Hz, 3H); IR (neat) 1760; Mass Spec (EI) 306 (45), 262 (32), 234 (86), 215 (31); Calcd. for C20H18O3 : C-78.40 H-5.92; Found: C-78.49 H-6.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[NH:11]1[CH2:15][CH2:14][C@H:13]2[CH2:16][N:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][C@@H:12]12.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH2:15][CH2:14][C@H:13]3[CH2:16][N:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][C@@H:12]23)=[CH:4][N+:3]=1[O-:10]
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Reactant: CCOC(=O)N1C[C@@H]2CCN[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(Cl)[n+]([O-])c3)[C@@H]2C1

Procedure:
The titled compound was prepared in analogy to examples 2.2 and 2.3 using 2-chloro-5-(chloromethyl)pyridine 1-oxide (712 mg, 4 mmol), (3aS,6aS)-ethyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.1 g, 5.97 mmol), and K2CO3 (553 mg, 4 mmol). The obtained crude product was used without further purification in the next reaction step.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C([O-])(O)=O.[Na+]>O.C1COCC1>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:9]2[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:26][CH:25]=3)[C:8]2=[O:24])=[CH:15][CH:16]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc(N)cc3)C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-tetrahydropyrimidin-2-one (L) (438 mg, 1.24 mmol) and triethylamine (0.22 mL, 1.6 mmol) in abs. THF (50 mL) there was added a solution of methanesulphonyl chloride (0.11 mL, 1.48 mmol) in 5 mL of abs. THF within a period of 15 min. The reaction mixture was stirred over a period of 48 h at RT, sat. NaHCO3 solution (20 mL) was added, and the mixture was stirred for 30 min. H2O (30 mL) was added, and the mixture was extracted with EtOAc (3×30 mL). The combined organic phases were washed with sat. NaCl solution (30 mL), dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by means of column chromatography (SiO2 (50 g) using cyclohexane/EtOAc 1:1 (500 mL) as eluent). The desired product N-{4-[3-(4-tert-butyl benzyl)-2-oxotetrahydropyrimidin-1-yl methyl]phenyl}methanesulfonamide (5) was obtained as a white solid (398 mg, 75% of theory) having a melting point of 132-135° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18]C(=O)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)[CH3:22])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
To a cooled (˜15° C.) and stirred solution of 18 g (57.4 mmol) of trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester in 135 mL of dioxane was added within 5 min 63.2 mL (63.2 mmol, 1.1 eq) of aqueous 1M NaOH. The reaction was homogenised with 13 mL of MeOH and 28.7 mL (28.7 mmol, 0.5 eq) of aqueous 1M NaOH after 3 h, then stirred for additional 1.5 h. The reaction was evaporated to remove the dioxane, partitioned between Et2O (×3)/H2O, dried over Na2SO4 and evaporated to yield 17.13 g (quantitative) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester, MS: 272 (MH+).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12]>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].C1(C)C=CC=CC=1>[Cl:12][C:1]1[CH:6]=[CH:5][C:4]([C:8](=[O:9])[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])=[CH:3][CH:2]=1
Reactant: Cl
Reactant: C[C@H](C(=O)Cl)c1ccccc1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: Cc1ccccc1
Product: C[C@H](C(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
Into a 20 L four-necked flask (flask B), 691 g of (S)-2-phenylpropionic chloride and 4.4 L of toluene were put and cooled to −10° C. in an atmosphere of nitrogen, and 1.41 g (4.00 mmol) of iron(III) acetylacetonate was added thereto. While maintaining the reaction temperature to be at most −10° C., the Grignard reagent prepared in the flask A was dropwise added thereto over a period of 4 hours in an atmosphere of nitrogen, and the temperature was raised to room temperature after completion of the dropwise addition, followed by stirring overnight, and then the mixture was cooled to 10° C., and 4 L of diluted hydrochloric acid was added thereto. The organic phase was separated, the aqueous phase was extracted with toluene, the toluene layer and the organic phase were put together, washed with water and saturated salt solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product. The crude product was purified by silica gel column chromatography (developing solvent: hexane/toluene=1/1), and recrystallization from ethanol was carried out to obtain 329 g (1.34 mol) of (S)-1-(4-chlorophenyl)-2-phenylpropane-1-one [H-Ph-CH(CH3)—C(O)-Ph-Cl] as white crystals (yield: 34%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH3:11][S:12][C:13]1[N:17]([CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:16]2[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=2[N:14]=1.N1CC(=O)NC1=O.C(O)(C(F)(F)F)=O>>[CH3:10][C:3]1([CH2:2][NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH2:18][N:17]3[C:16]4[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=4[N:14]=[C:13]3[S:12][CH3:11])=[CH:20][CH:21]=2)[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7]1
Reactant: CSc1nc2ccccc2n1Cc1ccc(C(=O)O)cc1
Reactant: CC1(CN)NC(=O)NC1=O
Agent: O=C1CNC(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccccc2n1Cc1ccc(C(=O)NCC2(C)NC(=O)NC2=O)cc1
Yield: 38.1 %

Procedure:
5-(aminomethyl)-5-methylhydantoin (109a)(55 mg, 0.31 mmol) was coupled with 4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoic acid (108 mg, 0.37 mmol) using general coupling method B to give 50 mg (39%) of the product hydantoin as a TFA salt. MS found: (M+H)+=425.
Reaction SMILES: [CH2:1]([C@H:3]1[O:8][C@:7]([C@@H:10]2[CH2:14][S:13][C:12](=[O:15])[N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([OH:9])[CH2:6][C@H:5]([OH:25])[CH2:4]1)[CH3:2].O[C@:27]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[CH2:1]([C@H:3]1[O:8][C@:7]([C@@H:10]2[CH2:14][S:13][C:12](=[O:15])[N:11]2[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)([O:9][CH3:27])[CH2:6][C@H:5]([OH:25])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Product: CC[C@@H]1C[C@@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4R,6R)-6-ethyl-2,4-dihydroxy-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl[C:13]1[CH:18]=CC=C[CH:14]=1.C(Cl)Cl>CO>[N:3]1[C:2]2[C:7](=[CH:14][CH:13]=[CH:18][N:1]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccn1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: c1cnc2ncccc2c1
Temperature: 120 °C

Procedure:
To a mixture of aminopyridine (1.12 g, 5.833 mmol) and AlCl3 (3.11 g, 0.023 mol) was added chlorobenzene (10.0 mL) in a sealed vessel under Ar. The reaction was sealed and heated to 120° C. for 12 h. The reaction mixture was cooled to RT and the mixture was poured over ice/HCl mixture and extracted with EtOAc (3×50.0 mL). The aqueous layer was neutralized via addition of solid NaHCO3 and extracted with EtOAc (5×50 mL). Combined organic layers were dried over Na2SO4 and evaporated to dryness to yield crude compound. Chromatography (Silica gel, CH2Cl2:MeOH, 99:1) yielded pure naphthyridin.