Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.BrC[CH2:62][F:63]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH2:62][F:63])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Reactant: FCCBr
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2 S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a solid: MS (ESI+) for C25H26Cl2FN3O m/z 475 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:21][C:14]1[CH:13]=[C:12]2[C:17]([C:18]3[CH2:19][CH2:20][NH:8][CH2:9][C:10]=3[N:11]2[CH3:22])=[CH:16][CH:15]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3ccc(Br)cc31)CCNC2
Reaction time: 1 h
Yield: 97.6 %

Procedure:
tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.75 g, 4.79 mmol) was dissolved in CH2Cl2 (10 mL) and trifluoroacetic acid (TFA) (10 mL) was added. After stirring for 1 h, the mixture was diluted with methylene chloride (50 mL), washed with saturated Na2CO3 solution, dried over sodium sulfate and concentrated to provide the title compound (1.24 g, 97%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J=1.4 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.3, 1.4 Hz, 1H), 4.01 (s, 2H), 3.55 (s, 3H), 3.15 (t, J=6.0 Hz, 2H), 2.72 (t, J=5.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24](O)=[O:25])=[C:7]([CH3:19])[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55]>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:25])=[C:7]([CH3:19])[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)O)c3)c3ccc(Cl)c(F)c32)cn1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)NS(C)(=O)=O)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[6-Chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl]-benzoic acid (0.107 g, 0.245 mmol) in THF (2 mL) at room temperature was added CDI (0.10 g, 0.61 mmol) and DMAP (0.005 g). The resulting mixture was stirred for 18 hrs, after which time DBU (0.15 mL, 0.98 mmol) and methane sulfonamide (0.07 g, 0.74 mmol) were added. The resulting mixture was stirred for and additional 18 hrs at room temperature, then subjected to standard aqueous workup. The crude residue was purified on silica gel (0-10% MeOH in DCM) to afford the title compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([Cl:31])[C:22]=1[Cl:32].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([Cl:31])[C:22]=2[Cl:32])[C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1Cl
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c(Cl)c1Cl
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A suspension of 26.7 g (0.096 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde (prepared in Example 96 (i) and (ii)) and 28.01 g (0.203 mol) of dry potassium carbonate in 350 mL of dimethylformamide was stirred under argon for 20 minutes. Then 30 g (0.10 mol) of methyl 4-bromomethyl-2,3-dichlorobenzoate was added and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was poured into water and extracted several times with ether. Filtration of the solid formed at the ether-water interface gave 19.35 g of product. The ether layer was washed 4 times with water, once with brine, and then concentrated under vacuum to give a solid. Recrystallization of the combined solids from methanol gave 32.55 g (68%) of product; mp 135°-173° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:18]=1[CH2:19][NH2:20].C(N(C(C)C)CC)C>>[Br:8][C:6]1[N:7]=[C:2]([NH:20][CH2:19][C:18]2[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:17]=2[Cl:16])[C:3]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:5]=1
Reactant: COC(=O)CCNc1ncc(Br)nc1Br
Reactant: NCc1c(F)ccc(F)c1Cl
Agent: CCN(CC)C(C)C
Product: COC(=O)CCNc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl

Procedure:
Methyl N-{5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}-β-alaninate was prepared from methyl N-(3,5-dibromopyrazin-2-yl)-β-alaninate and 2-chloro-3,6-difluorobenzylamine in the presence of N,N-diethylisopropylamine as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CCOCC)=O)=[N:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][NH2:24])[CH3:20]>C1COCC1>[CH2:19]([O:21][CH2:22][CH2:23][NH:24][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=2[N:7]=1)=[O:12])[CH3:20]
Reactant: CCOCCOC(=O)c1nc2cc(Cl)ccc2o1
Reactant: CCOCCN
Solvent: C1CCOC1
Product: CCOCCNC(=O)c1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A mixture of 2-ethoxyethyl 5-chlorobenzoxazol-2-carboxylate (10 g) and 3.5 g of ethoxyethylamine in 10 ml of THF was stirred at room temperature for 2 hours. The precipitated product was filtered and washed well with hexane to give 9 g of product; mp 110°-111° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cccs1
Yield: 69.7 %

Procedure:
To a solution of 10.0 g (41.5 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 27.7 ml (200 mmol) of triethylamine in 10.0 ml of methylene chloride, 5.35 ml (50.0 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:20) to obtain powder. The powder was recrystallized from methanol/ethyl acetate (=1:20) to obtain 8.05 g of the desired compound (yield: 70.5%, yellow prisms).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])[CH:4]=1.[OH-].[K+].C(O)C.[C:25](#[N:29])/[CH:26]=[CH:27]/[CH3:28]>O1CCCC1>[CH3:28][CH:27]([CH2:26][C:25]#[N:29])[C:9]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=[CH:7][CH:6]=1)[C:10]#[N:11]
Reactant: N#CC(c1cccc(C(F)(F)F)c1)N1CCOCC1
Reactant: C/C=C/C#N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CC#N)C(C#N)(c1cccc(C(F)(F)F)c1)N1CCOCC1

Procedure:
To a solution of α-(α,α,α-trifluoro-m-tolyl)-4-morpholineacetonitrile in 100 ml. of tetrahydrofuran is added 1.0 ml. of 30% KOH-ethanol solution. To the mixture is added 2.56 g. of crotononitrile and the mixture is stirred at room temperature for 18 hrs. The mixture is concentrated to dryness under vacuum and the residue is dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate. The eluent is concentrated to an oil (17.3 g) which is crystallized from hexane and recrystallized from CHCL3 -hexane to give 3-methyl-2-morpholino-2-(α,α,α-trifluoro-m-tolyl)glutaronitrile as crystals, m.p. 115°-118° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].ClC1C=C(C(OO)=[O:41])C=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([S:28]([C:29]([F:31])([F:32])[F:30])=[O:41])=[CH:26][CH:27]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(c3nc(COc4ccc(SC(F)(F)F)cc4)cs3)CC2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(=O)C(F)(F)F)cc4)cs3)CC2)nc1
Reaction time: 1.5 h

Procedure:
To a solution of 5-Ethyl-2-{4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine (Example 16) in DCM at room temperature was added 3-chloro-benzenecarboperoxoic acid (2 eq.). The reaction was allowed to stir for 1.5 hours and an additional portion of 3-chloro-benzenecarboperoxoic acid (1 eq.) was added to the reaction mixture. The reaction was stirred at room temperature for an additional 4 hours. The organic solution was washed with sodium bicarbonate; the organic layer was isolated, dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by column chromatography to afford the desired product. 1H NMR (DMSO-d6): δ 8.40 (2H, s), 7.58 (2H, d), 7.22 (1H, s), 7.02 (2H, d), 5.17 (2H, s), 3.74 (2H, m), 3.16 (1H, m), 2.96 (2H, m), 2.57 (2H, m), 2.22 (4H, m), 1.24 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(O)(=O)/C=C/C(O)=O.[NH2:23][CH2:24][CH2:25][C:26]#[N:27].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:27][CH2:26][CH2:25][C:24]#[N:23])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: N#CCCN
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCC#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 200.3 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (4.95 g, 24.8 mmol) in DMF (25 ml) was added 3-aminopropionitrile fumarate (3.18 g, 12.4 mmol) and DIPEA (15 ml, 84.3 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum and the residue diluted with water (50 mL). It was extracted with EtOAc (3×100 mL) and the organic phase washed with brine solution and dried (Na2SO4). Removal of solvent gave 4-(2-cyanoethylamino)-3-nitro-benzoic acid methyl ester (6.19 g, 98.5%). MS-ESI m/z 250 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.8 (t, 2H), 3.8 (m, 2H), 6.9 (d, 1H), 8.2 (m, 1H), 8.5 (t, 1H), 8.9 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([NH2:16])[N:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([N:17]=[O:18])=[C:4]([NH2:16])[N:3]=1
Reactant: Nc1cc(OCc2ccccc2)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCc2ccccc2)n1
Temperature: 80 °C

Procedure:
2,6-Diamino-4-benzyloxypyrimidine (0.5 g, 2.3 mmol) was dissolved in warm acetic acid (30%, 10 ml) and the reaction mixture was heated to 80° C. A solution of sodium nitrite (0.22 g, 3.19 mmol) in water (5 ml) was added dropwise over 1 h, when an excess of oxidant was evident by starch-iodide paper. The reaction mixture was allowed to cool to room temperature, and the violet crystals which deposited were collected and washed with water (0.53 g, 98%), m.p. decomposed 209° C.; (Found: C, 55.32; H, 5.28; N, 26.47% C11H11N5O2 0.1 H2O C, 55.98; H, 4.75; N, 29.69%); νmax/cm−1 3408 (NH), 2952 (CH2), 1610 (C6H5), 1518 (NO); δH (200 MHz, d6-DMSO) 5.69 (2H, s, OCH2), 7.44-7.68 (5H, m, C6H5), 8.0 (2H, d, NH2), 8.17 (1H, s, NH) , 10.19 (1H, s, NH); m/z (+EI) 245 (M+, 25%), 91 (100), 65 (9).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].N1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CN(C)C=O>[N:12]1([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
A mixture of 2,4-dinitrobenzonitrile 4.20 g (21.75 mmol) and morpholine 5.7 mL (66.0 mmol) in N,N-dimethylformamide 20 mL was stirred at room temperature for 20 hours. The reaction mixture was poured into water. The precipitate was collected and washed with water to give the title compound 4.20 g as orange solid. Yield 74.5%.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH2:16].N1C=CC=CC=1>CO>[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cnc1NCCCN

Procedure:
2-Chloro-3-methyl-5-nitropyridine (15.5 g), 1,3-diaminopropane (30 ml) and pyridine (10 ml) were stirred together and, after the initial exotherm had subsided, the mixture was heated under reflux for 1.5 hr. On cooling the mixture was treated with methanol and the bulk of crystalline bi-product filtered off. The solution was stripped, the residue taken up in water and the pH adjusted to 6.5 with hydrochloric acid. After filtering through `Hyflo` the solution was extracted with chloroform. The pH was raised to 14, (NaOH) and extracted with ether. After drying (K2CO3), the ether extracts were stripped to give a yellow solid which was triturated with ether/pentane to give 2-(3-aminopropylamino)-3-methyl-5-nitropyridine, (12.9 g; 68%) m.p. 93°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12]>>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH3:12])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccncc1F
Product: CCOC(=O)c1ccncc1F

Procedure:
3-fluoro-isonicotinic acid and ethyl alcohol were processed according to the method of Example 128A to provide the product. MS (ESI+) m/z 170 (M+H)+;
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18]>C(O)C.O>[Cl:1][CH2:2][C:3](=[N:15][NH:16][C:17]([NH2:19])=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1
Reactant: O=C(CCl)COc1ccc(Cl)cn1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(=O)NN=C(CCl)COc1ccc(Cl)cn1

Procedure:
1-Chloro-3-(5-chloropyrid-2-yloxy)propan-2-one (400 mg.) was dissolved in ethanol (4 ml.) with warming, and stirred while a solution of semicarbazide hydrochloride (223 mg.) in water (2 ml.) was added. The mixture was cooled in ice for 11/2 hours and filtered, and the filter cake was washed with a 1:1 v/v mixture of ethanol and water (1 ml.), then with water (3 × 1 ml.). The product was dried in a desiccator over silica gel to give 1-chloro-3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropane, RF = 0.72 (5% v/v methanol in ethyl acetate), m.p. 115°-117° C.
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].N1C=CC=CC=1.[C:52](OC(=O)C)(=[O:54])[CH3:53]>ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:52](=[O:54])[CH3:53])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(C)=O
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (200 mg, 0.32 mmol), Pyridine (1.26 mL), and acetic anhydride (0.3 mL, 2.9 mmol) in 6.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)[CH3:14]>>[CH2:13]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH3:14]
Reactant: CC[C@@H]1COC(=O)N1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (1.4 mL) and (R)-4-ethyloxazolidin-2-one (979 mg) described in Preparation Example 26, the title compound (2.6 g) was obtained.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.[C-:16]1([CH2:21][N:22]2[C:26](=[O:27])[NH:25][NH:24][C:23]2=[O:28])[CH:20]=[CH:19][CH:18]=[CH:17]1.[CH-]1C=CC=C1.[Fe+2:34]>O1CCCC1>[C-:16]1([CH2:21][N:22]2[C:23](=[O:28])[N:24]=[N:25][C:26]2=[O:27])[CH:17]=[CH:18][CH:19]=[CH:20]1.[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:10]1.[Fe+2:34]
Reactant: O=c1[nH][nH]c(=O)n1C[c-]1cccc1
Reactant: Ic1ccccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1N=NC(=O)N1C[c-]1cccc1
Reaction time: 2 h

Procedure:
With reference to EXAMPLE 1-1, 11 mg (0.034 mmol) of iodobenzene diacetate was added to a mixture of 10 mg (0.033 mmol) of 4-(ferrocenylmethyl)urazole and 0.5 mL of tetrahydrofuran-d8 at room temperature. The mixture was stirred for 2 hours to give the tetrahydrofuran solution of 4-(ferrocenylmethyl)-1,2,4-triazoline-3,5-dione. A tetrahydrofuran (0.5 mL) solution of 5 mg (0.013 mmol) of cholecalciferol (VD3, manufactured by Solvay Pharmaceutical, Co.) was added to the resulting solution, followed by stirring at room temperature for an hour. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:2) to give 8 mg (90%) of the titled cholecalciferol/4-(ferrocenylmethyl)-1,2,4-triazoline-3,5-dione adduct (VD3-FMTAD) as a yellow oily substance.
Reaction SMILES: ClC1C=CC(C(CCC(O)=O)=O)=CC=1C(F)(F)F.N1CCC[C@H]1C(O)=O.[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([C:32]([CH2:34][CH2:35][C:36]([N:38]2[CH2:45][CH2:44][CH2:43][C@H:39]2[C:40]([OH:42])=[O:41])=[O:37])=[O:33])=[CH:30][C:29]=1[C:48]([F:51])([F:50])[F:49].[C:52]([O-:55])(=[S:54])[CH3:53].[K+]>C(O)C.O>[C:52]([S:54][CH:34]([C:32](=[O:33])[C:31]1[CH:46]=[CH:47][C:28]([Cl:27])=[C:29]([C:48]([F:51])([F:49])[F:50])[CH:30]=1)[CH2:35][C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41])=[O:37])(=[O:55])[CH3:53]
Reactant: CC([O-])=S
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(O)CCC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The preceding compound is converted to 3-(4-chloro-3-trifluoromethylbenzoyl)propionic acid, hydroxysuccinimide ester and coupled to L-proline as in Example 16. The 1-([3-(4-chloro-3-trifluoromethylbenzoyl)propionyl]-L-proline is brominated as in Example 20 and the product reacted with potassium thioacetate in ethanol-water (1:1) as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: ClC1C(C(C)CC)=NC(C2C=NC=CC=2)=CN=1.[NH:18]([C:20]1[C:25]([CH:26]([CH3:29])[CH2:27][CH3:28])=[N:24][C:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22][N:21]=1)[NH2:19].[C:36](OCC)(=O)[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(O)C.O>[CH3:29][CH:26]([C:25]1[C:20]2[N:21]([C:36]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:19][N:18]=2)[CH:22]=[C:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:24]=1)[CH2:27][CH3:28]
Reactant: CCC(C)c1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCC(C)c1nc(-c2cccnc2)cnc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1nnc2c(C(C)CC)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 3-methyl-2-oxopentanoic acid there is obtained rac-N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-methyl-2-oxovaleramide as an amorphous, colorless solid. Subsequent acidic hydrolysis to rac-3-methyl-2-oxo-N-[(3-pyridylcarbonyl)methyl]valeramide hydrochloride (beige, crystalline solid, melting point 158°-159°) and ring closure gives rac-3-(1-methylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow solid, melting point 146°-148° (from acetonitrile). The conversion into rac-2-chloro-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine is also effected analogously to Example 1. Hydrazinolysis to rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine in the form of beige crystals, melting point 166°-167° (from ethanol/water) and subsequent condensation with diethyl malonate gives ethyl rac-8-(1-methylpropyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 335 (M)+, which is converted by saponification into the above acid, MS: 267 (M-CO 2)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)(=[O:12])[CH3:11]>Cl.C(O)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]([C:10](=[O:12])/[CH:11]=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14]1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)c1ccsc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(O)cc1)c1ccsc1

Procedure:
10 g 4-hydroxybenzaldehyde and 10.4 g 3-acetyl thiophene were dissolved in 40 ml of a solution of 4% hydrochloric acid in acetic acid.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][S:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:14])=[C:7]([CH3:13])[CH:8]=3)=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:30]([F:31])([F:32])[F:33]
Reactant: FC(F)(F)c1cc(-c2ccc(CCl)cc2)ccc1Cl
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2ccc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 2C and 6B. MS m/z 481 (M+1).