Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].C([O:37][C:38](=[O:41])[CH2:39]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:39][C:38]([OH:41])=[O:37])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N(CCCc2cccc(O)c2)Cc2ccc(OC(F)(F)F)cc2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(N(CCCc2cccc(OCC(=O)O)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared by alkylation of 3-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol with tert-butyl-bromo-acetate followed by standard TFA hydrolysis.
Reaction SMILES: O1CCCC1.Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[N:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>C(OCC)(=O)C.O>[Cl:26][C:27]1[N:32]=[C:31]([N:17]2[CH2:16][CH2:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[CH:19][CH2:18]2)[N:30]=[CH:29][N:28]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: Clc1ncnc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(C2=CCN(c3ncnc(Cl)n3)CC2)cc1
Yield: 84.6 %

Procedure:
To a tetrahydrofuran (10 mL)-water (4.0 mL) solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (1.43 g, 6.67 mmol) and sodium carbonate (1.56 g, 14.7 mol), 2,4-dichloro-1,3,5-triazine (1.00 g, 6.67 mmol) was added at 0° C. and the resultant mixture was stirred for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with each of saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (1.64 g, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH3:21])[CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cccc(-c2ccc(Cl)c(C(=O)O)c2)c1
Temperature: 50 °C

Procedure:
2-Chloro-5-iodobenzoic acid (2.00 g, 7.08 mmol), m-tolylboronic acid (1.15 g, 8.50 mmol), Na2CO3 (2.70 g, 25.5 mmol) and Pd(OAc)2 (94 mg, 0.42 mmol) were dissolved in water (9 mL) and heated at 50° C. for 2 hours. The mixture was filtered and washed with water and filtrate was acidified with 2.5 M HCl, extracted into ethyl acetate and dried over anhydrous Na2SO4, the solvent was evaporated in vacuo to obtain crude 4-chloro-3′-methylbiphenyl-3-carboxylic acid as a grey solid in quantitative yield. 1H NMR (300 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.55-7.50 (m, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.25 (d, J=6.6 Hz, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][C:3]1=[O:15].[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]1=[O:15]
Reactant: Cn1ccc(C2CCC(=O)CC2)cc1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cn1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-methyl-4-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: C([O:4][CH:5]([CH3:23])[C:6]([N:8]([C:11]1[C:12]([Cl:22])=[N:13][N:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)[CH2:9][CH3:10])=[O:7])(=O)C.[OH-].[Li+].Cl>CO.C1COCC1>[Cl:22][C:12]1[C:11]([N:8]([CH2:9][CH3:10])[C:6](=[O:7])[CH:5]([OH:4])[CH3:23])=[CH:15][N:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=1
Reactant: CCN(C(=O)C(C)OC(C)=O)c1cn(-c2cccnc2)nc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(C(=O)C(C)O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-1-oxopropan-2-yl acetate (2.4 g, 7.1 mmol) in MeOH (9 mL) and THF (9 mL) was added lithium hydroxide (LiOH, 2 M, 7.0 mL, 14 mmol). The reaction mixture was stirred for two hours at room temperature, and then the reaction mixture pH was made neutral by the addition of aq. 2M HCl. After the mixture was then extracted with EtOAc, the organics phases were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound C13 as a white solid (1.9 g, 88%): mp 137-138° C.; 1H NMR (400 MHz, DMSO) δ 9.08 (d, J=2.5 Hz, 1H), 8.98 (s, 1H), 8.58 (dd, J=4.7, 1.1 Hz, 1H), 8.23 (ddd, J=8.4, 2.6, 1.3 Hz, 1H), 7.59 (dd, J=8.3, 4.7 Hz, 1H), 4.97 (d, J=7.6 Hz, 1H), 4.08 (m, 1H), 3.57 (d, J=50.6 Hz, 2H), 1.10 (d, J=6.5 Hz, 3H), 1.07 (t, J=7.1 Hz, 3H); ESIMS m/z 295.6 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.FC(F)(F)S(O[CH2:43][CH:44]([F:46])[F:45])(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH:23]([CH2:43][CH:44]([F:46])[F:45])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)F)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a solution of 10B (345 mg, 0.893 mmol) in THF (5 mL) at −78° C., was added LDA (2 M, heptane, THF and ethylbenzene) (0.536 mL, 1.071 mmol). The red/black mixture was stirred at −78° C. for 20 min, then a solution of 2,2-difluoroethyl trifluoromethanesulfonate (210 mg, 0.982 mmol) in THF (0.5 mL) was added dropwise. The reaction was removed from the cooling bath and was stirred at rt for 4 h. The reaction mixture was quenched with sat. NH4Cl, diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 12 g column and eluted with a gradient from 0 to 50% ethyl acetate/hexanes) to give 10C (70 mg, 0.155 mmol, 17.41% yield) pale yellow oil. MS (ESI) m/z: 450.9 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.15 (d, J=7.91 Hz, 1H) 7.97-8.11 (m, 1H) 7.50 (d, J=7.47 Hz, 1H) 7.24-7.43 (m, 5H) 5.10-5.29 (m, 2H) 4.57-4.87 (m, 2H) 4.00-4.39 (m, 3H) 2.91 (br. s., 3H) 2.57-2.87 (m, 1H) 2.19 (s, 1H) 1.05-1.33 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: OCCCC1CCNCC1
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCCO)CC1)c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
A mixture of 0.200 g (0.663 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.190 g (1.33 mmol) of 3-piperdin-4-yl-propan-1-ol in N,N-dimethylformamide (5 mL) is heated to 130° C. and stirred for 2 days. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.130 g (47%) of 3-chloro-N-[5′-chloro-4-(3-hydroxy-propyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a light brown foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4](=[O:18])[CH:3]=1.[Cl:19]N1C(=O)CCC1=O>C(#N)C>[Cl:19][C:3]1[C:4](=[O:18])[N:5]([CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=1[Cl:1]
Reactant: CCCCC(CC)Cn1c(=O)cc(Cl)n(C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCCCC(CC)Cn1c(=O)c(Cl)c(Cl)n(C)c1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 111.2 %

Procedure:
To a solution containing 20 g of 6-chloro-3-(2-ethylhexyl)-1-methyluracil thus-obtained in 50 ml of acetonitrile was added 8.6 g of N-chlorosuccinimide, the mixture was heated to 40° C. and stirred for 2 hours. After allowing the mixture to cool, the acetonitrile was distilled off under reduced pressure, to the residue was added water and it was extracted with 100 ml of chloroform. The organic phase was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 22 g of 5,6-dichloro-3-(2-ethylhexyl)-1-methyluracil as an oily product.
Reaction SMILES: [CH3:1][C:2]([CH2:26][CH3:27])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:7](=[O:13])[NH:8]2.CC(=CC)CC1C=CC=C2C=1C(=NNC1C=CC(S(N)(=O)=O)=CC=1)C(=O)N2>>[CH3:1][CH:2]([CH2:26][CH3:27])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:7](=[O:13])[NH:8]2
Reactant: CCC(C)=Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Agent: CC=C(C)Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Product: CCC(C)Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 79 %

Procedure:
Reduction of the mixture of 4-{N′-[4-(2-methyl-1-butenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide and 4-{N′-[4-(2-methyl-2-butenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide according to Procedure M gave the title compound in 79% yield: 1H NMR (DMSO-d6): δ0.87-0.90 (m, 6H), 1.21-1.25 (m, 2H), 1.47-1.63 (m, 1H), 2.82 (dd, J=12.6, 8.1 Hz, 1H), 2.95 (dd, J=12.6, 6.6 Hz, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.25 (s, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 11.12 (s, 1H), 13.04 (s, 1H); APCI−MS m/z 385 (M−1)−.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH2:17])[C:13]([I:18])=[C:12]([C:19]([NH:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:20])[C:11]=1[I:33])=[O:9])(=[O:3])[CH3:2].[Br:39][CH:40]([CH2:44][CH2:45]Br)[C:41](Br)=[O:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[C:1]([O:4][CH:5]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:45][CH2:44][CH:40]([Br:39])[C:41]2=[O:42])[C:13]([I:18])=[C:12]([C:19]([NH:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:20])[C:11]=1[I:33])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Br)C(Br)CCBr
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A solution of N,N'-bis-[2,3-diacetyloxypropyl]-5-amino-2,4,6-triiodo-1,3-benzenedicar boxamide (8.73 g, 10 mmol) in N,N-dimethylacetamide (100 ml) was treated with 2,4-dibromobutyroyl bromide (4.02 g, 13.0 mmol) under an atmosphere of nitrogen and the reaction mixture was stirred for 50 hours at ambient temperature. The mixture was then treated with ground potassium carbonate (1.65 g, 12.0 mmol) and stirred for 30 minutes at ambient temperature. An additional portion (1.65 g, 12.0 mmol) of finely ground potassium carbonate was added and the mixture was stirred for 1.9 hours. The suspended salts were filtered and the solvent was evaporated to obtain a brown oil. This crude product was purified by silica gel flash chromatography to isolate N,N'-Bis-[2,3-diacetyloxypropyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]2,4,6-triiodo-1,3-benzenedicarboxamide, as a white powder (7.28 g, 71% yield), m.p. 110°-112°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Product: O=c1nc(N2CCN(C3CCOCC3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 6.7 %

Procedure:
The synthesis was performed using 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9 and dihydro-2H-pyran-4(3H)-one (10 mg, 0.10 mmol) in a similar manner to Synthesis Example 72 to obtain the title compound (2.6 mg, yield: 6.6%).
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[CH3:16][O:17]C1C=C2C(=CC=1)CC(=O)CC2.IC>>[CH3:16][O:17][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:3]=1)[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: COc1ccc2c(c1)CCC(=O)C2
Solvent: CI
Product: COc1ccc2c(c1)CCC(=O)C2(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound A2, the title compound was prepared from 6-methoxy-3,4-dihydro-1H-naphthalen-2-one and iodomethane.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([C:6]1([CH2:15][CH:16]=[CH2:17])[C:13](=[O:14])[N-:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:5].[Na+].[Cl-].[Cl-].[Ca+2]>O>[CH3:1][CH2:2][CH2:3][CH:4]([C:6]1([CH2:15][CH:16]=[CH2:17])[C:13](=[O:14])[NH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:5]
Reactant: C=CCC1(C(C)CCC)C(=O)[N-]C(=O)NC1=O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CCC1(C(C)CCC)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Sodium seconal (2 g) was dissolved in a small volume of water and mixed with a conc. aqueous solution of CaCl2. The white precipitate which separated out was filtered, washed with water, then with ether and air dried on the filter funnel. A white powder (2.3 g) assumed to be the Ca salt of seconal was collected. This was dissolved in methanol (50 ml) and, after addition of 1.1 g of sodium chloroacetate and 2 ml DMF, was refluxed for 6 hours, and then allowed to stir at room temperature overnight. After evaporation of the solvent, the residue was treated with water (30 ml) and acidified with conc. HCl. The mixture was extracted with chloroform (3 × 30 ml) and the organic layer evaporated to dryness. The residue was stirred with 30 ml of 10% NaHCO3 solution and then extracted with chloroform. The chloroform extract, on evaporation, yielded 0.82 g of unreacted seconal. The bicarbonate layer was acidified and extracted with chloroform. The organic layer upon evaporation yielded 0.86 g of a gummy material which had an NMR spectrum consistent with the expected acid. This acid was redissolved in 10% NaHCO3 and the above procedure of acidification and chloroform extraction was repeated, leading to a yield of 0.62 g of a colorless gum which slowly crystallized on standing. This material was analytically pure.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[CH3:8][C@@H:9]1[CH2:14][C:13](=O)[CH2:12][C@H:11]([CH3:16])[O:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:8][C@@H:9]1[CH2:14][CH:13]([NH:7][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[N:6]=2)[CH2:12][C@H:11]([CH3:16])[O:10]1
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Reactant: Cc1n[nH]c(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1n[nH]c(NC2C[C@@H](C)O[C@@H](C)C2)n1
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
To a solution of 3-methyl-1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (0.75 g, 22%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:10]([N:12](CC)CC)C.C[Si](C#N)(C)C>C(#N)C.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].O>[Br:1][C:2]1[C:3]([C:10]#[N:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: N#Cc1ncc(Br)cc1Br
Reaction time: 16 h
Yield: 73.2 %

Procedure:
3,5-dibromopyridine 1-oxide (25.09g, 0.099 mol) was dissolved in acetonitrile (200 mL) and triethylamine (28 mL, 0.198 mol) and trimethylsilylcyanide (40 mL, 0.297 mol) were added. The reaction was stirred 16 hours and then diluted with dichloromethane, aqueous sodium carbonate, water, and then filtered through Celite eluting with dichloromethane. The mixture was extracted with dichloromethane and purified by silica gel chromatography (3:2 hexanes:ethyl acetate gradient elution) to afford 3,5-dibromo-2-pyridinecarbonitrile (18.98 g, 73% yield) as a tan solid. 1H NMR (CDCl3) δ 8.68 (d, J=2 Hz, 1 H), 8.20 (d, J=2 Hz, 1 H); MS m/z 262 M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:25][CH2:24][CH:21]2[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]3[CH:26]=[CH:27][CH:28]=[C:13]([CH3:12])[CH:14]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C(=O)N2CCC(CO)CC2)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
53.3 g (0.28 mol) of 4-methylbenzenesulphonyl chloride in 60 ml of pyridine are added to a solution of 52 g (0.22 mol) of 1-(3-methylbenzoyl)-4-piperidinemethanol in 100 ml of pyridine. The mixture is stirred at 20° C. for 4 h, and then poured into ice. The phase is extracted with dichloromethane, and the organic phase washed with 10N aqueous hydrochloric acid solution and dried over magnesium sulphate. The solvents are evaporated off under reduced pressure and 70 g of white solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.[BH4-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([OH:12])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: O=C1Cc2ccccc2Sc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1Cc2ccccc2Sc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17 G. of 3-bromo-10,11-dihydro-11-oxodibenzo[b,f]thiepin (0.056 mole) are dissolved in a mixture of 150 cc. DMF and 150 cc. absolute alcohol. 1.7 G. sodium borohydride (0.045 mole) are added and the mixture is left stirring overnight at room temperature. The ethanol is evaporated and the residual DMF solution is diluted with water and extracted with ether three times. The ether extracts are washed several times with water, dried and evaporated to a thick oil. A quantitative yield of the alcohol is obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](O)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCc1ccc(F)cc1F
Reactant: CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCC(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 2,4-difluorobenzylamine (0.43 g, 3.0 mmol) in methylene chloride (30 mL) were added octanoic acid (0.43 g, 3.0 mmol) and DMAP (0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.1 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL), and brine (75 mL) and dried over anhydrous Na2SO4. Concentration in vacuo afforded 0.78 g (96%) of an oil, which solidified upon standing.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:30])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=O)=O)=[CH:21][C:20]=3[F:29])[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:32]([O:34][NH2:35])[CH3:33].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:32]([O:34][N:35]=[C:1]([C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:28])=[CH:21][C:20]=3[F:29])[CH:13]=2)[CH2:7][C:6]=1[OH:30])[CH2:2][CH3:3])[CH3:33]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(S(C)(=O)=O)cc3F)c2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3ccc(SC)cc3F)c2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 0.70 g (1.8 mmol) of 2-propionyl-3-hydroxy-5-(3-(2-fluoro-4-(methylsulfonyl)phenoxy)-phenyl)cyclohex-2-en-1-one in 5 mL of methylene chloride and 10 mL of absolute ethanol, at room temperature was treated with 0.22 g (2.3 mmol) of ethoxyamine hydrochloride and 0.19 g (2.3 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted twice with 30 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and the solvent evaporated off leaving the product as a dark yellow oil. Purification via flash chromatography (silica gel, methylene chloride/hexane) the above named product as a light amber oil in a yield of 0.6 g (77 percent of theoretical). 1H NMR (CDCl3): δ1.2-1.5 (m, 6H, both --CH2CH3 's), 2.58 (s, 3H, --SCH3), 2.50-3.65 (m, 7H), 4.25 (q, J=7 Hz, 2H, --OCH2), 6.8-7.5 (m, 7H, aromatics), 14.9 (broad s, 1H, enol H) (Compound 5).