Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>CN(C)C=O>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[CH2:20][CH2:19][O:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: BrCCC1OCCO1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCCC3OCCO3)cc2)S1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 15.0 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione, 8.80 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 17 ml of 2-(2-bromoethyl)-1,3-dioxolane and 80 ml of dimethylformamide were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 6.67 g of the title compound, melting at 102-104° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][OH:30])=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1>FC(F)(F)C(O)=O.ClCCl>[Br:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][OH:30])=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(N(C)CCO)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1c[nH]c2ncc(Br)c(N(C)CCO)c12
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 14.8 %

Procedure:
2-{[5-Bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-methyl-amino}-ethanol (10 mg, 0.0197 mmol) was dissolved in a solution of trifluoroacetic acid (1 mL) and dichloromethane (1 mL) and stirred at 23° C. for 1.5 hours. The solvent was evaporated and the resulting oil was dissolved in 1 mL DMSO and 100 μL ethylenediamine and purified by mass triggered reverse phase HPLC to afford 2-{[5-Bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-methyl-amino}-ethanol (1.1 mg, 0.00266, 13% yield). 1H-NMR [500 MHz, d6-DMSO] δ: 8.14 (s, 1H), 7.31 (m, 1H), 7.27 (s, 1H) 7.21 (dd, 1H), 7.02 (d, 1H), 6.96, (td, 1H), 6.67, (s, 5H), 3.14 (t, 2H), 2.75 (s, 4H); MS [MH+] m/z: 376, 378.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12].CC1C=C(C)C=C(C)C=1S(O[C:29]1[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])=[CH:38][C:37]=2[O:54][CH3:55])=[C:33]([CH3:56])[N:32]=[C:31]([NH2:57])[N:30]=1)(=O)=O>C(#N)CC.C(=O)([O-])O.[Na+]>[NH2:57][C:31]1[N:30]=[C:29]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:51])([CH3:52])[CH3:53])([CH3:49])[CH3:48])=[CH:38][C:37]=2[O:54][CH3:55])=[C:33]([CH3:56])[N:32]=1
Reactant: CCC[C@H](N)CCO
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 120 °C
Yield: 80.7 %

Procedure:
Trifluoroacetic acid (0.154 mL) was added to the mixture of (S)-3-aminohexan-1-ol (586 mg) and the product from step (i) (616 mg) in propionitrile (6 mL). After the mixture was heated at 120° C. for 23 h, the reaction mixture was cooled to RT, diluted with sat. sodium hydrogen carbonate and extracted with EtOAc. The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (430 mg) as a colorless oil; 1H NMR (CDCl3); 6.83 (1H, d), 6.44 (1H, d), 6.39 (1H, dd), 4.79 (2H, br s), 4.15-4.04 (1H, m), 4.00 (2H, t), 3.85 (3H, s), 3.77 (2H, t), 3.60 (2H, s), 3.50-3.40 (1H, m), 3.33-3.22 (1H, m), 2.36 (3H, s), 2.00-1.88 (2H, m), 1.86-1.71 (1H, m), 1.48-1.32 (1H, m), 1.30-0.95 (4H, m), 0.86 (9H, s), 0.75 (3H, t), 0.01 (6H, s); LC-MS: m/z 534.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C:9]([C@@H:10]([CH3:30])[CH2:11]2)=[CH:8][C:7](=[O:31])[CH2:6][CH2:5]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:32])[C:9](=[CH:8][C:7](=[O:31])[CH2:6][CH2:5]2)[C@@H:10]([CH3:30])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: COCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Product: COCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
As described in Example 5(c), 600 mg of 11β,21-dihydroxy-17methoxyacetoxy-6α-methyl-4-pregnene-3,20-dione is reacted with acetic anhydride, worked up, and chromatographed, thus isolating 480 mg of 21-acetoxy-11β-hydroxy-17-methoxyacetoxy-6α-methyl-4pregnene-3,20-dione.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19](I)=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:10])[CH3:9].[CH2:24]([OH:27])[C:25]#[CH:26]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]([O:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]([C:26]#[C:25][CH2:24][OH:27])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:10])[CH3:9]
Reactant: C#CCO
Reactant: COC(=O)c1cc(I)cc(C)c1OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)cc(C)c1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (0.943 mL, 6.76 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.092 g, 0.132 mmol) were added to a mixture of methyl 2-(acetyloxy)-5-iodo-3-methylbenzoate (1.0 g, 2.99 mmol) and propargyl alcohol (0.161 mL, 2.69 mmol) in THF (20 mL) at room temperature, and then copper (I) iodide (0.053 g, 0.278 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (50 mL), brine (40 mL), dried (MgSO4), and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 0-20% EtOAc in hexanes over 30 min) to afford methyl 2-(acetyloxy)-5-(3-hydroxyprop-1-yn-1-yl)-3-methylbenzoate, as a yellow solid. 1H NMR (500 MHz, CHCl3): δ 7.97 (s, 1 H); 7.53 (s, 1 H); 4.91 (s, 2 H); 3.88 (s, 3 H); 2.22 (s, 3 H); 2.16 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=3)(=[O:27])=[O:26])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(-c3ccc(C#N)n3C)cc2)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 4-isopropyl-benzenesulfonyl chloride (120 mg, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]4-isopropylbenzenesulfonamide (0.049 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19]=[O:20])[NH:11][CH:10]=[C:9]1[C:21]([O:23][CH3:24])=[O:22].[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH2:19][OH:20])[NH:11][CH:10]=[C:9]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCOC(=O)C1=C(C=O)NC=C(C(=O)OC)C1c1ccccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(CO)NC=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 0.83 h
Yield: 55.6 %

Procedure:
To a mixture of powder (329 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate in ethanol (10 ml) was added sodium borohydride (25.11 mg) under ice-cooling. After further stirring for 50 minutes, the mixture was adjusted to pH 4 to 5 with dilute hydrochloric acid. After removal of the ethanol, water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried and the residual crystals (about 280 mg) were dissolved in a mixture of diethyl ether and n-hexane and kept in a refrigerator to give pure crystals (184 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 187° to 188° C.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)[CH:3](OCC)OCC.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH2:27])=[S:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.O>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:2]2[S:26][C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:27][CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: NC(=S)Nc1ccccn1
Reactant: CCOC(OCC)C(Br)c1ccnc(SC)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CSc1nccc(-c2cnc(Nc3ccccn3)s2)n1

Procedure:
4-(1-Bromo-2,2-diethoxy-ethyl)-2-methylsulfanyl-pyrimidine (18-3, 0.050 g, 0.156 mmol) and 2-pyridylthiourea (0.024 g, 0.16 mmol) were stirred in 1 mL EtOH and 0.10 mL water. p-Toluenesulfonic acid monohydrate (5 mg, 0.03 mmol) was added and the reaction was heated to reflux. After 8 h an addional 30 mg (0.156 mmol) p-toluenesulfonic acid monohydrate and the reaction was refluxed an additional 16 h. The reaction was concentrated and purified by flash column chromatography (elute with a gradient: 3-6% MeOH in DCM). 1H NMR (DMSO-d6) δ11.75 (s, 1H), 8.50 (d, 1H, J=5.4 Hz), 8.49 (m, 2H), 7.77 (t, 1H, J=6.7 Hz), 7.60 d, 1H, J=5.5 Hz), 7.13 (d, 1H, 8.2 Hz), 7.02 (t, 1H, J=6.6 Hz), 2.55 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH3:21])[C:19]([SH:22])=[N:18][CH:17]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]([CH3:21])[C:19]([S:22][CH2:2][C:3]3([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]3)=[N:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Cn1c(-c2ccc(Cl)cc2)cnc1S
Reactant: OCC1(CO)CCC1
Product: Cn1c(-c2ccc(Cl)cc2)cnc1SCC1(CO)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 19a from [1-(hydroxymethyl)cyclobutyl]methanol and 5-(4-chlorophenyl)-1-methyl-1H-imidazole-2-thiol. 1H NMR (300 MHz, CDCl3) δ 7.41-7.25 (m, 5H), 3.62 (s, 2H), 3.49 (s, 3H), 3.46 (s, 2H), 2.04-1.63 (m, 6H).
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=4)[N:19]([CH3:27])[CH:18]=3)[C:13]([O:15]C)=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1.CO>O1CCOCC1>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=4)[N:19]([CH3:27])[CH:18]=3)[C:13]([OH:15])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21

Procedure:
Aqueous sodium hydroxide (14.7 ml of 1M) was added to a solution of methyl 2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetate from (b) (1.97 g, 4.9 mmol) in a 3:1 mixture of methanol and 1,4-dioxane at ambient temperature. The mixture was heated to reflux for 1 hour before recooling and removing the organic solvents in vacuo. The residue was redissolved in water and acidified with drops of concentrated hydrochloric acid. The resultant precipitate was extracted with diethylether, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was crystallised from diisopropylether to give the subtitle compound (1.59 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](CCCO)=[C:20]([O:23][CH2:24][C:25]4C=CC=C[CH:26]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[O:23][CH2:24][CH2:25][CH2:26]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(OCc4ccccc4)c(CCCO)c3O2)cc1
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(c3O2)CCCO4)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 2.0 g (4.1 mmole) of [(2R)-7-(benzyloxy)-8-(3-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 100 mL of methanol was added to a slurry of 0.30 g of 10% palladium on carbon in 30 mL of methanol in 500 mL Parr hydrogenation bottle. The mixture was treated with 50 psi of hydrogen on a Parr shaker for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to 1.6 g of a colorless oil. The oil was dissolved in 100 mL of benzene, 2.1 g (8.0 mmole) of triphenylphosphine and 1.6 g (8.0 mmole) of diisopropylazodicarboxylate added and the mixture stirred at room temperature for 5 days. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant to give 1.2 g of the (R)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.35 δ (2H); doublet 6.6 δ (1H); doublet 6.35 δ (1H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); triplet 4.1 (2H); doublet of doublets 4.0 δ (1H); multiplet 2.55 δ (2H); singlet 2.45 δ (3H); multiplet 1.9 δ (2H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:42](O)=[O:43])[CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:42]([C:39]4([C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[O:38])[CH2:41][CH2:40]4)=[O:43])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 29.6 %

Procedure:
4-(Dimethylaminomethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (88 mg) was dissolved in N,N-dimethylformamide (2.5 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (101 mg), triethylamine (0.0633 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (201 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of heptane to the resultant residue. The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (39.8 mg, 30%).
Reaction SMILES: O[CH:2]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[CH2:8][CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].C(OCC)C>ClC(Cl)C>[CH3:19][C:13]1[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH:3]=[CH:2][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[CH2:11][CH2:10]1
Reactant: Cc1cccc(N2CCN(CCCC(O)c3ccc4c(c3)CCC(=O)N4)CC2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: Cc1cccc(N2CCN(CCC=Cc3ccc4c(c3)CCC(=O)N4)CC2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 Grams of 6-{1-hydroxy-4-[4-(2,3-dimethylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril and 0.5 g of p-toluenesulfonic acid were dissolved in 100 ml of dichloroethane then the mixture was refluxed for 20 minutes. The reaction mixture was concentrated under a reduced pressure to dryness then to the residue thus obtained were added 10N-NaOH and diethyl ether and stirred at a room temperature for 30 minutes. The crystals thus precipitated were collected by filtration and separated by a silica-gel chromatography. Recrystallized from ethanol-acetone-chloroform to obtain 6-{4-[4-(2,3-dimethylphenyl)piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril in colorless needle-like crystals. Yield: 1.9 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([NH2:21])[CH2:20][CH2:19]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:21][CH:18]2[CH2:20][CH2:19]2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (6.1 g, 25.0 mmol) and cyclopropylamine (1.9 mL, 27.5 mmol) in dichloromethane (125 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.3 g; 27.5 mmol) is added in one portion. The reaction is stirred at ambient temperature for 48 hours. The solvent is evaporated and the crude is stirred in ice-cold 1N hydrochloric acid (100 mL) for 30 min. The solid product is isolated by suction filtration, washed with small portions of water and recrystallized from ethanol/water to deliver 5.2 g of the title compound as colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[C:23](=[O:25])=[O:24]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([N:12]([CH3:13])[CH3:14])=[O:15])=[C:16]([CH:17]=1)[C:23]([OH:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)NCc1ccc(C(C)(C)C)cc1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)NCc1ccc(C(C)(C)C)cc1C(=O)O
Temperature: -70 °C
Yield: 80 %

Procedure:
A 500-mL, three-neck, round-bottomed flask equipped with a magnetic stirrer, addition funnel and thermocouple was purged with nitrogen and charged with 107a (9.36 g, 40.0 mmol) and THF (120 mL). The reaction was cooled to −70° C. and t-butyllithium (1.7 M in pentane, 56 mL, 95.2 mmol) was added dropwise. The reaction was allowed to warm to −45 to −35° C. for 0.5 h and then cooled back down to −78° C. The reaction was then cannulated into a 1-L, three-neck, round-bottomed flask which was filled with ˜100-200 g of dry ice under a flow of nitrogen. The mixture was warmed to room temperature and then concentrated under reduced pressure to dryness. Water (250 mL) and hexanes (250 mL) were added and the solution shaken. The aqueous layer was separated and extracted with methyl t-butyl ether ((150 mL). The aqueous layer was separated and then filtered through Cellpure P65 to clarify it. The aqueous filtrate was acidified with 20 mL of 12.1 M hydrochloric acid and stirred at ambient temperature overnight. After this time, the aqueous solution was decanted off, and the remaining solid was dried overnight under vacuum to afford an 80% yield of 107b (8.91 g) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.97 (br s, 1H), 7.80 (d, 1H, J=2.1 Hz), 7.56 (dd, 1H, J=6.0, 2.1 Hz), 7.32 (d, 1H, J=8.1 Hz), 6.78 (t, 1H, J=5.7 Hz), 4.46 (d, 2H, J=5.7 Hz), 2.82 (s, 6H), 1.28 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[F:21][C:22]1[C:23]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:25]([C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[C:23]=4[C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)=[O:26])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Product: O=C(c1cccc(F)c1-c1ncccn1)N1CC2CN(c3cnc4cc(F)c(F)cc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and Intermediate 50 in the last step MS (ESI): mass calculated for C25H19F3N6O, 476.16; m/z found 477.2 [M+H]+. 1H NMR (500 MHz, CDCl3) 8.74 (t, J=12.5, 2H), 8.25 (d, J=20.5, 1H), 7.65 (dd, J=10.5, 8.4, 1H), 7.52-7.40 (m, 2H), 7.26-7.12 (m, 3H), 3.97-3.74 (m, 3H), 3.73-3.52 (m, 4H), 3.38 (dd, J=11.1, 4.6, 1H), 3.22-3.02 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:14])=[N:8][CH3:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1ccc(F)cc1
Product: CN=C(Cl)c1ccc(F)cc1

Procedure:
A suspension of 4-fluoro-N-methyl-benzamide (CAS: 701-49-5, 0.106 g, 0.69 mmol) in thionyl chloride (202 mL, 2.78 mmol) was refluxed for 1 h 30 min. The solvent was removed under reduced pressure, then toluene was added and the solvent was evaporated under reduced pressure to afford a yellow oil used immediately for the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:5][N:6]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][N:5]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1nnc(N)s1
Product: CSC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1

Procedure:
By the procedure of Example 8(i), 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole (from the dihydrobromide) is reacted with 1-nitro-2,2-bis-methylthioethylene to give 1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Reactant: CN1CCNCC1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1
Yield: 85.7 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 85.7%).