Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=O)[N:10]([CH3:11])[C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O>C(OCC)(=O)C>[Cl:19][C:9]1[N:10]([CH3:11])[C:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Cl)c2[nH]c(=O)n(C)c12
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc(Cl)n(C)c12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Methyl 7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (150 mg, 0.63 mmol) was dissolved in 3 mL of phosphorous oxychloride and heated at 110° C. overnight. The reaction mixture was allowed to cool to room temperature, poured into a crushed ice, and stirred for 1 h. The resultant was diluted in ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained (147 mg, 90%) was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:9]1(O)[CH2:14][CH2:13]C[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[C:1]([O:7][CH:8]1[CH2:13][CH2:14][CH2:9][CH2:10][CH2:11]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: OC1CCCCC1
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC1CCCCC1
Yield: 84 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of cyclohexanol and 100 mg of sulfated tin oxide catalyst prepared according to example 1 above, in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford cyclohexyl acetoacetate as a viscous colorless liquid in 84% yield.
Reaction SMILES: [CH:1]1[C:6](C(O)=O)=[CH:5][C:4]2[C:10]3([O:26][C:27](=[O:28])[C:3]=2[CH:2]=1)[C:19]1[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[C:14]([OH:25])[CH:13]=[CH:12][C:11]3=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:6]1[CH:1]=[CH:2][C:3]([C:27]([OH:28])=[O:26])=[C:4]([C:10]2[C:11]3[CH:12]=[CH:13][C:14]([OH:25])=[CH:15][C:16]=3[O:17][C:18]3[C:19]=2[CH:20]=[CH:21][C:22]([CH:23]=3)=[O:24])[CH:5]=1
Reactant: O=C(O)c1ccc2c(c1)C1(OC2=O)c2ccc(O)cc2Oc2cc(O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
5(6)-carboxy fluorescein is dissolved in NMP to a concentration of 0.2 M. Activation is performed with 0.9 eq. HATU and 1 eq. DIPEA for 2 min before coupling for at least 2×20 min or until the Kaiser test is negative.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[I:15]I>C(O)C.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([NH2:10])=[C:8]([I:15])[CH:9]=1
Reactant: II
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-amino-3-nitro-benzoic acid methyl ester (4.6 g, 23.45 mmol) in ethanol (120 mL) was added iodine (8.33 g, 32.83 mmol), followed by Ag2SO4 (10.24 g 32.83 mmol). The mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 4.98 g (66%) of 4-amino-3-iodo-5-nitro-benzoic acid methyl ester.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([N:28]=[S:29]([CH3:32])([CH3:31])=[O:30])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][N:18]=1)C1C=CC=CC=1.CO.C1COCC1.CN(C=O)C>[Pd].C(O)C>[CH3:32][S:29](=[N:28][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[OH:8])=[N:18][CH:19]=[N:20]2)=[C:25]([CH3:27])[CH:24]=1)([CH3:31])=[O:30]
Reactant: Cc1cc(N=S(C)(C)=O)cc2ncnc(Nc3ccc(F)cc3OCc3ccccc3)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(N=S(C)(C)=O)cc2ncnc(Nc3ccc(F)cc3O)c12
Temperature: 70 °C

Procedure:
To 0.5 g (1.1 mmol) of N-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-5-methyl-quinazolin-4-amine are added 50 mg palladium on charcoal (10%) and MeOH and THF and mixture is hydrogenated in a Parr apparatus (RT; 3 bar; 3 h). DMF and Ethanol are added and mixture heated to 70° C., the catalyst is filtered off and the solvent is evaporated.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5]1>C(O)C>[OH:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5]1
Reactant: COC(=O)C1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CCC(O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (442.6 mg, 11.70 mmol) was added portionwise to a solution of methyl 3-oxocyclopentane-carboxylate A-10 (1.66 g, 11.70 mmol) in absolute ethanol (42.0 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 90 mins, then quenched slowly with a 1 N aqueous solution of hydrogen chloride (10 mL), and concentrated to ca. 15 mL under reduced pressure. The aqueous layer was extracted with methylene chloride (3×50 mL); the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give crude methyl 3-hydroxycyclopentanecarboxylate A-11 as a yellow oil (1.33 g, Yield=79%). This material was used for next step without purification. MS (ESI), [M+1]+ 145.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:2]=1.CN(C)C=O>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:2]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccnc2)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)Nc2cccnc2)c1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 3-(pyrid-3-ylaminosulphonyl)-nitrobenzene (4.279 g, 15.3 mmol) in ethanol (500 ml)/dimethylformamide (50 ml) was added 10% palladium catalyst on charcoal (1 g) and the reaction mixture was hydrogenated at atmospheric pressure for 2 hours. The reaction mixture was then filtered through kieselguhr before being evaporated under reduced pressure to give the product as a white solid (3.749 g, 98%)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[C:11]([O:18][CH3:19])[C:10]=1OC)C1C=CC=CC=1.[CH2:22]([OH:24])C>[Pd]>[NH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH2:19][O:24][CH3:22]
Reactant: COc1c(CCN)ccc(OCc2ccccc2)c1OC
Reactant: CCO
Agent: [Pd]
Product: COCOc1cc(O)ccc1CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 18.00 g of 2-(4-benzyloxy-2-methoxy-methoxyphenyl)ethylamine, 3.6 g of 10% palladium on carbon (Degussa Inc.:E101 NE/W) and 230 mL of ethanol was stirred under a hydrogen atmosphere at room temperature for 1 hour. After the catalyst was filtered off through a diatomaceous earth, the filtrate was concentrated under reduced pressure to give 12.65 g of 4-(2-aminoethyl)-3-methoxymethoxyphenol as a colorless solid.
Reaction SMILES: Cl[C:2]1C=C(O)C=C[C:7]=1F.BrBr.[Br:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=1[OH:21].BrC1C(Cl)=C(F)C=CC=1O>C(=S)=S>[Cl:20][C:16]1[C:15]2[CH:2]=[CH:7][O:21][C:14]=2[C:13]([Br:12])=[CH:18][C:17]=1[F:19]
Reactant: Oc1cc(Cl)c(F)cc1Br
Reactant: Oc1ccc(F)c(Cl)c1
Agent: BrBr
Agent: Oc1ccc(F)c(Cl)c1Br
Solvent: S=C=S
Product: Fc1cc(Br)c2occc2c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5 gm (34.1 mMol) 3-chloro-4-fluorophenol and 1.76 mL (34.1 mMol) bromine in 20 mL carbon disulfide was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate and concentrated under reduced pressure to provide a mixture of 2-bromo-4-fluoro-5-chlorophenol and 2-bromo-3-chloro-4-fluorophenol.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:21].I[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:21]
Reactant: Nc1[nH]c(=O)c(C(=O)NCC2CCNCC2)cc1Cl
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(CNC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Temperature: 60 °C
Reaction time: 15 h
Yield: 49.1 %

Procedure:
A mixture of 6-amino-5-chloro-2-oxo-N-(4-piperidinylmethyl)-1,2-dihydro-3-pyridinecarboxamide dihydrochloride (step 2, 100 mg, 0.28 mmol), iodoethane (49 mg, 0.31 mmol) and potassium carbonate (172 mg, 1.25 mmol) in N,N-dimethylformamide (6 ml) was stirred at 60° C. for 15 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was suspended in tetrahydrofuran (50 ml), and the solution was filtered through a pad of Celite. The filtrate was concentrated in vacuo, and the obtained residue was chromatographed on a column of aminopropyl silica gel eluting with methanol/dichloromethane (1:2.5) to give 43 mg (49%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:12]1[CH:13]=[C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16][C:11]=1[C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2[C@@H]1CCCNC1
Yield: 74.6 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (320 mg, 0.63 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was diluted with water and the pH value of the solution was adjusted to >7 with sodium carbonate. The resulting solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 190 mg (74%) of 3-(2-fluoro-4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]([F:18])([C:14]([F:17])([F:16])[F:15])[C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O>O.CCO>[C:1]([C:6]([OH:13])([C:5]([F:18])([F:4])[C:14]([F:15])([F:16])[F:17])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(O)(C#N)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of KCN (1.4 eq.) in water (0.5 M) was added with stirring to an ice-cooled solution of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (1 eq.) in EtOH and water (40:60 vol). The mixture was stirred for 6 h at 0° C. and then acidified with 6N sulphuric acid and extracted with Et2O. The organic phase was dried (Na2SO4), and the solvents were removed under reduced pressure. The residue was vacuum distilled. The product fraction was collected at 74-76° C./0.5 mbar. (400 MHz, CDCl3) δ: 5.88 (1H, s), 4.40-4.23 (2H, m), 3.04 (1H, s), 1.33 (3H, t, J=7.1 Hz).
Reaction SMILES: COC1C=CC(C[C@@:8]2([C:26]([O-:28])=[O:27])[C@@H:11]([CH2:12][CH:13]=[N:14][NH:15][C:16]([NH2:18])=[NH:17])[C:10](=[O:19])[N:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:15]([N:14]=[CH:13][CH2:12][C@H:11]1[C:10](=[O:19])[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C@@H:8]1[C:26]([OH:28])=[O:27])[C:16]([NH2:18])=[NH:17]
Reactant: COc1ccc(C[C@@]2(C(=O)[O-])[C@@H](CC=NNC(=N)N)C(=O)N2c2ccccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NN=CC[C@H]1C(=O)N(c2ccccn2)[C@@H]1C(=O)O

Procedure:
The crude ester 82 was treated with TFA/DCM (0.75 mL/1 mL). After one and half hours, LC-MS analysis indicated completion of the reaction. The solvent was removed and the residue was purified by preparative HPLC (Vydac reverse phase C-18 column, 22×250 mm ID). Mobil phase: A=0.1% TFA in water, B=0.1% TFA in acetonitrile. The flow rate was 12 mL/min. The gradient time was 5% B to 50% B over 45 min. The desired product, 83, was obtained as a white solid (5.5 mg). Anal. C19H24N6O4, Mol. Wt.: 290.28. Found: ESI-MS: 291.0 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH2:49][CH3:50])=[C:37]([OH:51])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH2:49][CH3:50])=[C:37]([O:51][CH3:3])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CCCC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: CCCC1=C(OC)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/3 v/v, 40 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-hydroxy-4-propyl-1H-pyrrol-2(5H)-one (1.0 g, 2.71 mmol, 1 eq) and MeOH (10 ml), the product was further purified by preparative HPLC; yield: 0.120 g (11.6%); MS m/z: 384.1 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 0.96 (t, 3H), 1.6-1.4 (m, 6H), 1.94-1.87 (m, 1H), 2.47-2.39 (m, 1H), 4.08 (s, 3H), 5.90 (bs, 1H), 6.92 (bs, 1H), 7.03-6.94 (m, 2H), 7.54 (bs, 1H), 7.83 (s, 1H), 7.94 (s, 1H); HPLC (METHOD [A]): rt 14.38 min (100%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Sc1cccc(Br)c1
Product: CC(=O)c1ccc(Sc2cccc(Br)c2)cc1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in the last paragraph of the portion of Example 66 which is concerned with the preparation of starting materials, 4'-fluoroacetophenone was reacted with 3-bromobenzenethiol to give 4'-(3-bromophenylthio)acetophenone in 82% yield, m.p. 54°-57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:26]N1C(=O)CCC1=O>ClCCCl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:26][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Cl)c2)=NO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
In a solution of 13.7 g of 3-(3-chloro-4-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole in 100 mL of 1,2-dichloroethane, 6.6 g of N-bromosuccinimide and 0.1 g of α,α′-azobisisobutyronitrile were added, and stirred at 70° C. for 3 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, washed with water (70 mL×2), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and then the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 12.1 g of the aimed product as pale yellow crystal.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=O.[OH-].[Na+]>CO>[NH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:12][CH:13]=1
Reactant: O=C(NCCc1ccc(Sc2ccc(O)cc2)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCCc1ccc(Sc2ccc(O)cc2)cc1
Yield: 87 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]acetamide (480 mg) in methanol (5.0 ml) was added 1N sodium hydroxide solution (2.8 ml). The mixture was refluxed for 12 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane (40 ml), 1N hydrochloric acid solution (2.0 ml) and water (15 ml). After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 4-[[4-(2-aminoethyl)phenyl]thio]phenol (300 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)cc1
Yield: 65.2 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.058 mMol) 4-methylbenzoyl chloride, 0.010 gm (66%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=1[C:23]([O:25]CC)=[O:24].[Mg].[Cl-].[NH4+]>CO>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C@H:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@@H:11]([C:23]([OH:25])=[O:24])[CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C1=C(c2cc(F)c(F)cc2F)CCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
1-tert-Butyl 3-ethyl 4-(2,4,5-trifluorophenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (9.98 g) was dissolved in methanol (100 ml), and thereto was added magnesium (6.29 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. In an ice-bath, to the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (80 ml), and thereto was added sodium ethoxide (20% ethanol solution, 10.62 g) at room temperature, and the mixture was refluxed for 4 hours. The reaction mixture was cooled, and concentrated under reduced pressure. To the residue was added a 5% aqueous sodium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 ml) and ethanol (40 ml), and thereto was added 1M aqueous sodium hydroxide solution (41.6 ml) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The mixture was cooled, and the reaction mixture was concentrated under reduced pressure. To the residue was added a 5% aqueous sodium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (7.89 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)=[CH:25][N:24]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][O:21][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)=[CH:25][N:24]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: Fc1ccc(-n2ccnn2)cn1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4ccnn4)cn3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (720 mg; 60 wt %; 432 mg NaH contained; 17.99 mmol) in DMF (9 mL) at 0° C. was treated with a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (3.9 g; 13.84 mmol) in DMF (9 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was treated with a solution of 2-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridine (2.499 g; 15.22 mmol) in DMF (10 mL). The reaction was stirred at 0° C. for 45 minutes, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture partitioned between ethyl acetate and water. The organic layer was washed twice more with water, dried over sodium sulfate, filtered and evaporated to a residue. The residue was chromatographed (Horizon 65i silica cartridge; 30% to 45% ethyl acetate/heptane). The fractions containing the desired product were combined and evaporated to a white solid. Crystalline solid was also recovered from the chromatography fractions. The solid isolated from chromatography was recrystallized from EtOH/heptane. The solid (4 g) was suspended in EtOH (150 ml), then heated until completely dissolved, allowed to cool to RT and heptane (100 ml) was added. The mixture was aged at RT overnight, cooled to 0° C. for 5 minutes and filtered to provide the title compound). LCMS: calc. 425.17 obs: 426.09 (M+1). 1H NMR (CDCl3): δ 8.48 (d, 1H), 8.20 (s, 2H), 7.97 (dd, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.26 (s, CDCl3), 6.89 (d, 1H), 4.47 (br t, 2H), 4.47 (t, 2H), 2.87 (m, 2H), 2.15 (m, 1H), 1.86 (br t, 2H), 1.58 (m, 1H), 1.57 (S, H2O), 1.37 (m, 2H), 1.12 (m, 1H), 0.94 (m, 1H), 0.70 (m, 1H), 0.61 (m, 1H), −0.08 (q, 1H).