Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][CH2:13][C:14]1[CH:43]=[CH:42][C:17]([CH2:18][N:19]([CH:32]2[CH2:41][C:40]3[N:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]2)[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:44][C:45]1[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:44][C:45]1[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:21])=[O:22])[CH:32]2[CH2:41][C:40]3[N:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]2)=[CH:42][CH:43]=1)=[O:48]
Reactant: NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C(O)c1c(Cl)cncc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)c1c(Cl)cncc1Cl
Yield: 39.4 %

Procedure:
Using the EDCI coupling general procedure F: Reaction of N-(4-Aminomethyl-benzyl)-2-nitro-N-(5,6,7,8-tetrahydro-quinolin-7-yl)-benzenesulfonamide (75 mg, 0.17 mmol), 3,5-dichloroisonicotinic acid (75%, 55 mg, 0.22 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), 4-methyl morpholine (100 μL, 0.89 mmol), and EDCI (32 mg, 0.17 mmol) for two days at 50° C. followed by column chromatography on silica gel (1:1:98 MeOH—NH4OH—CH2Cl2) gave the title compound (42 mg, 40%) as a yellow foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: COC(=O)C(CCBr)NC(=O)OC(C)(C)C
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
Potassium carbonate (935 mg, 6.77 mmol) was added in one portion to a solution of 4-[4-(benzyloxycarbonylamino)butyl]phenol (506 mg, 1.69 mmol) and N-Boc bromide 30 (501 mg, 1.69 mmol) in anhydrous DMF (10 mL). The reaction mixture was stirred at 70° C. (oil bath) for 14 h, cooled to room temperature, and diluted with ethyl acetate (100 mL) and hexanes (20 mL). The mixture was washed with water (4×20 mL) and brine (40 mL) and concentrated under reduced pressure. Flash silica gel column chromatography using ethyl acetate/CH2Cl2 (1:25, 1:20, v/v) gave the desired product 31 as a thick yellow oil (718 mg, 83% yield). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.48-1.68 (m, 4H), 2.12-2.38 (m, 2H), 2.48-2.60 (m, 2H), 3.10-3.24 (m, 2H), 3.75 (s, 3H), 3.97-4.06 (m, 2H), 4.41-4.52 (m, 1H), 4.70 (br s, 1H), 5.09 (s, 2H), 5.25-5.37 (m, 1H), 6.70-6.80 (m, 2H), 6.95-7.09 (m, 2H), 7.30-7.38 (m, 5H). m/z (ESI) 515 [C28H38N2O7+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[OH-].[Na+].Cl[CH2:11][CH:12]([OH:15])[CH2:13]Cl>C(O)C>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][CH2:11][CH:12]([OH:15])[CH2:13][S:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2]
Reactant: OC(CCl)CCl
Reactant: CN(C)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCSCC(O)CSCCN(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
2-(Dimethylamino)ethanethiol hydrochloride (10.78 g, 78 mmole) was added portion-wise to a solution of sodium hydroxide (6.2 g, 155 mmole) in ethanol (40 mL) at 0° C. under nitrogen. A further portion of ethanol (20 mL) was added and the mixture stirred at this temperature for 10 minutes. 1,3-Dichloro-2-propanol (5.29 g, 41 mmole) was added dropwise. On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. The precipitated solid was filtered off and the washed with ethanol. The filtrate was evaporated. The resulting oil was taken up into acetone, filtered and evaporated to give the desired product (8.90 g, 68%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(CC)=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
210.0 g (1.10 mol) of 4-bromo-2-fluorophenol are dissolved in 1.1 l of ethyl methyl ketone, and 175.0 g (1.27 mol) of potassium carbonate and 150.0 ml (1.26 mol) of benzyl bromide are added. The mixture is refluxed for 5 h and stirred at room temperature for 16 h. The batch is filtered, and the filtrate is concentrated to dryness. The crude product is crystallised from heptane at reduced temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H][H]>C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: COc1ccc(O)cc1
Solvent: CCO
Product: COC1CCC(O)CC1

Procedure:
4-Methoxyphenol (100 g) in ethanol (759 ml) was hydrogenated under 50 psi hydrogen using Nishimura catalyst (10.0 g) at rt for 4.5 h. The catalyst was filtered off; the solvent was removed in vacuo to yield the desired product as 95% pure yellowish liquid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH:6]([C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1)=O.C(N)C1C=CC=CC=1>C(O)C>[C:3]([C:2]([C:1]#[N:5])=[CH:6][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:4]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: N#CCC#N
Solvent: CCO
Solvent: NCc1ccccc1
Product: N#CC(C#N)=Cc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
Malononitrile (132 mg, 2 mmol) was dissolved in ethanol (6 mL), and 5-formylsalicylic acid (332 mg, 2 mmol) was added. After cooling with ice bath, benzylamine (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The separated yellow crystal was filtered and recrystallized (ethanol) to give the title compound (139.9 mg, 32.7%) as a light yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]1[C:15](=[O:16])[CH:14]=[CH:13][C@@H:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:11]1.N1C=CN=C1>CN(C)C=O>[Si:5]([O:9][C@@H:10]1[C:15](=[O:16])[CH:14]=[CH:13][C@@H:12]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:11]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: COc1ccc(CO[C@@H]2C=CC(=O)[C@@H](O)C2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2C=CC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
tert-Butyldimethychlorosilane (26 mg, 0.18 mmol, 1.5 equiv) was added to an ice-cooled solution of (4S,6S)-6-hydroxy-4-(4-methoxybenzyloxy)cyclohex-2-enone (29 mg, 0.12 mmol, 1 equiv) and imidazole (24 mg, 0.35 mmol, 3 equiv) in dimethylformamide (0.5 mL). After 45 min, the reaction mixture was partitioned between water (15 mL), saturated aqueous sodium chloride solution (15 mL), and ethyl acetate (20 mL). The layers were separated. The organic layer was washed with water (2×20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography to provide 29 mg of the product, (4S,6S)-6-(tert-butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)cyclohex-2-enone, as a colorless oil (87%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].[NH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](=[O:16])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2)=[O:8]
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
A mixture of 1-[(R)-methoxycarbonylamino-cyclohexyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid (0.410 g), 6-aminomethyl-isoquinolin-1-ylamine (0.227 g), N-methyl morpholine (0.58 mL) and 0.423 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. The mixture was concentrated and the remaining residue was purified by HPLC (RP-18; H2O/CH3OH 95/5→0/100) to give 0.350 g (58%) of the title compound as a white solid. (+)-APCI-MS: 468 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:12]4[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(=O)[nH]c34)cc2F)cc1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to give the title compound as a white solid. Yield: 33 mg (44%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:26]=[O:27])=[CH:11][CH:12]=1
Reactant: Brc1ccc(-c2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(-c3ccc(Br)cc3)cc12
Temperature: 25 °C

Procedure:
In a 100-ml round-bottom flask is placed 2.8 mL of dimethylformamide (2.74 g, 3.74 mmol). The flask and the content was cooled in an ice-salt bath for about 0.5 hour and 0.86 mL (1.44 g, 94 mmol) of freshly distilled phosphorusoxychloride is subsequently added with stirring to the dimethylformamide dropwise. Then a solution of 1.0 g of 32 (85 mmol) in 1 mL of dimethylformamide is added to the above solution slowly. After the addition, the temperature of the solution is brought to 40° C. and allowed to stir for an hour. At this time, 1N NaOH (10 mL) was added to the reaction mixture dropwise. The resulting mixture is heated rapidly to the boiling point and allowed to cool to room temperature. The resulting precipitate is collected on a filter and the solid was further washed with water. Compound 33 obtained from this procedure was pure enough for the next reaction. MS (Es+ve) m/z 300, (Es−ve) m/z 298.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:15][C:4]([C:5]=2[C:6]=34)=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][C:2]1[CH:3]=[C:4]2[CH2:15][C:7]3[C:6]4[C:5]2=[C:14]([CH2:13][CH2:12][C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:1]=1
Reactant: BrBr
Reactant: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cc2c3c(c1)Cc1cccc(c1-3)CC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
8,9-dihydro-4H-cyclopenta[def]phenanthrene (4.0 g, 20.8 mmol) was put into a 250 ml round bottom flask (RBF), and CCl4 (100 ml) was added thereto. The reaction mixture was cooled to 0° C., and Br2 (3.3 g, 20.8 mmol) was dropwise added thereto. The reaction solution was incubated for 4 hours and a 10% NaSO3 solution was added thereto. The organic phase was separated, concentrated under a reduced pressure, and recrystallized from n-hexane to obtain 4.7 g of a 2-bromo-8,9-dihydro-4H-cyclopenta[def]phenanthrene compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])[N:3]=1.C(O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>[Cu]I.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.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CN(C)C=Nc1ncc(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 1-liter, 3-neck-round-bottom flask was equipped with an air stirrer, reflux condenser, and a nitrogen inlet. The 4-chloro-2-(dimethylaminomethyleneamino)-5-iodopyrimidine (65.2 g), ethanol (84 mL), and triethylamine (336 mL) were charged and heated to reflux. Copper (I) iodide (105 mg) and dichlorobis(triphenyl)phosphine palladium II (386 mg) were added. Neat 1-chloro-4-ethynylbenzene (30.1 g) was added and the mixture was refluxed approximately 2.5 hours. The mixture was cooled to ambient temperature, stirred for 1.5 hours and filtered. The filter cake was slurried in water:ethanol (4:1 v/v, 120 mL), filtered and dried in vacuo at 50° C. to give 4-chloro-5-(4-chlorophenylethynyl)-2-dimethylaminomethyleneaminopyrimidine as a yellow solid: 55.7 g m.p. 195–197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:11])[C:3]=1[C:4]([OH:6])=[O:5].CO[C:14](OC)([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[O:6])[O:5][C:14]([CH3:16])([CH3:15])[S:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)c1c(S)cccc1Cl
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)c2c(Cl)cccc2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 g (106 mmol) of 2-chloro-6-mercaptobenzoic acid, 26 ml (212 mmol) of 2,2-dimethoxypropane and 2 g of Amberlyst 15 (strongly acidic ion exchange resin) are refluxed in 1 l of toluene for 3 h. 100 ml are then distilled off in the course of 2 h, a further 10 ml of 2,2-dimethoxypropane are added, boiling is continued for a short time, and the mixture is stirred overnight at room temperature, filtered and concentrated in vacuo. Yield: 22.4 g (92%) of oil, 1H-NMR (CDCl3) δ=1.82 (s); 7.18-7.40 (m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:14]1([CH2:20][CH2:21]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:20][CH2:21][O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]2[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Product: O=C(C=Cc1ccc(F)c(F)c1)OCCc1ccccc1
Yield: 38 %

Procedure:
Reaction of 3,4-difluorocinnamic acid and β-phenylethyl alcohol as outlined in method A provided 67J-17-A as snow-white crystals (38% yield): mp 53°-57° C., 1H NMR (CDCl3) δ:7,49 (d, 1H, J=16 Hz), 7.30-7.05 (m, 8H) 6.27 (d, 1H, J=16 Hz), 4.36 (t, 2H, J=7.0 Hz), 3.82 (s, 3H), 2.95 (t, 2H, J=7.0 Hz); FABMS (NBA, +VE m/z 289 (M+H). Anal. (C17H14O2F2) C,H.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[CH:7][C:8]=2[OH:14])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)(C)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 53.8 %

Procedure:
Using 5-[(1,1-dimethyl)ethyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11]#[N:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.Cl.[OH-].[Na+]>COCCOC>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][CH2:10][CH2:11][NH2:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#CCSc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: NCCSc1cc(Cl)cc(Cl)c1
Yield: 81.8 %

Procedure:
To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2 g) in 3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of 10M borane dimethyl sulfide complex and the mixture heated at reflux for 0.5 hours. The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL of concentrated hydrochloric acid is added. This mixture is heated at reflux for 0.5 hr. The clear solution is then cooled and basified with 5N sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give 1.0 g of a colorless oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C=O)c(O)cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1cc(CO)c(O)cc1O
Reaction time: 1 h
Yield: 65.3 %

Procedure:
One gram of 5-acetyl-2,4-dihydroxybenzaldehyde was hydrogenated in the presence of 1 g of 10% palladium on carbon in 150 ml of ethanol. After about 1 hour, hydrogen uptake ceased and hydrogenation was terminated. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in approximately 30 ml of ethyl acetate and cooled in the refrigerator. The resulting solid was recovered by filtration affording 0.66 g of the desired title intermediate, m.p.=151°-152° C. The same reaction when run on a 5-fold scale provide 2.76 g of material.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:25])[NH:14]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1cccc(Cl)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Yield: 91.7 %

Procedure:
A solution of [2-(2-chloro-6-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (120 mg, 0.32 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at 25° C. The solution was heated to reflux for 3 h, concentrated and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2-(2-chloro-6-methoxy-phenyl)-1H-indol-6-ylamine (80 mg, 91%) as a white solid. MH+ 272.9.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[C:24]([S:35][CH3:36])=[N:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[NH2:28])=O)C.O>O=S(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:21](=[O:20])[C:23]3[C:24]([S:35][CH3:36])=[N:25][N:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:27]=3[N:28]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(SC)nn(-c2ccccc2)c1N
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CSc1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)n(-c3ccc(Cl)cc3)c(=O)c12
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-N-(4-chloro-phenyl)-benzamide (1.14 g, 3.67 mmol) in SOCl2 (4.5 mL) is heated to 80° C. for 2 h before SOCl2 is removed in vacuo. The resulted imidoyl chloride intermediate is dissolved in anhydrous dichloroethane (18 mL) and transferred into a sealed tube. After adding 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.12 g, 4.04 mmol) and TiCl4 (0.80 mL, 7.3 mmol), the reaction tube is sealed and heated at 150° C. overnight. After cooling down to room temperature the reaction mixture is poured into water (200 mL) and extracted with chloroform (3×100 mL). The organic layers are combined, washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography to provide 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as a white solid product; HPLC-MS calculated for C24H16BrClN4OS (M+H+) 523.0, found 523.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3ccnc3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: C([O:8][C:9](=[O:26])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]1=[O:25])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:21]([O:20][C:18]([NH:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][C:9]([OH:26])=[O:8])[C:12]1=[O:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(CC(=O)O)C1=O
Yield: 95.1 %

Procedure:
Palladium on carbon (10%, 500 mg) was added to a solution of (R)-(3-tert-butoxycarbonylamino-2-oxo-piperidin-1-yl)-acetic acid benzyl ester (2.31 g, 6.37 mmol) in ethanol (50 mL). The atmosphere was replaced with hydrogen and maintained with a balloon filled with hydrogen and the above mixture was vigorously stirred. After 16 hours the hydrogen was removed and CELITE was added to the mixture with stirring and then the mixture was filtered though a pad of CELITE. The solvent was removed under reduced pressure and the resulting residue was azeotroped with toluene to provide (R)-(3-tert-butoxycarbonylamino-2-oxo-piperidin-1-yl)-acetic acid (1.65 g, 6.06 mmol, 95%). C12H20N2O5 calculated 272.3 observed [M+1]+ 271.2; rt=1.80 min.