Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 2-(4-methoxyphenyl)ethaneamine (500 mg, 3.31 mmol), 4′-chloro[1,1′-biphenyl]-4-carboxylic acid (846 mg, 3.64 mmol) and 1-hydroxybenzotriazole (760 mg, 4.96 mmol) in dimethylformamide (10 ml) was added ethyldimethylaminopropylcarbodiimide hydrochloride (951 mg, 4.96 mmol) at 0° C., and the mixture was was stirred at room temperature for 16 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound (1.03 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:11](=[O:16])[CH2:12][S:13]([CH3:15])=[O:14])[NH:8]2)=[CH:4][C:3]=1[Cl:23].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:7]([C:11](=[O:16])[CH2:12][S:13]([CH3:15])(=[O:32])=[O:14])[NH:8]2)=[CH:4][C:3]=1[Cl:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1

Procedure:
Stir a mixture of 6.0 g of 6-bromo-5-chloro-2-[(methyl-sulfinyl)acetyl]-3-phenylindole and 6.0 g of m-chloroperbenzoic acid in 150 ml of chloroform at room temperature for 2 hours. Concentrate the mixture to about 50 ml, in vacuo, and filter and wash the product with 20 ml of cold chloroform to obtain 6-bromo-5-chloro-2[(methylsulfonyl)acetyl]-3-phenylindole, m.p. 224°-225°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH:16]=[CH:23][C:22]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)c1cccnc1Nc1ccc(F)cc1
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C=CC(=O)c2cccnc2Nc2ccc(F)cc2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
To a solution of 1-(2-(4-fluorophenylamino)pyridin-3-yl)ethanone (100 mg, 0.434 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (85.30 mg, 0.434 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 8h and the reaction was monitored by TLC. After 6h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7f) (160 mg, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][N:60]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1M HCl solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (13.6 g, 88%). 1H-NMR (400 MHz, CDCl3): δ=1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1H), 3.22-3.43 (m, 1H), 4.03-4.12 (m, 1H), 4.42 (q, 3H), 4.54-4.69 (m, 1H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1H), 8.10 (br, 1H). MS: m/z=209 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1oc2ccc(Br)cc2c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
To a solution (200 mL) of 1-(5-bromo-2-hydroxyphenyl)ethanone (25.0 g) in N,N-dimethylformamide were added potassium carbonate (24.0 g) and methyl bromoacetate (11.5 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was filtered, 1,8-diazabicyclo[5.4.0]undec-7-ene (23.2 mL) was added to the filtrate, and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and ice water was added. The precipitate was washed with ethanol-water to give the title object compound (16.8 g, 52%) as a pale-red solid.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH:43]1([CH:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>ClCCl>[C:43]1([CH:49]([CH:51]2[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]2)[O:2][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: OC(c1ccccc1)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OC(c1ccccc1)C1CCCCC1
Yield: 25.9 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (71 mg, 0.19 mmol), 4-N,N-dimethylaminopyridine (7.5 mg, 0.06 mmol, 0.3 eq), 1,3-dicyclohexylcarbodiimide (64 mg, 0.31 mmol, 1.6 eq) in dichloromethane (5.0 mL) was treated with (±) cyclohexylphenylcarbinol (45 mg, 0.24 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 27 mg (26%) of L-isoleucine, N-[1-(2-(1-phenyl-1-cyclohexylmethoxy)-2-oxoethyl)-L-prolyl] benzylamide (RD-08-71, Z6338).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:13])[C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.[H-].[Na+].CN(C=O)C.Cl[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1>C1COCC1>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([C:6]2[C:7]([NH:11][S:12]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:13])=[O:14])=[N:8][CH:9]=[N:10][C:5]=2[O:4][CH2:3][CH2:2][O:1][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
2-Phenyl-ethenesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (150 mg) was dissolved in THF (10 ml) and sodium hydride (45 mg; 55-65% in mineral oil) was added. The mixture was stirred for 15 min at rt., followed by the addition of DMF (2 ml) and 2-chloro-5-trifluoromethyl-pyridine (146 mg) and heating to 75° C. for 5 h. Then the reaction mixture was evaporated to dryness and water (15 ml) and citric acid was added. The precipitated product was filtered off, washed with water and dried. 2-Phenyl-ethenesulfonic acid {5-p-tolyl-6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide (130 mg) could be obtained as a white powder. tR=5.92 (LC); [M+H]+=557.38 (ES+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:40]([C:36]4[S:35][CH:39]=[CH:38][CH:37]=4)(=[O:42])=[O:41])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(S(=O)(=O)c4cccs4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A30 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), thiophene-2-sulfonyl chloride (9 mg, 0.049 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.07 (m, 4H), 3.08 (s, 3H), 3.14 (m, 2H), 3.41 (m, 2H), 5.53 (m, 1H), 7.31 (m, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.83 (m, 2H), 7.95 (m, 2H), 8.37 (s, 1H), 10.14 (s, 1H). Exact mass calculated for C20H21N5O7S3 539.06, found 540.2 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[NH2:28][C:26]([C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)=[O:27]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C(N)=O)cc2)cc1
Yield: 8.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (4.00 g, 11.7 mmol) in 100 mL of dichloromethane and 4-aminobenzamide (3.20 g, 23.5 mmol) in 26 mL of pyridine. The crude product was triturated with a hot mixture of acetonitrile and DMF, filtered, recrystallized from ethanol-water-DMF, triturated with a hot mixture of methanol and DMF, and filtered to yield 0.563 g of the title compound, mp >270° C.
Reaction SMILES: C([O:4][C@H:5]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[OH:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:17]([O:16][CH2:15][C@@H:5]([OH:4])[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[OH:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)O[C@H](COCc1ccccc1)[C@@H](O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O[C@H](COCc1ccccc1)[C@@H](O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of (1S,2R)-3-(benzyloxy)-1-(2-chlorophenyl)-1-hydroxypropan-2-yl acetate (Preparation example 374, 1.2 g, 3.58 mmole) in MeOH (16.2 mL) and H2O (1.8 mL) was added K2CO3 (1.48 g, 10.74 mmole) at 0° C. The mixture was stirred for 1.5 hr at 0° C. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0° C. then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (1.0 g, 94%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([NH:5][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
A solution of t-butylamine (0.2962 g, 4.05 mmol) and triethylamine (0.70 ml, 5.02 mmol) in dichloromethane (2 ml) was cooled to 0° C. in an ice-bath. To the above solution was added a solution of 2,4-difluorobenzoyl chloride (0.3652 g, 2.07 mmol) in dichloromethane (3 ml) dropwise and stirred for 2.5 hours. The mixture was added to saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous NaHCO3 and dried over MgSO4. The solvent was evaporated to give the title compound (0.4086 g; 93%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH:22]1([CH2:25][NH:26][CH3:27])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:22]1([CH2:25][N:26]([CH3:27])[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CC1)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-cyclopropyl-N-methylmethanamine hydrochloride (77335-18-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=352.4 [MH+].
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23]Cl)[N:9]=1.[N-:34]=[N+]=[N-].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH2:34])[N:9]=1
Reactant: O=c1n(CCCCl)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCCn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Temperature: 80 °C

Procedure:
3-(3,5-Bis(trifluoromethyl)phenethyl)-4-benzyl-1-(3-chloropropyl)-5-oxo-1,2,4-triazole (Description 2, 2.5 g, 0.005 mol) was dissolved in DMF (30 ml) and sodium azide (0.495 g, 0.0076 mol) added and the reaction heated to 80° C. for 16 hours. The reaction was cooled, diluted with water (50 ml) and extracted into ethyl acetate (75 ml). The organic layer was washed with water (3×25 ml), brine and dried (MgSO4). The solvent was removed and the resulting azide (colourless off) was dissolved in ethanol (30 ml) and hydrogenated over palladium hydroxide (0.300 g) at 50 psi for 4 hours. The catalyst was filtered and the solvent removed in vacuo to furnish the title compound as a colourless oil. (2.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1(N)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: NN1CCCCC1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N4CCCCC4)n3)cc2s1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 18.9 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol) and piperidin-1-amine (0.03 g, 0.3 mmol) in DMSO (0.03 g, 0.3 mmol) was heated under microwave (CEM) at 80° C. and 130 W (Powermax® off) for 20 min. Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC (5-50% CH3CN in water) to give a light yellow solid (20 mg) as a TFA salt. MS (ESI pos. ion) Found m/z: 354, (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Chloro-benzoic acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(CCl)cc1
Reactant: C=CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCc1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allylphenol, (6.14 g, 0.046 moles), 4-methoxybenzyl chloride, (6.3 ml, 0.046 moles), potassium carbonate (8.3 g, 0.06 moles) and a catalytic amount of potassium iodide were mixed together in about 200 ml acetone, and heated to reflux, with stirring. The reaction was allowed to proceed overnight, then cooled to room temperature and diluted with about 100 ml water. The product was extracted into ethyl acetate (3 times, 300 ml each time), and then dried over magnesium sulfate/potassium carbonate, filtered and concentrated in vacuo to yield the title compound as a light yellow solid, m.p. 59-61° C.
Reaction SMILES: C([CH:3]([C:11]1[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)#N.C(=O)([O-])[O-:22].[K+].[K+].O>CS(C)=O.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([C:11]2[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CCCOc1cccnc1C(C#N)c1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1cccnc1C(=O)c1ccc(F)cc1
Yield: 85.8 %

Procedure:
Under oxygen atmosphere, a mixed solution of 2-(α-cyano-4-fluorobenzyl)-3-propoxypyridine (5.42 g) and potassium carbonate (3.07 g) in DMSO-water (200-40 ml) was stirred at room temperature for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3→1:2), to give 2-(4-fluorobenzoyl)-3-propoxypyridine (4.46 g) as pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O.O>C(C(C)=O)C(C)C>[CH3:24][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: COS(=O)(=O)OC
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 90 °C

Procedure:
Five parts of 3,5-diphenylpyrazole are dissolved in 25 parts (by volume) of methyl isobutyl ketone. Solid anhydrous sodium hydroxide (1.1 parts) is added and the mixture is heated to 90°C. Dimethyl sulfate (3.43 parts) is added and the mixture is next heated to 112°C. to 115°C. The reaction mixture is sampled after 1.5 hours, and no unreacted 3,5-diphenylpyrazole is found to be present. The reaction mixture is cooled to 50°C., and 30 parts of water are added. The pH is next adjusted to between 11 and 12 by the addition of aqueous sodium hydroxide. The organic layer is washed twice with 30 parts water. For yield determination the methyl isobutyl ketone is removed in vacuo, producing 4.95 parts (93% crude yield) of an oil which crystallizes on cooling (melting point 52°C. to 53°C). Analysis of the product shows it to be 85.5% pure as 1-methyl-3,5-diphenylpyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:17])[NH:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]n(-c2ccccc2)c2cc(Br)ccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-1-phenyl-1,2-dihydroindazol-3-one (5 g, 17.30 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), potassium carbonate (3.7 g, 34.91 mmol, 2.00 equiv), CH3I (2.7 g, 19.01 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at 80° C. in an oil bath. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40) to yield 6-bromo-3-methoxy-1-phenyl-1H-indazole as a yellow solid.