Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+].Cl>C(Cl)Cl.C(O)(=O)C>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([OH:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=Cc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1)N1CCN(Cc2cccc(O)c2)CC1
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of piperazine-1-carboxylic acid phenylamide (2.0 g) and 3-hydroxybenzaldehyde (3.0 g) in DCM (200 mL) was added acetic acid (1.1 mL) followed by portion-wise addition of NaB(OAc)3H (6.0 g). The reaction mixture was stirred overnight. A solution of 10% aq. NaOH (30 mL) was added until the pH of the aqueous phase was 11. A solution of 1 N HCl was then added until the pH of the aqueous phase was 6-7. The aqueous phase was extracted with DCM (200 mL). The combined organic layers were dried (MgSO4) and concentrated. Chromatography of the residue gave the title compound as a white solid (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[H-].[Na+].I[CH2:39][C:40]#[N:41]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:39][C:40]#[N:41])[CH2:28][CH2:29]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)cc1
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(CC#N)CC2)CC1c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 66.1 %

Procedure:
To a solution of 4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide (216 mg, 0.382 mmol) in DMF (1 mL) was added sodium hydride (55% dispersion in mineral oil, 6 mg, 0.14 mmol). After stirring for 30 min at ambient temperature iodoacetonitrile (9 μl, 0.12 mmol) was added And the suspension was stirred for 18 h at this temperature. After the addition of further iodoacetonitrile (9 μl, 0.12 mmol) the resulting dark brown solution was stirred for further 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL) and was washed with aqueous sodium carbonate (1 M, 10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic phases were dried over sodium sulfate. Purification by chromatography (SiO2, (ethyl acetate:triethylamine=95:5):methanol=100:0 to 70:30) afforded the title compound (45 mg, 88%) as a white foam. MS m/e: 567.1 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccc(Cl)cc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 75.8 %

Procedure:
Example 11 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.028 g) and (4-chlorophenyl)acetic acid (0.019 g) to give the title compound (0.033 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[N:11][OH:12])=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1.C1C(=O)N([Cl:31])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([Cl:31])=[N:11][OH:12])=[C:7]([C:13](=[O:14])[NH:15][CH3:16])[C:6]=2[CH:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNC(=O)c1c(C=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C(Cl)=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A mixture of 5-bromo-2-((hydroxyimino)methyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.25 mmol) and NCS (40 mg, 0.30 mmol) in DMF (2 mL) was stirred at 60° C. for 18 h. The mixture was used for the next step without purification, 5-bromo-N-hydroxy-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carbimidoyl chloride was obtained (90 mg, yield: 65%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.33 (s, 1H), 8.65 (d, J=4 Hz, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 3.20 (s, 6H), 2.80 (d, J=4.8 Hz, 3H). MS (M+H)+: 438/440.
Reaction SMILES: C(OC[O:10][C:11]1([CH2:24][CH:25]([CH3:29])[CH:26]([F:28])[F:27])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)C1C=CC=CC=1.Cl>CO>[F:28][CH:26]([F:27])[CH:25]([CH3:29])[CH2:24][C:11]1([OH:10])[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: CC(CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)C(F)F
Agent: Cl
Solvent: CO
Product: CC(CC1(O)CCNCC1)C(F)F
Yield: 71.3 %

Procedure:
A mixture of tert-butyl 4-((benzyloxy)methoxy)-4-(3,3-difluoro-2-methylpropyl)piperidine-1-carboxylate (0.33 g) and 5 M HCl in MeOH (4 mL) was stirred in methanol (15 mL) for 3 hrs. The solvent was then removed under vacuum to obtain crude product (4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (0.11 g). LC-MS: m/z 194.2 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12](Br)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)C1C=CC=CC=1.[F:34][C:35]([F:47])([F:46])[O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][N:28]1[C:24]([C:10]2[CH:11]=[C:12]([C:40]3[CH:39]=[CH:38][C:37]([O:36][C:35]([F:34])([F:46])[F:47])=[CH:42][CH:41]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:25][N:26]=[N:27]1
Reactant: COCCCn1nnnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCCn1nnnc1-c1cc(-c2ccc(OC(F)(F)F)cc2)c(O)cc1O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the mixture of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-1-(3-methoxy-propyl)-1H-tetrazole (200 μmol), and 4-(trifluoromethoxy)phenyl boronic acid (2 eq.) was added palladium tetrakistriphenylphosphine (45 mg), followed by toluene (1.2 ml), ethanol (1.2 ml) and saturated NaHCO3 solution (1.2 ml). The resulting mixture was stirred at 80° C. for 12 hours. The product was extracted with ethyl acetate (3×2000 μL), and the combined organic layers were washed with aqueous NaCl (2 ml), and dried. To the residue was added palladium on alumina (100 μL), followed by MeOH (2 ml). Triethyl silane (0.5 ml) was added to the reaction, and the resulting mixture was stirred at room temperature for 70 hours. Hexane (2 ml) was added to the reaction mixture and the top 4.5 ml of the solution was filtered through Baker filter cartridges and then dried in a genevac. The residue was purified by reverse phase HPLC to provide 5-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-4′-trifluoromethoxy-biphenyl-2,4-diol. LCMS: 411 [M+H].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=1)=O)C.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=1)=[O:3]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1ccc2c(-c3ccc(F)cc3)c(-c3cccc(C)n3)nn2c1
Product: Cc1cccc(-c2nn3cc(C(=O)NCCN(C)C)ccc3c2-c2ccc(F)cc2)n1
Yield: 10 %

Procedure:
Heat 3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-6-carboxylic acid ethyl ester (75 mg, 0.2 mmol) in 2 ml of N,N-dimethylethylenediamine at 90° C. for 6 hr in a sealed glass tube with stirring. Extract reaction solution once with water/methylene chloride and concentrate the organic layer in vacuo. Purify using preparative TLC (Silica Gel, 90:10 methylene chloride/methanol) to give 12 mg (10%) of the title compound MS ES+ m/e 418.2 (M+1).
Reaction SMILES: C[C:2]1(C)[O:7][C:6]2[C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=[CH:11][C:5]=2[C:4](=[O:16])[O:3]1.C[O-].[Na+]>CO>[OH:7][C:6]1[C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=[CH:11][C:5]=1[C:4]([O:3][CH3:2])=[O:16]
Reactant: CC(C)Oc1cccc2c1OC(C)(C)OC2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(OC(C)C)c1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
A solution of 2,2-dimethyl-8-(propan-2-yloxy)-4H-1,3-benzodioxin-4-one (123b, 1.40 g, 5.92 mmol) in methanol (12 mL) was treated with sodium methoxide in methanol (0.5 M, 24 mL, 12 mmol) and stirred at room temperature for 3 hours, 40 minutes. The solvents were evaporated and the residue partitioned between ammonium chloride solution (sat., aq., 20 mL) and ethyl acetate (2×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under vacuum to give methyl 2-hydroxy-3-(propan-2-yloxy)benzoate (123c, 1.24 g, 93% yield) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]=O.Cl>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2/[CH:22]=[C:7]1\[O:8][C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccc(Br)cc23)Oc2cc(O)ccc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.50 g, 3.3 mmol) and 5-bromo-1H-indole-3-carboxaldehyde (0.90 g, 4.0 mmol) in ethanol (10 mL) was added with concentrated hydrochloric acid (1.0 mL), and the mixture was stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain (Z)-2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (1.1 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)CCSc1ccc(OC)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
4-Methoxythiophenol (4.80 g) was added to a stirred solution of methyl acrylate (3.08 ml) in dichloromethane (60 ml) at 0° C. Potassium carbonate (4.72 g) was added and the mixture was allowed to warm to room temperature overnight. The mixture was filtered over a plug of Celite® and the solvent was removed in vacuo to give the title compound as a yellow liquid (7.70 g, 100%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].O1CCOCC1>O>[C:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCCCCCCCCCC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O
Yield: 73 %

Procedure:
0.3 Mole of methacrylic acid chloride and 0.3 mole of 12-aminododecanoic acid were reacted in a mixed solvent of dioxane and water under Schotten Baumann reaction conditions to obtain N-methacryloyl-12-aminododecanoic acid in a yield of 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([OH:23])CCC>Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:23])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCOc1ccccc1-c1nc(Cl)cc(Cl)n1
Reactant: CCCCO
Agent: Cl
Solvent: O
Product: CCCOc1ccccc1-c1nc(O)cc(Cl)n1

Procedure:
A stirred solution of 4,6-dichloro-2-(2-propoxyphenyl)pyrimidine (16.68 g) in concentrated hydrochloric acid (40 ml), n-butanol (80 ml) and water (40 ml) was heated under reflux for 3 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was washed with water and diethyl ether and recrystallized from isopropanol to yield the title compound, 8.46 g, m.p. 115.5°-116.5° C. A sample (1 g) of this material was recrystallized twice from isopropanol to yield the pure title compound, 0.42 g, m.p. 118°-118.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7](/[C:10](=[N:13]\[S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])/[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH:13][S:14]([C:16]([CH3:17])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CC/C(=N/S(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](NS(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Reaction time: 2.5 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-methanesulfonyl-thiazol-5-yl)-prop-(Z)-ylidene]-amide (93 mg, 0.29 mmol) in THF (5 mL) was added a 1 M solution of lithium tri-sec-butylborohydride (L-Selectride) (0.58 mL, 0.58 mmol) in THF dropwise. After 2.5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (100 mL), and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-thiazol-5-yl)-propyl]-amide.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:51][CH2:52][C@H:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:51][CH2:52][CH:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: O[C@H](CCl)c1ccccc1
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)ccc1OC(CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-1-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-benzonitrile (1 g, 2.43 mmoles) was dissolved in tetrahydrofuran (30 ml) and triphenylphosphine (1.27 g, 4.84 mmoles), (S)-2-chloro-1-phenyl-ethanol (1.13 g, 7.26 mmoles) added. The reaction was cooled to 0° C. and diethylazodicarboxylate (0.842 g, 4.8 mmoles) added. The reaction temperature was allowed to come to room temperature and the reaction stirred for 2.5 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate, washed with 0.5 N sodium hydroxide several times, washed once with brine and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) to yield 1.1 g of 4-[1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile, (82%).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:30][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)[C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[CH2:12][CH2:13]2)=[O:9])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D134) (26 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-((2R)-4-fluoropiperidine-2-carboxamido)cyclopropyl)benzoate (D96) (39 mg) and 4-(trifluoromethyl)-benzylbromide (0.015 ml). (Cs2CO3: 1.3 eq; reaction time: 18 hrs; RT).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[NH2:21][NH2:22]>C(O)COCCO>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8](=[N:21][NH2:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1N

Procedure:
In the manner given in Preparation 1, 5-(trifluoromethyl)-2-aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 5-(trifluoromethyl)-2-aminobenzophenone hydrazone.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].[CH:21]([O:24][C:25]1[C:26](=O)[C:27](=[O:33])[C:28]=1[O:29]C(C)C)([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CO>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@H:3]([NH:2][C:26]2[C:27](=[O:33])[C:28](=[O:29])[C:25]=2[O:24][CH:21]([CH3:23])[CH3:22])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)Nc1c(OC(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of methyl (2S)-2-amino-3-(4-biphenylyl)-propanoate hydrochloride (415 mg, 1142 mmol),3,4-diisopropoxy-3-cyclobutene-1,2-dione (281 mg, 1.42 mmol), DIPEA (247 μl, 1.42 mmol) and MeOH (10 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2; DCM/MeOH, 98:2) to give the title compound (358 mg). δH (DMSO-d6, 390K) 8.50 (1H, d, J 8.0 Hz), 7.63-7.56 (4H, m), 7.47-7.42 (2H, m), 7.36-7.32 (3H, m), 5.24-5.18 (1H, m), 4.80-4.75 (1H, m), 3.74 (3H, s), 3.31 (1H, dd, J 14.2, 5.2 Hz), 3.13 (1H, dd, J, 14.2, 9.4 Hz), 1.38 (3H, d, J 6.0 Hz), 1.37 (3H, d, J 6.1 Hz); m/z (ES+, 70 V) 394 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[C:6](I)=[CH:7][O:8]2.[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[CH:21]=[CH:20][C:19]([C:7]2[O:8][C:9]3[C:4]([C:5](=[O:16])[CH:6]=2)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)=[N:18]1
Reactant: COc1cc(OC)c2c(=O)c(I)coc2c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3cc[nH]n3)oc2c1
Temperature: 0 °C
Yield: 89.6 %

Procedure:
A mixture of 5,7-dimethoxy-3-iodochromone (166 mg) prepared in Example 16, pyrazole (136 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours-with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (122 mg; yield=90.0%) as white bulk crystals. Melting point: 197°-198° C. Mass spectrum (M+): 272. 1 H-NMR(CDCl3, δ ppm): 6.77 (s, 1H, H3), 6.55 (d, 1H, H6), 7.81 (s, 1H, H8), 8.12 (s, 1H, H3'), 6.41 (d, H4'), 6.54 (s, 1H, H5'), 3.96 (s, 3H, 5MeO), 4.06 (s, 3H, 7MeO).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1.[CH3:28][NH:29][CH3:30]>CO.C1COCC1>[CH3:28][N:29]([CH3:30])[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccccc1)N1CCN(c2cc(Cl)nnc2-c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1cc(N2CCN(C(=O)c3ccccc3)CC2)c(-c2ccccc2)nn1
Temperature: 60 °C

Procedure:
To (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone (1 g) dissolved in methanol (40 ml), and dimethyl amine in THF (10 ml) was added under nitrogen atmosphere and the reaction mixture was heated to 60° C. for 18 hrs. The progress of reaction was monitored by TLC. After consumption of starting material, reaction mixture was cooled to room temperature and neutralized with solid sodium bicarbonate. The mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to afford (4-(6-(dimethylamino)-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone as yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:23])[CH2:19][CH2:20][C:21]#[CH:22].Cl>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][OH:23])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Pd]
Agent: Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCc2cc(C#CCCCO)ccc21
Reaction time: 2 h
Yield: 105.9 %

Procedure:
To 3.73 g (12.5 mmol) 5-Bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 25 ml piperidine were added 722 mg (0.63 mmol) tetrakis-(triphenylphosphine)-palladium and 120 mg (0.625 mmol) CuI. The solution was purged with argon, and was heated to 80° C. over a period of 45 min, during which 0.9 ml (9.4 mmol) 4-pentyn-1-ol were added. Additional 0.9 ml (9.4 mmol) 4-pentyn-1-ol were added and the mixture was stirred for 2 h, poured on ice water and 2M HCl was added. The inorganic phase was extracted with ether, the combined organic phases were washed with water and dried over Na2SO4. Purification on silica gel with hexane/EtOAc 4:1 to 2:1 yielded 3.0 g (79%) 5-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as light brown solid, MS: 302 (MH+). (See also: Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672)