Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9](=[O:25])[CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([C:9](=[O:25])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:26])[OH:11])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)N(C)Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(=O)N(C)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using N-benzyl-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-hydroxy-N-methyl-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([F:10])[CH:4]=1)#[N:2].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:10][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH2:12][CH2:13][CH2:14][OH:15])[C:1]#[N:2]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCO)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 4-cyano-2-fluoro phenol (5 g, 0.0365 mol; from prep N(iv) above), 3-bromopropanol (10.15 g, 0.073 mol) and potassium carbonate (7.6 g, 0.054 mol) in dry acetone (50 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 5% ethyl acetate in petroleum ether to yield (5.5 g) of the sub-title compound as a solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1.[C:30]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)(=[O:32])[CH3:31]>C1COCC1>[OH:32][C:30]([C:17]1[S:13][C:14]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=2)=[N:15][CH:16]=1)([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH3:31]
Reactant: N#Cc1ccc(-c2nccs2)cc1C(F)(F)F
Reactant: CC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(C#N)c(C(F)(F)F)c2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A solution of diisopropylamine (0.08 mL, 0.59 mmol) in THF (7 mL) was cooled to −78° C., and 1.6M n-BuLi in hexanes (0.49 mL, 0.78 mmol) added. The reaction mixture was allowed to stir at 0° C. for 30 min, again cooled to −78° C. and a solution of 4-(thiazol-2-yl)-2-(trifluoromethyl) benzonitrile (0.1 g, 0.39 mmol) in THF (2 mL) added dropwise at −78° C. for 30 min 4-Acetyl pyridine (0.048 mL, 0.43 mmol) in THF (2 mL) at −78° C. was then slowly added, the reaction was stirred for 1 hour and quenched with saturated ammonium chloride (2 mL), and water (10 mL). The reaction mixture was extracted with ethyl acetate (20 mL), the organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain crude product. The crude product was product purified by Prep TLC (5% methanol in dichloromethane) to give 4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (30 mg, 21%) as pale yellow solid in 99.1% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, 2H), 8.36-8.32 (m, 2H), 8.24 (d, 1H), 8.03 (s, 1H), 7.52-7.51 (m, 2H), 6.81 (s, 1H), 1.97 (s, 3H). LC-MS m/z calculated for [M+H]+376.07. found 375.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][C:13]([CH3:15])=O.N1CCCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:13]([CH3:15])([CH3:12])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)c2ccc(F)cc2O1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
1-(4-Fluoro-2-hydroxy-phenyl)-ethanone (5.0 g, 32.44 mmol), acetone (11.92 mL, 162.2 mmol) and pyrrolidine (2.7 mL, 32.44 mmol) were dissolved in 20 mL benzene, and the reaction mixture was refluxed for four hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 N HCl. The organic layer was dried over MgSO4, and solvent was evaporated under reduced pressure. The resulting residue was chromatographed (15% ethyl acetate in hexanes eluting through silica) and solvent was removed to yield 3.33 g (17.16 mg, 53%) of 7-fluoro-2,2-dimethyl-chroman-4-one as an oil. MS: 195 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[NH2:16][C:17]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:18]([NH:20][CH3:21])=[O:19]>>[CH2:22]([C:17]([NH:16][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:18](=[O:19])[NH:20][CH3:21])[CH2:24][CH3:25])[CH3:23]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1ccc(Cl)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 83 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=354.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:19]([Mg]Br)[CH2:20][CH3:21]>C1COCC1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12]([CH:15]([OH:16])[CH2:19][CH2:20][CH3:21])=[CH:13][N:14]=2)=[CH:7][CH:8]=1
Reactant: CCC[Mg]Br
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Solvent: C1CCOC1
Product: CCCC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 2-(4-(trifluoromethyl)phenyl)pyrimidine-5-carbaldehyde (1.0 g, 3.96 mmol) in THF (20 mL) was added n-propylmagnesium bromide (2.97 mL of a 2.0M solution in THF, 5.95 mmol). The solution was stirred at 0° C. for two hours. The mixture was quenched with saturated aqueous NH4Cl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give (+/−)-1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butan-1-ol (1.1 g) as a red oil. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 2H), 8.50 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 4.79-4.68 (m, 1H), 1.98-1.91 (m, 1H), 1.85-1.63 (m, 2H), 1.47-1.29 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[OH:20][CH2:21][CH:22](CO)[OH:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH:21]([CH2:22][OH:23])[OH:20])=[O:6]
Reactant: OCC(O)CO
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCC(=O)OCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
1.0 g (3.7 mmol) of methyl 4,8,12-trimethyltridec-3-enoate was slowly added dropwise to a solution of 0.86 g (9.3 mmol) of glycerol and 0.62 g (4.4 mmol) of potassium carbonate in dry N,N-dimethylformamide (4 mL) at 100° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 287 mg of the title compound (24% yield) as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=[C:22]([CH3:30])[N:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:24][CH:23]=[C:22]([CH3:30])[N:21]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: Cc1ccc(OCCN)c(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)c(C)n1
Temperature: 100 °C
Reaction time: 27 h
Yield: 5.5 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2,6-dimethylpyridin-3-yloxy)ethylamine hydrochloride (584 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2,6-dimethylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:29]([O:28][C:26]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:18])([F:16])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidine (ACROS Co., 2.0 g) was dissolved in methylene chloride (10 ml), and pyridine (0.6 ml) and ethyl chloroformate (0.8 ml) were added thereto. The mixture was stirred at room temperature for 5 hr. After completion of the reaction, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (1:2)) to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid ethyl ester (2.03 g, yield 81%).
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.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=2)=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(Cl)c2)n(C)n1

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 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=470.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH2:21][CH3:22]>>[CH2:20]([O:23][C:24](=[O:29])[C:25]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:27])[CH3:26])[CH2:21][CH3:22]
Reactant: Cc1c(-c2cccc(Cl)c2)c2cc(O)ccc2n1C
Reactant: CCCOC(=O)C(C)(C)Br
Product: CCCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(Cl)c1)c(C)n2C

Procedure:
The above compound was prepared from 3-(3-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid propylester using a procedure analogous to that of Example 102.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:25])[CH2:10][N:11]=C(C1C=CC=CC=1)C1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[CH3:7][O:8][C:9](=[O:25])[CH:10]([NH2:11])[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(N)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Dry tetrahydrofuran (250 ml) was cooled to −78° C. Potassium tert-butoxide (6.37 g; 56.72 mmol) was dissolved in dry tetrahydrofuran (100 ml) and added. (Benzhydrylideneamino) acetic acid methyl ester (14.35 g; 56.72 mmol) was added and the reaction mixture was stirred 30 min at −78° C. Benzoyl chloride (6.59 g; 56.72 mmol) was added dropwise and the reaction mixture was stirred 30 min at −78° C. Hydrochloric acid (1.0 M; 175 ml) was added dropwise. The reaction mixture was heated to room temperature and 2/3 of the solvent was removed in vacuo. Water (700 ml) was added and the reaction mixture was washed with diethyl ether (400 ml). The aqueous phase was evaporated in vacuo and the residue was dissolved in methanol and evaporated (2×150 ml). Methanol (80 ml) was added. The mixture was filtrated and the filtrate was evaporated in vacuo. The residue was recrystallised from tetrahydrofuran/diethyl ether to afford 8.86 g of 2-amino-3-oxo-3-phenylpropionic acid methylester as a hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:26])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:26][C:18]1[CH:17]=[C:16]([CH2:15][O:13][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:10][CH2:9][CH2:8]3)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc3c(cc2[N+](=O)[O-])CCC3)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
7.17 g of 6-nitroindan-5-ol was dissolved in 80.0 mL of DMF, and 10.9 g of methyl 4-(bromomethyl)-2-fluorobenzoate and 6.63 g of potassium carbonate were added thereto, followed by stirring at 50° C. overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain 11.1 g of methyl 2-fluoro-4-{[(6-nitro-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]#[N:18])=[CH:12][C:3]=1[C:4]([O:6]CCCCC)=O.[CH3:19][NH2:20].C[O-].[Na+]>>[NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]#[N:18])=[CH:12][C:3]=1[C:4]([NH:20][CH3:19])=[O:6]
Reactant: CCCCCOC(=O)c1cc(C#N)cc(C)c1N
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 68.6 %

Procedure:
The above-described method (Example 3) was repeated to stir pentyl 2-amino-5-cyano-3-methylbenzoate (1.50 g, mmol) with methylamine (10.8 g, mmol, 40% in methanol) and sodium methoxide (441 mg, 0.12 mmol, 30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and stirred with diisopropyl ether. 2-Amino-5-cyano-N,3-dimethylbenzamide (0.79 g, 70.6% of theory, 96.4 area % LC) was obtained as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:16]=[C:4]2[N:3]=1.O.[NH2:28][NH2:29]>O1CCOCC1.O>[CH3:15][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[CH:20]=[N:28][NH:29][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:16]=[C:4]2[N:3]=1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc4ncccc4c3)cc2n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc5ncccc5c4)cc3n2)c1
Reaction time: 8 h

Procedure:
There was suspended, in 1,4-dioxane (2.0 mL), 6-(5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-quinoline (83 mg, 0.23 mM) prepared in the preceding step 1, then hydrazine monohydrate (110 μL, 2.3 mM) was added to the suspension and the mixture was stirred for 8 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate thus obtained was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting solid was dried in vacuo, suspended in ethanol (2.0 mL), then acetic acid (6.5 μL, 0.11 mM) and metatolualdehyde (30 μL, 0.25 mM) were added to the suspension and the mixture was stirred at room temperature for 2 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (60 mg, overall yield of these two steps: 56%).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:32]3[CH:33]=[CH:34][S:30][CH:31]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccsc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-thiopheneboronic acid. The title compound was obtained in 5% yield as a yellow oil. MS (m/e): 488.5 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[NH:17][C:16]4[CH:20]=[C:21]([C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])[CH:22]=[CH:23][C:15]=4[NH:14][C:13]=3[CH:31]=2)[CH:5]=[C:4]([F:32])[N:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[NH:17][C:16]4[CH:20]=[C:21]([C:24]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])[CH:22]=[CH:23][C:15]=4[NH:14][C:13]=3[CH:31]=2)[CH:5]=[C:4]([F:32])[N:3]=1
Reactant: COC(=O)C(C)(C)c1ccc2c(c1)NC(=O)c1ccc(Nc3cc(F)nc(F)c3)cc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)c1ccc2c(c1)NC(=O)c1ccc(Nc3cc(F)nc(F)c3)cc1N2
Temperature: 25 °C

Procedure:
A mixture of Example 205A (0.52 g, 1.18 mmol) and LiOH (0.144 g, 6.0 mmol) in 20 mL of THF and 20 mL of H2O was heated under reflux overnight. After the solution cooled to room temperature, the solution was neutralized with 10% HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtrated and concentrated under vacuum to give the title compound. MS (DCI) m/e 425 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.27 (br, 1H), 9.72 (s, 1H), 9.68 (s, 1H), 7.98 (s, 1H), 7.75 (d, J=8.73 Hz, 1H), 7.06 (s, 1H), 6.96-6.99 (m, 3H), 6.74 (dd, J=8.73, 2.18 Hz, 1H), 6.62 (s, 2H), 1.46 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([NH:14][S:28]([CH2:27][CH2:26][N:17]2[C:16](=[O:15])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:25])(=[O:29])=[O:30])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: NN1CCN(Cc2ccccc2)CC1
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NN1CCN(Cc2ccccc2)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (4-benzyl-piperazin-1-yl)-amide was prepared by an analogous procedure as described for example 1 i) starting from 140 mg (0.73 mmol) 4-benzyl-piperazin-1-ylamine and 200 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. The product was obtained in crude form as a light yellow foam.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ccn(Cc2cccc(Cl)c2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4cccc(Cl)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-chloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9]4=[C:10]([CH2:21][C:7]=1[C:8]=24)[CH:11]=[CH:12][CH:13]=3)=[O:4].[N:22]1([C:28](=[O:30])[CH3:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:28]([N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:17]3[NH:16][C:15](=[O:20])[C:14]4[C:9]5=[C:10]([CH2:21][C:7]=2[C:8]=35)[CH:11]=[CH:12][CH:13]=4)=[O:4])[CH2:24][CH2:23]1)(=[O:30])[CH3:29]
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3cccc4c3c2c1C4
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CC(=O)Nc2ccc3[nH]c(=O)c4cccc5c4c3c2C5)CC1
Yield: 58 %

Procedure:
Prepared from the reaction of 2-chloro-N-(5-oxo-5,9-dihydro-4H-cyclopenta[lmn]phenanthridin-1-yl)-acetamide 8 and 1-piperazin-1-yl-ethanone (0.1 mL) according to General Procedure B. White solid in 58% yield, mp155–157° C. 1H-NMR (300 MHz, DMSO-d6) □ 11.44(s, 1H); 9.85(s, 1H); 7.93(d, 2H); 7.61(m, 2H); 7.13(d, 1H, J=8.2 Hz); 4.25(s, 2H); 3.56(s, 4H); 3.24(s, 2H); 2.57(s, 2H); 2.54(s, 2H); 2.02(s, 3H). Anal (C22H22N2O3 1.3 H2O) C H N.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][CH2:14][C:4]=2[N:5]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=1>O1CCOCC1>[CH:9]1([O:8][C:6]2[N:7]=[C:2]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=3)[C:3]3[CH2:16][CH2:15][CH2:14][C:4]=3[N:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1nc(OC2CCCC2)nc2c1CCC2
Reactant: Nc1ccc(CCO)cc1
Solvent: C1COCCO1
Product: OCCc1ccc(Nc2nc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 15.4 %

Procedure:
Following General Procedure B1, 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.200 g, 0.84 mmol), dioxane (3 mL) was reacted with 4-aminophenethyl alcohol (0.172 g, 1.26 mmol) to afford the title compound (0.044 g, 22%) as a white solid. MW=339.43. 1H NMR (DMSO-d6, 300 MHz) δ 9.23 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 5.49-5.40 (m, 1H), 3.65-3.50 (m, 2H), 2.73 (t, J=7.6 Hz, 2H) 2.69-5.59 (m, 5H), 2.09-1.90 (m, 4H), 1.80-1.53 (m, 6H); APCI MS m/z 340 [M+H]+.