Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:5]=1)([O-])=O>C(O)(=O)C.[Zn]>[C:24]([O:23][C:22](=[O:28])[NH:21][C:17]1([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[NH:8][C:9](=[O:10])[C:4]([NH2:1])=[CH:5][C:6]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19][CH2:20]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3[nH]c(=O)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3[nH]c(=O)c(N)cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
Tert-butyl (1-(4-(5-nitro-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl)phenyl)cyclobutyl)carbamate (10.95 g, 23.77 mmol) was dissolved in acetic acid (250 mL) at room temperature. Zinc powder (10 g, 153 mmol) was added at 30° C. and the resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was partitioned between water (250 mL) and ethyl acetate (250 mL). The aqueous phase was extracted with fresh ethyl acetate (3×200 mL) and the combined organic layers were washed with water (200 mL), brine (200 mL), dried on anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The obtained crude was purified by Biotage silica gel chromatography (gradient 0% to 3% methanol in dichloromethane) to give the title compound (4.3 g, 43%). It was used for the next step without further purification. LCMS (Method A) RT 5.96 min, M+1=432.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1>C(OCC)(=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:22][CH:21]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 31.3 %

Procedure:
A mixture of 3-amino-4-methoxybenzanilide (0.973 g, 4.00 mmol) in ethyl acetate (75 mL) was heated briefly to ˜60° C. The mixture was filtered to clarity and 4-fluorophenyl isothiocyanate (0.49 mL, 4.04 mmol) was added to the filtrate. After 3 days, the mixture was concentrated until a crystalline precipitate was obtained, then allowed to stand several hours at room temperature. Filtration followed by trituration of the collected solid in ether afforded the product (0.4949 g); m.p. 182-183° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)[CH:10]=1.[H-].[Na+].Cl[C:27]1[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=1>C1COCC1.O>[C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:10]=2)[CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCN(c2cc(N)ncn2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1
Temperature: 25 °C

Procedure:
1-[4-(6-Amino-pyrimidin-4-yl)-piperazin-1-yl]-ethanone TFA salt (72 mg, 0.22 mmol) was stirred in anhydrous THF under N2. Sodium hydride (26 mg, 60% dispersion, 0.65 mmol) was added followed by the addition of 2-chlorothiazole-5-carbonitrile (62 mg, 0.43 mmol). The reaction was heated to reflux and after 30 minutes additional 2-chloro-thiazole-5-carbonitrile (85 mg, 0.59 mmol) was added. After a total of 1.5 hours, the reaction was cooled to room temperature, diluted with water and the bulk of the tHF was removed in vacuo. The resulting mixture was adjusted to pH 7 with 1 M HCl (aq). The resulting precipitate was filtered, washed with water and after air drying was washed with hexane. 1H-NMR (400 MHz, DMSO) 12.11 (1H, s), 8.45 (1H, s), 8.26 (1H, s), 6.23 (1H, s), 3.62–3.55 (m, 8H), 2.05 (s, 3H). M+1=330.2.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=O)=[CH:11][CH:10]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:12]1(=[C:15]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
To a 3-necked round-bottomed flask were added zinc powder (0.40 g, 6.12 mmoL) and anhydrous THF (15 mL). To the stirred suspension was slowly added by syringe TiCl4 (0.32 mL, 0.55 g, 2.9 mmoL) at RT under a nitrogen atmosphere. The reaction mixture was heated at reflux for 2 h. A solution of cyclohexanone (0.24 mL, 0.227 g, 2.3 mmoL) and methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.20 g, 0.78 mmoL) in anhydrous THF (5 mL) was added to the reaction mixture. The reaction mixture was heated a reflux for 2 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. To the reaction mixture was added H2O (5 mL) followed by 10% K2CO3 (5 mL). The quenched reaction mixture was filtered through a pad of Celite with the aid of H2O and EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase was dried (MgSO4), filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography on silica gel with a CH2Cl2:MeOH gradient (100:0 to 95:5) to give 0.176 g (70%) of compound 156 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (m, 6H), 2.10 (m, 2H), 2.17 (m, 2H), 3.80 (s, 3H), 6.66 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 7.86 (d, J=7.8 Hz, 2H), 9.34 (s, 1H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].C(OCCC)CC>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCCOCCC
Solvent: CCOC(C)=O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Maleic acid (1.161 g, dissolved in 10 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (20 ml) with stirring at room temperature followed by adding 10 ml of dipropyl ether. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 126.8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:32][NH2:33].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:32][NH2:33])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a stirring solution of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (240 mg, 1.13 mmol) and 4-methylmorpholine (131 μL, 1.19 mmol) in THF (3 mL) was added isobutyl chloroformate (147 μL, 1.13 mmol). After 1 h the reaction mixture was added through a syringe filter to a stirring solution of hydrazine (1.24 mL, 1.24 mmol, 1 M in THF) in THF (1 mL). After stirring a further 30 min at room temperature, the reaction mixture was poured into NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (MeOH/DCM) to give 152 mg (59%) of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazide INT-50 as a white solid. LCMS-ESI (m/z) calculated for C14H14N2O: 226; found 227 [M+H]+, tR=1.62 min (Method 10).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:19][C:20]([C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:25]=[CH:26][C:27]=2[N+:28]([O-])=O)=[O:21])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:38]1CCN2C(=NCCC2)CC1>O.CO.ClCCCl.C(OC(OCC)OCC)C.[Fe]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:28]=[CH:38][N:19]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:5]([O:4][CH3:3])[CH:6]=2)[C:20]3=[O:21])=[CH:32][CH:33]=1
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)ccc2[N+](=O)[O-])ccc1OCCN1CCCC1
Reactant: C1CCC2=NCCCN2CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: ClCCCl
Product: COc1cc(-n2cnc3ccc(-c4ccc(Cl)cc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
This acid (0.14 g, 0.5 mmol) was dissolved in dichloromethane (2 ml) and oxalyl chloride added (87 μl, 1 mmol). The mixture was stirred for 60 min at room temperature under argon. The solvent was evaporated and the residue added to a solution of 3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenylamine [Example A4] (0.10 g, 0.44 mmol) and triethylamine (70 μl, 0.5 mmol) in dichloromethane (4 ml). The mixture was stirred for 90 mins at room temperature under argon and then washed with a saturated aqueous solution of NaHCO3 (5 ml) and brine (5 ml). The organic layer was dried over MgSO4, the solvent evaporated and the residue purified by flash chromatography on silica gel (eluting with methanol-dichloromethane-aq. ammonia). 4′-Chloro-4-nitrobiphenyl-3-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]amide was obtained in 54% yield; m/z [APCI+] 496 (100%, M+H+). Iron powder (45 mg, 0.81 mmol) and ammonium chloride (72 mg, 1.35 mmol) were mixed in water (2 ml) and 4′-chloro-4-nitrobiphenyl-3-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]amide (0.13 g, 0.27 mmol) added, dissolved in MeOH (2 ml). The mixture was heated at 80° C. for 90 min and then filtered while hot. Dichloromethane (30 ml) was added to the cooled filtrate. The organic layer was washed with water (10 ml), saturated aqueous NaHCO3 (10 ml) and brine (10 ml), then dried and the solvent evaporated to give a yellow gum. This was dissolved in 1,2-dichloroethane (10 ml) and triethylorthoformate (4 ml). The mixture was refluxed for 16 h under argon, then after cooling DBU (0.2 ml) was added and the mixture was stirred for 10 mins at room temperature. The solvent was evaporated and the residue purified by flash chromatography on silica gel (eluting with methanol-dichloromethane-aqueous ammonia) to yield the title compound as an orange gum;
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:11]1)=[O:7])(C)(C)C.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1

Procedure:
2-(3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-2,3-dihydro-1 H-isoindole-1,3-dione (1 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.50 g) to give 4-amino-5-chloro-N-(1-(3-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)propyl)-pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: O[C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].COCCN(CCOC)S(F)(F)[F:25]>C(Cl)Cl>[F:25][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(=O)c1ccc(OCC(C)(C)O)c(OC)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(C)(C)F)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of methyl 4-(2-hydroxy-2-methyl-propoxy)-3-methoxy-benzoate (509 mg, 2.00 mmol) in DCM (5 mL) at 0° C. was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-sulfanyl)ethanamine (406 μL, 2.20 mmol) dropwise. The mixture was stirred at 0° C. for 1 h before the cooling bath was removed and the mixture was stirred for 1 h at room temperature. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with water, brine, dried (Na2SO4) and evaporated to dryness. Purification of the residue by column chromatography (0-20% EtOAc in Hex) gave methyl 4-(2-fluoro-2-methyl-propoxy)-3-methoxy-benzoate (450 mg, 70%). ESI-MS m/z calc. 256.1, found 257.1 (M+1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:37]2[CH:36]=[CH:35][C:34]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:15]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (57%). LCMS: 514.20 (M+1)+; HPLC: 99.74% (@ 254 nm), (Rt; 5.183); 1H NMR (CDCl3, 400 MHz) δ 11.88 (bs, 1H), 8.30 (s, 1H), 8.16 (t, 1H), 8.08 (d, 2H, J=8.8 Hz), 7.91 (s, 1H), 6.97 (d, 2H, J=8.8 Hz), 5.94 (s, 1H), 5.43-5.36 (m, 1H), 4.66 (d, 2H, J=5.6 Hz), 3.30 (bs, 4H), 2.58 (bs, 4H), 2.41 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 1.60 (d, 6H, J=6.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36](Br)([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH:36]([CH3:38])[CH3:37])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CC(C)Br
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OC(C)C)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with isopropyl bromide
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ncc(Br)cn1
Product: Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 2-amino-5-bromopyrimidine (226 mg, 1.3 mmol) according to general procedure II. Obtained as a brown solid (60 mg, 14%). MS (ISP) 449.2 [(M+H)+]; mp 255-256° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[F:20])=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[N:28]=[CH:27][NH:26][N:25]=1)=O>C(O)(=O)C>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:5]1[CH:4]=[C:3]2[N:21]=[C:22]([C:24]3[NH:28][CH:27]=[N:26][N:25]=3)[NH:1][C:2]2=[N:7][C:6]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)c1nc[nH]n1
Solvent: CC(=O)O
Product: Fc1cnccc1-c1cc2nc(-c3nnc[nH]3)[nH]c2nc1-c1cccnc1
Yield: 57.3 %

Procedure:
A solution of N-(6′-amino-3″-fluoro-3,2′:3′,4″-terpyridin-5′-yl)-1H-1,2,4-triazole-3-carboxamide (0.070 g, 0.19 mmol) in acetic acid (2.5 mL) was heated in a sealed tube at 120° C. for 18 h. The solvent was evaporated and the residue was suspended in ethyl acetate and 4% sodium bicarbonate aqueous solution. The solid formed was filtered and dried in vacuo to give the title compound (0.039 g, 59% of yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])([CH3:21])([CH3:20])[CH3:19].N12CCN(CC1)CC2>>[C:18]([O:22][C:23](=[O:26])[C:24]([CH:16]([C:13]1[O:12][C:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:15][CH:14]=1)[OH:17])=[CH2:25])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OCc2ccccc2)o1
Reaction time: 96 h

Procedure:
5-Formyl-2-furancarboxylic acid benzyl ester (0.2 g, 0.87 mmol), acrylic acid tert-butyl ester (0.52 mL), and 1,4-diazabicyclo[2.2.2]octane (20 mg, 0.18 mmol) were mixed, and the mixture was stirred for 4 days. Excess acrylic acid tert-butyl ester was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.C(O)(=O)C.C(O)(=O)C.[I:20]C1C=CC=CC=1.II.CN(C=O)C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:10]=[C:9]([I:20])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: Ic1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: II
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1c(F)cc(Cl)cc1I
Temperature: 100 °C

Procedure:
To a 250 mL flask were added 4-chloro-2-fluorobenzoic acid (4 g, 22.92 mmol), Pd(OAc)2 (0.257 g, 1.146 mmol), iodobenzene diacetate (8.12 g, 25.2 mmol), iodine (6.40 g, 25.2 mmol) and DMF (60 mL). The solution was heated under a nitrogen atmosphere at 100° C. for 20 h. LCMS showed about half of 4-chloro-2-fluorobenzoic acid was converted to the product (LCMS retention time 0.98 min, no MH+ peak). After cooling to room temperature, the solution was diluted with EtOAc and washed three times with 1 N HCl. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated to give a dark brown oil (16.4 g, 42% pure), which was taken to the next step without purification.
Reaction SMILES: [OH-].[K+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1>C(O)C>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([O-:15])=[O:14])=[CH:6][CH:5]=1.[K+:2]
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Aqueous potassium hydroxide (1 mL of 0.1 N, 0.1 mmol) was added to a solution of 2-(bis-(4-hydroxyphenyl)-methyl)-benzoic acid [32 mg, 0.1 mmol, Adamczyk, M. and Grote, J. Organic Preparations and Procedures International, 2001, 33(1), 95] in 5 mL of ethanol and the mixture was stirred for additional 2 h at room temperature. The mixture was evaporated to dryness under reduced pressure to give 36 mg (100% yield) of the desired compound as a white solid, mp>300° C. 1H NMR (D2O, 300 MHz): δ6.41 [s, 1H, —CH], 6.66 [d, 4H, J=8.8 Hz, Ar—H], 6.80 [d, 4H, J=8.8 Hz, Ar—H], 7.03 [d, 1H, J=7.7 Hz, Ar—H], 7.35 [t, 1H, J=7.7 Hz, Ar—H], 7.44 [t, 1H, J=7.7 Hz, Ar—H], 7.74 [dd, 1H, J1=7.7 Hz, J2=2.2 Hz, Ar—H].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1.[Cl:12][C:13]1[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C1COCC1>[Cl:12][C:13]1[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([NH:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH2:7]1)=[O:16]
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexylamine (4.8 g) and TEA (8.3 mL, 59.4 mmol) in THF (150 mL) is stirred for 20 min at rt. 2,6-Dichloro-nicotinoyl chloride (5.0 g, 23.8 mmol) in THF (50 mL) is added dropwise under cooling and the mixture is stirred at rt for 2 h. The reaction mixture is filtered and the filtrate is concentrated. The residue is treated with water, filtered off, washed with water and dried to give the sub-title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(CBr)cn1
Product: N#Cc1ccc(N(Cc2ccc(F)nc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 5-(bromomethyl)-2-fluoropyridine