Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([O:22][Si:2]([CH3:1])([CH3:8])[CH3:9])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)C(O)c1cccc(Br)c1
Reactant: C[Si](C)(C)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)C(O[Si](C)(C)C)c1cccc(Br)c1
Reaction time: 8 h
Yield: 64 %

Procedure:
N-trimethylsilylimidazole (9.5 mL, 64.86 mol) was added to a solution of the crude 1-(3-bromo-phenyl)-2,2-dimethyl-propan-1-ol in tetrahydrofuran (100 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into distilled water, followed by extraction with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=20:1) to give the title compound as a colorless oil (11.0 g, 64% in two steps).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])=[CH:6][CH:5]=1.[OH-:18].[NH4+].[OH-].[K+]>O.C(Cl)Cl>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:16]([NH2:17])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: NCc1ccc(-c2ccccc2C(N)=O)cc1
Temperature: 72.5 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
4-Aminomethyl-2′-cyanobiphenyl hydrochloride (XVII) (100 g, 0.408 mole) was suspended in a mixture of water (500 ml) and methylene chloride (200 ml) at 25-30° C. and adjusted the pH to 9.0-9.5 with ammonium hydroxide (65 ml, 20% w/w) at 25-30° C. to get a clear solution. Organic layer was separated, washed with water (100 ml) and dried over sodium sulfate. Thereafter, organic layer was concentrated at below 60° C. and tert.butanol (300 ml) was added to the residue. The reaction mass was heated to 70-75° C. Thereafter, powdered potassium hydroxide (32.35 g, 0.491 mole) was added and heated to reflux for completion of the reaction. Water (400 ml) was added and aqueous layer was separated and extracted with methylene chloride (500 ml). The combined organic layer was washed with water (200 ml) and dried over sodium sulfate. Methylene chloride solution was cooled to 2-5° C. and the pH adjusted to 1.2-1.4 with hydrochloric acid. The precipitated product was stirred for one hour and filtered, washed with methylene chloride to afford the title compound as white powder (90 g, 84.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:25]=[C:26]([C:16]2[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(Cl)c1
Yield: 44.4 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.032 g (44%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][CH2:12][C:13](=O)[CH2:14][CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:9][CH:13]([CH2:14][CH3:15])[CH2:12][CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc(N)c1N
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)Nc1c(N)ncc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a room-temperature solution of 5-chloro-4-methylpyridine-2,3-diamine (200 mg, 1.27 mmol, 1.0 equiv) and 3-pentanone (400 uL, 3.78 mmol, 3.0 equiv) in THF (0.5 mL) and TFA (0.5 mL) was added sodium triacetoxyborohydride (807 mg, 3.81 mmol, 3.0 equiv) as a solid in one portion. The resulting mixture was allowed to stir overnight at room temperature. The reaction was then diluted with EtOAc and washed with saturated aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC to provide the title compound (49.4 mg, 17%). m/z=228.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: CO
Reactant: O=C(O)C=Cc1ccccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccccc1O
Yield: 92 %

Procedure:
A solution of 200 g (1.218 mole) of 2-hydroxycinnamic acid in 2L of anhydrous methanol was treated with 10 drops of concentrated sulfuric acid. This solution was refluxed for 72 hr., using a Soxhlet extractor charged with 200 g of 3A molecular sieves. The methanolic solution was then concentrated under reduced pressure and cooled to afford 200 g (92%) of white crystals, which were used directly in the next step without additional purification.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][C@H:10]1[CH3:18])(=[O:8])[CH3:7].C(N(CC)CC)C.[F:26][C:27]([F:51])([F:50])[C:28]1[N:32]2[N:33]=[C:34]([N:37]3[CH2:42][CH2:41][CH:40]([C:43]4[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=4)[CH2:39][CH2:38]3)[CH2:35][CH2:36][C:31]2=[N:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:46]2[CH:47]=[CH:48][C:43]([CH:40]3[CH2:39][CH2:38][N:37]([C:34]4[CH2:35][CH2:36][C:31]5[N:32]([C:28]([C:27]([F:51])([F:50])[F:26])=[N:29][N:30]=5)[N:33]=4)[CH2:42][CH2:41]3)=[CH:44][CH:45]=2)[CH2:11][C@H:10]1[CH3:18])(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCN(CCO)C[C@H]1C
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
Methanesulfonyl chloride (0.165 mL, 2.12 mmol) was added dropwise to (R)-2-(4-acetyl-3-methylpiperazin-1-yl)ethanol (360 mg, 1.94 mmol) and triethylamine (0.404 mL, 2.90 mmol) in DCM (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes, warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (15 mL). The organic layer was passed through a phase separating cartridge and concentrated in vacuo. The residual orange gum was dissolved in DMF (5 mL) and added to 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 46, preparation of starting materials) (235 mg, 0.64 mmol) and potassium carbonate (445 mg, 3.22 mmol) in DMF (10 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 100° C. for 3 hours and the solvent was removed in vacuo. The residue was partitioned between DCM (100 mL) and water (100 mL) and the organic phase was separated. The aqueous phase was re-extracted with DCM (100 mL), and the is combined organic phases were washed with brine (100 mL), passed through phase separating cartridge and concentrated under reduced pressure to give an orange gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford a pale yellow gum, which was triturated with ether to give 6-[4-(4-{2-[(3R)-4-acetyl-3-methylpiperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (101 mg, 29.4%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 42%. Melting point: 202-205° C. (Ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1([C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])[S:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+].C(OCC)C>[C:8]1([C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])[S:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCC(=O)O
Reactant: O=C(c1ccc(S(=O)(=O)Cl)cc1)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCNS(=O)(=O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
103 mg (1.10-3 mole) of 4-aminobutyric acid dissolved in 4 ml of a 0.5 N solution of caustic soda are added dropwise to 287 mg (1.10-3 mole) of 4-(2-thenoyl)benzenesulphonyl chloride in 5 ml of ethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
A solution of 5-bromosalicylaldehyde (12.0 g, 59.7 mmol) in DMF (50 ml) was treated with K2CO3 (16.5 g, 120 mmol) and benzyl bromide (11.2 g, 65.6 mmol). The reaction was stirred at ambient temperature for 18 hours, diluted with ethyl acetate and filtered. The filtrate was washed with HCl (0.05 M), saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried (Na2SO4) and evaporated and the residue triturated with hexane/ethyl ether. The product was filtered off to give 2-benzyloxy-5-bromobenzaldehyde as a white solid (15.8 g, 90%) m.p. 70-72 ° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.[Cl:54][C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][C:64]=1[O:65][CH:66]([CH3:68])[CH3:67])/[C:58](=[N:60]/O)/[NH2:59]>C(#N)C>[Cl:54][C:55]1[CH:56]=[C:57]([C:58]2[N:60]=[C:17]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16]4)[O:19][N:59]=2)[CH:62]=[CH:63][C:64]=1[O:65][CH:66]([CH3:68])[CH3:67]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2noc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)C4)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.4 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid (190 mg, 0.722 mmol) in acetonitrile (3 mL) in a 5 mL microwave vial was added HOBT (330 mg, 2.16 mmol), DCC (298 mg, 2.16 mmol), and DIEA (0.115 mL, 0.656 mmol). The mixture was stirred at room temperature for approximately 16 hours. Next, (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (150 mg, 0.656 mmol) (prepared by General procedure B) was added and the reaction was heated to 150° C. under microwave irradiation (max 300 W) for 20 minutes. After cooling, the reaction mixture was filtered, concentrated, and purified via Analogix system using RediSep 40 g column, with a gradient of 0-40% EtOAc/Heptane over 30 min. at a flow rate of 30 ml/min. Fractions containing product were combined, rotovapped, and dried in a vacuum oven to give tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindoline-2-carboxylate (46.2 mg, 15.5%) LCMS (Table 1, Method c) Rt=3.40 min, m/z 456.22 (M+H)+; 1H NMR (400 MHz, DMSO) δ ppm 8.16 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.61 (m, 1H), 7.39 (d, 1H), 4.82 (sept, 1H), 4.70 (d, 4H), 1.48 (s, 9H), 1.35 (d, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=2)=[CH:9][CH:8]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccc(Cc2ncc[nH]2)s1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Cc3ncc[nH]3)s2)=NN1c1ccccc1
Reaction time: 10 h

Procedure:
A mixture of 2.64 g of 4-[5-(1-imidazolylmethyl)-thien-2-yl]-4-oxobutyric acid, 1.12 g phenylhydrazine, 40 ml water and 40 ml ethanol was stirred for 10 hours under reflux. After cooling the mixture was evaporated, the residue shaken with chloroform/dilute caustic soda solution, the chloroform phase washed with water, dried and evaporated. The residue was recrystallized from diisopropyl ether/ethyl acetate.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[CH3:22][O:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CC#N
Product: COc1ccc2ccc(NC(=O)c3ccccc3)nc2n1
Temperature: 4 °C
Yield: 39.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (13.4 g), N,N'carbonyldiimidazole (17.8 g) and 2-amino-7-methoxy-1,8naphthyridine (12.3 g). The product produced by precipitation in water (20 g; m.p. 80° C.) is dissolved in boiling acetonitrile (200 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)benzamide (7.8 g) is produced, m.p. 134° C. EXAMPLE 10
Reaction SMILES: C(N)(=O)C1C=CC=CC=1.Cl[C:11]1[N:12]=[C:13]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:32]=2[C:33]([NH2:35])=[O:34])[C:14]2[CH:19]=[CH:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C:15]=2[N:16]=1.[OH-].[NH4+].[CH3:43][O:44][C:45]1[CH:51]=[C:50]([CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][CH3:60])[CH2:54][CH2:53]2)[CH:49]=[CH:48][C:46]=1[NH2:47]>>[F:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:31]([NH:30][C:13]2[N:12]=[C:11]([NH:47][C:46]3[CH:48]=[CH:49][C:50]([CH:52]4[CH2:53][CH2:54][N:55]([CH2:58][CH2:59][CH3:60])[CH2:56][CH2:57]4)=[CH:51][C:45]=3[O:44][CH3:43])[NH:16][C:15]3=[N:17][CH:18]=[CH:19][C:14]=23)[C:32]=1[C:33]([NH2:35])=[O:34]
Reactant: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: NC(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: CCCN1CCC(c2ccc(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)c(OC)c2)CC1
Yield: 34.8 %

Procedure:
According to General Protocol III, 2-fluoro-6-[(2-{[2-methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.30 g, 0.65 mmol), 27% aqueous ammonium hydroxide, and 2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (0.18 g, 0.72 mmol) and isolated as a yellow solid (0.117 g); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.5 Hz, 3H), 1.45 (dq, J=14.9, 7.4 Hz, 2 H), 1.64-1.75 (m, 4 H), 1.88-1.98 (m, 2 H), 2.19-2.27 (m, 2 H), 2.42 (dt, J=7.4, 3.8 Hz, 1 H), 2.95 (d, J=11.0 Hz, 2 H), 3.84 (s, 3 H), 6.23 (dd, J=3.5, 2.0 Hz, 1 H), 6.76 (dd, J=8.4, 1.5 Hz, 1 H), 6.87 (d, J=1.5 Hz, 1 H), 6.90-7.00 (m, 2 H), 7.39-7.48 (m, 2 H), 8.01 (s, 1 H), 8.08 (s, 1 H), 8.17 (d, J=8.1 Hz, 1 H), 8.42 (d, J=8.4 Hz, 1 H), 10.42 (s, 1 H), 11.39 (s, 1 H); ESIMS (M+H)+=518.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])C.OC1C=CC(C)=CC=1C(C1C=CC=CC=1)=O.C(OCC)(=O)CC(OCC)=O.N12CCCN=C1CCCCC2.Cl>C(O)(=O)C>[CH3:22][C:19]1[CH:20]=[CH:21][C:9]2[O:8][C:7](=[O:23])[C:6]([C:4]([OH:5])=[O:3])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[CH:18]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(C)ccc2oc1=O
Agent: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc2oc(=O)c(C(=O)O)c(-c3ccccc3)c2c1
Temperature: 110 °C

Procedure:
A mixture of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester [prepared by heating 2-hydroxy-5-methylbenzophenone and diethyl malonate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-en; melting point: 129°-131° C.; NMR (200 MHz, CDCl3) ppm: 0.96 (3H, t, J=7.2 Hz), 2.31 (3H, s), 4.07 (2H, q, J=7.2 Hz), 7.01 (1H, bs), 7.2-7.4 (4H, m), 7.5-7.6 (3H, m)] (10.0 g), acetic acid (100 ml). and hydrochloric acid (60 ml) was heated under reflux at 110° C. for 15 hours. After the solvent was distilled off, ethyl acetate was added to the residue. The mixture was washed with water and dried, after which the solvent was distilled off, to yield 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid as colorless crystals (8.7 g).
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.N1(CCOC2C=CC(C(O)=O)=CN=2)CCCCCC1.[N:44]1([CH2:51][CH2:52][O:53][C:54]2[N:59]=[CH:58][C:57]([CH2:60][N:61]([CH2:82][CH3:83])[C:62]3[CH:67]=[C:66]([O:68]C)[CH:65]=[CH:64][C:63]=3[CH:70]3[CH2:79][CH2:78][C:77]4[C:72](=[CH:73][CH:74]=[C:75]([O:80]C)[CH:76]=4)[CH2:71]3)=[CH:56][CH:55]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[N:44]1([CH2:51][CH2:52][O:53][C:54]2[N:59]=[CH:58][C:57]([CH2:60][N:61]([CH2:82][CH3:83])[C:62]3[CH:67]=[C:66]([OH:68])[CH:65]=[CH:64][C:63]=3[CH:70]3[CH2:79][CH2:78][C:77]4[CH:76]=[C:75]([OH:80])[CH:74]=[CH:73][C:72]=4[CH2:71]3)=[CH:56][CH:55]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 84.5 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride according to an analogous synthetic method to Example 152, [6-(2-azepan-1-ylethoxy)pyridin-3-ylmethyl]ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (287 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (230 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[ClH:18].[ClH:18].[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: Nc1nc(N2CCCCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of (±)-(cis)-4-(2-amino-6-chloro-9H--purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (399 mg, 1.50 mmol) and piperidine (298 mg, 3.5 mmol) in absolute ethanol (10 mL) was refluxed under nitrogen for 1 hour. 1 N sodium hydroxide (1.5 mL) was added and the solution evaporated in dryness. The residue was chromatographed on silica gel. The title compound was eluted with 10% methanolchloroform as pale yellow glass (0.30 g). Precipitated as hydrochloride from acetonitrile; white powder (0.30 g, 52%); m.p. dec at 175-180° C.
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Br.[Br-].[OH2:14]>CO>[OH:14][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O
Reactant: CC(=O)c1ccccc1
Agent: Br
Agent: BrBr
Agent: [Br-]
Solvent: CO
Product: O=C(CO)c1ccccc1
Temperature: 60 °C

Procedure:
About 13 parts of bromine was added with stirring to a mixture of 474.6 parts of acetophenone in about 640 parts of methanol, while the mixture was stirred and maintained at a temperature between 5°-10° C. Hydrogen bromide gas was then introduced into the mixture until bromide coloration disappeared, at which point an additional amount of bromine was added over a 2 hour period to make a total of 631.3 parts. There was then added 71 parts of water while the mixture was stirred and externally cooled for a period of about 30 minutes. An excess of about 2700 parts of water was then slowly added to effect the precipitation in the form of crystals of α-bromo acetophenone from the mixture. The crystals were decanted by means of a vacuumed siphon, washed, then neutralized with a 20% sodium hydroxide solution, and decanted to dryness. There was then added about 940 parts water, 1600 parts of methanol, 333 parts of sodium bicarbonate and a sodium formate solution prepared from 161 parts of a 90% formic acid and sufficient sodium hydroxide to neutralize the acid. The mixture was heated to 60° C. with vigorous stirring for 7 hours after which time it was cooled to ambient temperature and filtered. Based on method of preparation and gas chromatographic analysis of the mixture, there was produced α-hydroxyacetophenone in quantitative yields.