Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:36]1([CH2:35][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:38][CH2:37]1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OCC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and (bromomethyl)cyclopropane (0.70 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.93 g, 83%).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=O.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:3]2[CH:1]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[O:5][C:4]=2[CH:11]=1
Reactant: COC(=O)COc1cc(OC)ccc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(OC)cc2o1
Yield: 56.1 %

Procedure:
A mixture of methyl 2-formyl-5-methoxyphenoxyacetate (27.7 g), 1,8-diazabicyclo[5.4.0]-7-undecene (40.8 g) and toluene (200 ml) was heated under refluxing conditions for 4 hours. The reaction mixture was concentrated under reduced pressure; after 6N hydrochloric acid was added, the residue was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; 10% hydrochloric acid-methanol (30 ml) was added to the residue, followed by heating at 70° to 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure; water was added, followed by extraction with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with chloroform-hexane (1:2, v/v), methyl 6-methoxybenzofuran-2-carboxylate (14.3 g, 57%) was obtained, which was then recrystallized from dichloromethane-isopropyl ether to yield colorless prisms having a melting point of 97° to 98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Cl[CH2:11][CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+].[Al+3].[Cl-].[Cl-].[Cl-].Cl>CC#N>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([CH2:11][CH2:12][C:13](=[O:14])[NH:5]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1F
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CC#N
Product: Cc1cc2c(cc1F)NC(=O)CC2
Temperature: 145 °C
Yield: 11.3 %

Procedure:
3-Fluoro-4-methylaniline (1.247 g, 9.96 mmol), 3-chloropropionyl chloride (1.269 g, 9.99 mmol), and K2CO3 (1.450 g, 10.5 mmol) in MeCN (10 mL) were stirred at 40° C. for 3 h. The reaction mixture was quenched with 4M HCl and the product extracted into CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue (1.168 g) was heated to 145° C. and small portions of AlCl3 (3.538 g, 26.5 mmol) were added over a period of 30 min. The reaction mixture was then cooled and 4M HCl added under stirring followed by extraction of the product into CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash CC (SiO2; CH2Cl2/MeOH 40:1) to give the title compound (97KK40) (0.201 g, total yield 11%). 1H NMR (CDCl3) δ 8.15 (br s, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 2.91-2.87 (m, 2H), 2.62-2.60 (m, 2H), 2.19 (d, J=1.8 Hz, CH3).
Reaction SMILES: [CH3:1][O-:2].[K+].Cl[C:5]1[CH:25]=[CH:24][C:8]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1>CO>[CH3:1][O:2][C:5]1[CH:25]=[CH:24][C:8]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: C[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C(=O)c2cccc(CCCC(=O)O)c2C)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
17.5 g of 89% potassium methylate were added under an inert atmosphere to a suspension of 7.5 g of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid (Example V) in 75 ml of methanol and was then heated at 120°-130°C for 17 hours under pressure. After cooling to room temperature, the mixture was rinsed with water and the methanol was eliminated under reduced pressure. The residue was dissolved in water, treated hot with activated carbon, iced and filtered. The filtrate was acidified to a pH of 1 with hydrochloric acid and the precipitate formed was recovered by filtration, was washed with water until the wash water was neutral and dried. The residue was crystallized from isopropyl ether to obtain 5.35 g of 4-(3'-p-methoxybenzoyl-2'-methyl-phenyl)-butyric acid in the form of colorless crystals melting at 100° and then 115°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH3:16])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OCC(=O)N2C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 104.1 %

Procedure:
7-Methoxy-4H-benzo[1,4]oxazin-3-one (11.61 g, 0.065 mol) in 100 mL dry DMF was stirred at 0° C. under nitrogen. Sodium hydride (60%, 2.85 g, 0.072 mol) was added in portions over 30 minutes, after which methyl iodide (4.44 mL, 0.071 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 2.5 hours, then poured into 1400 mL water. The resulting aqueous mixture was extracted four times with 400 mL EtOAc, and the combined organic layers were washed with water, then brine, dried (MgSO4), filtered, and evaporated under reduced pressure to provide 13.07 g of 7-Methoxy-4-methyl-4H-benzo[1,4]oxazin-3-one. (M+H)=194.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[C:7]([F:13])[CH:6]=1>CN(C=O)C>[NH2:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([C:1]#[N:2])=[CH:6][C:7]=1[F:13]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(N)c(F)c1
Temperature: 220 °C
Yield: 78.4 %

Procedure:
A solution of CuCN (135 mg, 1.51 mmol) and 4-bromo-2,6-difluorobenzenamine (200 mg, 0.96 mmol) in DMF (4 mL) was sealed in a microwave vial and degassed with Ar. The mixture was heated in microwave at 220° C. for 17.5 min. Ammonium hydroxide (10 mL) and water (10 mL) were added to the mixture and it was extracted with EtOAc (2×20 mL). The organics were combined, washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. Purification by flash chromatography yielded 116 mg of Intermediate 383.1 as a white solid. LCMS 155.3 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 4.27 (bs, 2H) 7.12 (dd, J=5.87, 2.20 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]([O:10]CC)=[O:9])=[O:2].CO.[OH-].[Na+].Cl>O>[CH:1]([C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]([OH:10])=[O:9])=[O:2]
Reactant: CCOC(=O)c1[nH]ncc1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1cn[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a suspension of ethyl 4-formyl-1H-pyrazole-5-carboxylate (SM2-B, 19 g, 115 mmol) in a solution of MeOH (76 ml) and water (130 mL) was added NaOH (14 g, 345 mmol) in water (130 mL) at 0° C. The reaction mixture was warmed to rt and stirred for 2 h. The solution was adjusted to pH of 1 with concentrated hydrochloride. The solid was collected, washed with water (50 mL), and dried in air to give the product (4-B) (12 g, 75%) as a light yellow solid. 1H NMR (300 MHz, DMSO): δ 8.45 (s, 1H), 10.29 (s, 1H). LC-MS (M+H)+=141.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].CO.O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(C(C)(C)C)c(Br)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)O)oc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 5-bromo-4-tert-butyl-furan-2-carboxylate (1.45 g, 5.57 mmol, prepared as described in the previous step) in a mixture of THF (15 mL), MeOH (10 mL), and H2O (5 mL) was treated with 3 M aqueous NaOH solution (3.00 mL, 9.00 mmol) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in H2O (60 mL) and extracted with Et2O (2×30 mL). The aqueous layer was acidified to pH˜2 using 2 M HCl. The precipitate was isolated by filtration, washed with H2O (20 mL), and air-dried to yield 5-bromo-4-tert-butyl-furan-2-carboxylic acid. The filtrate was extracted with EtOAc (3×20 mL) and the combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield a second crop of 5-bromo-4-tert-butyl-furan-2-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ: 7.25 (s, 1H), 1.35 (s, 9H).
Reaction SMILES: CN.Cl.[C:4]1([C:10]2([CH2:16][C:17](=O)[CH3:18])[CH:15]=[CH:14][CH2:13][CH:12]=[CH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]([BH3-])#[N:21].[Na+]>CCOCC.CO>[CH3:18][CH:17]([NH:21][CH3:20])[CH2:16][C:10]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[CH:14][CH2:13][CH:12]=[CH:11]1
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CNC(C)CC1(c2ccccc2)C=CCC=C1
Temperature: 0 °C

Procedure:
To 11.5 ml. (about 6 equivalents) of methylamine and 10 g. of molecular sieve 3A in 200 ml. of absolute methanol are added dropwise at 0° C. 17.8 ml. of 5 N methanolic hydrochloric acid (2 equivalents) and subsequently 9.4 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in a small amount of methanol. After the addition of 1.95 g. (0.75 equivalent) of sodium cyanoborohydride, the mixture is stirred at room temperature for 5 days. The mixture is worked-up as follows: The mixture is treated with ice-water and ether and extracted with 3 N aqueous hydrochloric acid. The hydrochloric acid extracts are made basic with concentrated aqueous ammonia and extracted with ether. The ether phase is dried with sodium sulfate, filtered and evaporated. The crude product obtained is chromatographed on silica gel with methylene chloride/methanol (10:1). There is obtained α,N-dimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine in the form of an oily product. This is converted as usual into the hydrochloride which, after crystallization from methylene chloride/ether, has a melting point of 155°-158° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18](C2C=CN=CC=2)[N:19]=1>>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:14]3[C:15]4[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:4][C:3]=2[O:2]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:31])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with 1-methyl-piperazine (30 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[I-:14].[K+].S([O-])(O)=O.[Na+]>Cl.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[I:14]
Reactant: [I-]
Reactant: Nc1cc(Br)ccc1Br
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: ClCCl
Product: Brc1ccc(Br)c(I)c1
Reaction time: 0.67 h
Yield: 72.8 %

Procedure:
2,5-Dibromoaniline 10 g was dispersed in diluted hydrochloric acid (concentrated hydrochloric acid 40 ml+water 30 ml), and an aqueous solution of NaNO2 3 g was dropwise added thereto at 0° C. The reaction solution was stirred for 40 minutes and then dropwise added at room temperature to an aqueous solution of potassium iodide 60 g which was separately prepared. After stirring at room temperature for 2 hours, methylene chloride and a small amount of sodium hydrogensulfite were added thereto, and the organic layer was extracted. The organic layer was washed with a 10% sodium hydrogensulfite aqueous solution and saturated brine and dried on anhydrous sodium sulfate, and then the solvent was distilled off. The product was refined by silica gel chromatography, whereby targeted 2,5-dibromoiodobenzene 10.5 g (yield: 73%) was obtained in the form of white crystal.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][CH2:15][NH:16][C:17]1[N:18]=[N:19][C:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:21]([CH3:24])[C:22]=1[CH3:23])[C:9](=[O:13])[C@H:10](Cl)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:14][CH2:15][N:16]([C:17]2[N:18]=[N:19][C:20]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:21]([CH3:24])[C:22]=2[CH3:23])[CH:10]([CH3:11])[C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NCCN(Cc2ccccc2)C(=O)[C@@H](C)Cl)nnc(-c2ccc(F)cc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCN(Cc3ccccc3)C(=O)C2C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Treat a 0° C. solution of (R)—N-benzyl-2-chloro-N-(2-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-ylamino)ethyl)propanamide (4.59 g, 10.4 mmol) in THF (104 mL) with NaH (60%, 625 mg, 15.6 mmol). Allow the reaction mixture to warm to ambient temperature and stir overnight. Cool the reaction to 0° C., and treat with additional NaH (60%, 208 mg, 5.20 mmol). Allow the reaction mixture to warm to ambient temperature and stir for 3 d. Partition the reaction mixture between brine and EtOAc. Separate the organic layer, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to provide the title compound as a white foam (3.64 g, 86%). ES/MS m/z 405.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH:33]2[CH2:38][CH2:37][CH:36]([P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:35][CH2:34]2)=[C:26]2[C:30]=1[C:29](=[O:31])[N:28]([CH3:32])[CH2:27]2>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH:33]3[CH2:34][CH2:35][CH:36]([P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:37][CH2:38]3)=[C:26]3[C:30]=2[C:29](=[O:31])[N:28]([CH3:32])[CH2:27]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1
Reactant: CCOP(=O)(OCC)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: COc1ccccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Product: CCOP(=O)(OCC)C1CCC(c2ccc(Nc3nc(Nc4ccccc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1

Procedure:
The title compound was prepared according to the procedure for Example 102 using 4-chloro-N-(2-methoxyphenyl)-5-(trifluoromethyl)pyrimidin-2-amine (7.2 mg, 0.024 mmol) and diethyl [4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexyl]phosphonate (Compound 193A, 9.0 mg, 0.024 mmol). The reaction mixture was purified by MDP (basic buffer) to give a white solid. The material was further purified by silica gel chromatography (ISCO Combi-flash system, eluting with 0-8% MeOH/DCM), affording the title compound as a white solid, 5 mg. (4:1 mixture, cis and trans unassigned). 1H NMR (CDCl3): 1.40 (t, J=7.1 Hz, 6H), 1.11 (t, J=7.6 Hz, 3H), 1.70-1.84 (m, 4H), 2.09-2.28 (m, 5H), 2.58 (m, 1H), 3.23 (s, 3H), 3.94, 3.95 (2×s, 3H), 4.14-4.23 (m, 4H), 4.39, 4.43 (2×s, 2H), 6.95-7.02 (m, 2H), 7.10 (m, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.93 (m, 1H), 8.26 (m, 1H), 8.38 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 10.64 (s, 1H). MS (ES+): m/z=648.33 [MH+]. HPLC: tR=4.53 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21]1[CH2:25][CH2:24][NH:23][CH2:22]1.C(Cl)CCl>CN(C)C1C=CN=CC=1.ClCCl.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:10](=[O:12])[N:23]1[CH2:24][CH2:25][S:21][CH2:22]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a mixture of 2-tert-butoxycarbonylamino-3-(2-fluoro-phenyl)-propionic acid (0.50 g, 1.77 mmol), thiazolidine (0.15 mL, 1.94 mmol) and 4-dimethylamino-pyridine (0.21 g, 1.77 mmol) in dichloromethane (15 mL) was added EDC (0.44 g, 2.31 mmol). The reaction mixture was stirred at room temperature overnight, diluted with chloroform, washed with 2 N HCl, water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (30% acetone in hexanes) and obtained as a colorless solid (0.39 g, 62%, mp 133-134° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:30]=[C:31]2[C:35](=[N:36][CH:37]=1)[NH:34][CH:33]=[CH:32]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([O:28][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:37][N:36]=2)[CH:32]=[CH:33]1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.25 g, 0.66 mmol), 5-hydroxy-7-azaindole (0.089 g, 0.663 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (0.091 g, 0.66 mmol) in DMF (3 ml) was stirred at 85° C. for 3 hours. The mixture was filtered and the filtrate was purified by preparative LCtMS eluting with acetonitrile/water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was dissolved in methylene chloride and washed with 0.5N aqueous ammonia followed by brine, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether, filtered and dried under vacuum to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.138 g, 45%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:31][CH2:32][CH3:33])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])[CH:3]([CH3:5])[CH3:4].[OH-:34].[Na+]>>[OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:31][CH2:32][CH3:33])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]([NH2:12])=[O:34])[CH:3]([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.90 g of 4-(1-hydroxy-2-methylpropyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)-phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide, 0.64 g of the title compound was obtained as a powder, melting at 153°-157° C.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[N:9]1)(C)(C)C>FC(F)(F)C(O)=O>[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[N:9]=1
Reactant: CC(C)(C)OC(=O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid tert-butyl ester (977 Mg) was dissolved in trifluoroacetic acid (TFA) (10 mL) and stirred at room temperature for 1 hr. The mixture was evaporated in vacuo to provide 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid as a brown oil, which was used without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]12[CH2:14][CH:8]3[CH2:9][C:10]([CH3:13])([CH2:12][C:6]([C:15]([OH:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2.Cl.[O-]S([O-])=O.[Na+].[Na+]>[Fe].C(OCC)(=O)C>[Br:1][C:8]12[CH2:7][C:6]3([C:15]([OH:17])=[O:16])[CH2:12][C:10]([CH3:13])([CH2:11][C:4]([CH3:3])([CH2:5]3)[CH2:14]1)[CH2:9]2
Reactant: BrBr
Reactant: CC12CC3CC(C)(C1)CC(C(=O)O)(C3)C2
Agent: [Fe]
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Product: CC12CC3(C)CC(Br)(C1)CC(C(=O)O)(C2)C3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round-bottomed flask, bromine (3 mL) was cooled to 0° C. and iron (0.56 g) was added. The mixture was stirred at 0° C. for 30 minutes. 3,5-dimethyladamantane-1-carboxylic acid (0.5 g) was added. The mixture was stirred at room temperature overnight. After adding ice and 6N aqueous HCl (10 mL), ethyl acetate (20 mL), and saturated aqueous Na2SO3 were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated Na2SO3 (50 mL, 3×) and dried over Na2SO4. After filtration and removal of the solvent, the product was used directly in the next step.