Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>O>[C:19]1([C:2]2([O:1][C:25](=[O:28])[CH2:26][CH3:27])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC(=O)Cl
Reactant: OC1(c2ccccc2)CCN(CCc2c[nH]c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(=O)OC1(c2ccccc2)CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture of 4 g. (0.0125 mole) of 3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole, 1.19 g. (0.0125 mole) of propionyl chloride and 7 g. of potassium carbonate in 50 ml. of chloroform was allowed to stir for 2 hours. Then 0.4 g. of additional propionyl chloride was added and allowed to stir another 30 minutes. The mixture was treated with 50 ml. of water and allowed to stir 30 minutes. The chloroform layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to an oil. The oil was crystallized from benzene-isooctane and yielded 3.0 g. (64%) of product which melted at 140°-142° C. After an additional recrystallization the analytical sample melted at 142°-144° C.
Reaction SMILES: [CH:1]1[CH2:7][CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([Br:11])(Br)Br.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[Br:11][CH:8]1[C:6]2=[CH:5][CH:4]=[CH:3][CH:2]=[C:7]2[CH2:1]1
Reactant: C1=CC=CCC=C1
Reactant: BrC(Br)Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrC1Cc2ccccc21
Temperature: 145 °C
Reaction time: 9.5 h

Procedure:
In a 250 mL round bottomed flask equipped with a drying tube and a condenser, a solution of cycloheptatriene (30.7 g, 300 mmol), bromoform (25.3 g, 100 mmol), anhydrous K2CO3 (15.0 g, 109 mmol), and 18-crown-6 (0.75 g) was heated with stirring at 145° C. for 9-10 h. The solution was allowed to cool and diluted with an equal volume of acetone. Silica gel (15.0 g) was added to reaction mixture and the insoluble solid residue was separated via vacuum filtration and the filter cake washed with acetone until the washings were colorless. The filtrate was concentrated and distilled to remove residual cycloheptatriene. The viscous, brown residue was precipitated into hot petroleum ether. After filtration to remove the precipitate, the filtrate was concentrated and distilled in vacuo through a Vigreaux column to give slightly impure product. Pure 1-bromobenzocyclobutene was obtained as a light yellow liquid by redistillation yield (2.95 g, 5.94%). 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 1H, ArH), 7.16 (d, 1H, J=7.0 Hz, ArH), 7.07 (d, 1H, J=6.4 Hz, ArH), 5.39 (m, 1H, CH), 3.85 (dd, 1H, J=4.4 Hz, J=14.7 Hz, CH2), 3.45 (d, 1H, J=14.7 Hz, CH2).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][O:8][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC(C)(C)C)cc1
Reaction time: 17 h
Yield: 76.8 %

Procedure:
Dissolve ethylene glycol mono-tert-butyl ether (2.62 g, 22.17 mmol) and triethylamine (3.36 g, 11.02 mmol) in 40 mL methylene chloride at 0° C. Dissolve para-toluenesulfonyl chloride (4.2277 g, 22.17 mmol) in 10 mL methylene chloride and add it dropwise to the reaction. After 30 minutes raise the reaction to room temperature and allow it to stir for 17 hours. Dilute the reaction with methylene chloride and wash it with water (1×), 1N HCl (1×), saturated aqueous sodium hydrogen carbonate (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 4.6387 g of crude toluene-4-sulfonic acid 2-tert-butoxyethyl ester. Dissolve this crude material (1.2423 g, 4.56 mmol) and di-benzyl iminodicarboxylate (1.4385 g, 5.04 mmol) (see Synthesis, 1988, 992-994) in 20 mL acetonitrile. Add potassium tert-butoxide (575.9 mg, 5.13 mmol) to the reaction mixture and heat it to reflux for 24 hours. Cool the reaction to room temperature and remove the solvent in vacuo. Dissolve the residue in methylene chloride and wash it with water (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 1.9215 g of crude material. Purify via Biotage chromatography (EtOAc/Hexanes) to afford 387.8 mg of (2-tert-butoxyethyl)dicarbamic acid benzyl ester (22%). MS (ES): m/z 386.3 (M+H).
Reaction SMILES: [CH2:1]([C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[C@@H:4]([CH3:7])[CH2:5]O)[CH3:2].[BrH:22].O>ClCCl>[Br:22][CH2:5][C@H:4]([CH3:7])[C@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:1][CH3:2]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CO
Reactant: Br
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CBr
Yield: 86.4 %

Procedure:
The product of Example 32 (2.6 g, 9 mmol) was dissolved in dichloromethane, and the mixture was cooled in an ice-water bath, then 48% hydrobromic acid (0.54 mL, 10 mmol) was added dropwise, after the addition was complete, it was reacted at room temperature for 16 hours. After that, water was added therein for separating, the aqueous phase was extracted with dichloromethane three times, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound 2.7 g, yield: 87%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(c1ccc(F)c(Cl)c1)N1CCOCC1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)N3CCOCC3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([S:20]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([Cl:11])=[C:10]3[C:2]([Br:1])=[N:3]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1nc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.3 g, 5.5 mmol) in DMF (42 mL) at 0° C. was added NaH (180 mg, 7.7 mmol) in portions. The reaction mixture was stirred at 0° C. for 5 minutes, then stirred at room temperature for 1.5 hours, after which it was cooled back to 0° C. Neat PhSO2Cl (0.7 mL, 5.6 mmol) was added and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and diluted further with H2O. The resulting precipitate was isolated by vacuum filtration to give 1-Benzenesulfonyl-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.8 g, 88%.) 1H NMR (DMSO-d6, 400 MHz) δ 9.11 (1H, s), 8.11 (2H, d, J 8.1 Hz), 7.84 (1H, t, J 7.5 Hz), 7.70 (2H, t, J 8.0 Hz.)
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound. HR-MS (ES, m/z) calculated for C34H42N6O3Cl2 [(M+H)+] 653.2768 observed 653.2766.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1C=CC=CC=1>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:31](=[O:33])[CH3:32]
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(C)=O)c1ccccc1-c1ccccc1
Yield: 76.8 %

Procedure:
Analogously to Example 47, 16.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 7.3 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 4.4 g of acetyl chloride to obtain, as reaction product, 14.0 g (76.2% of theory) of ethyl 4-[N-(biphenyl-2-yl)acetamido]butyrate as a viscous non-distillable oil. The saponification of this ester and recrystallization of the crude product obtained from isopropyl alcohol yields 10.1 g (79.0% of theory) of 4-[N-(biphenyl-2-yl)acetamido]butyric acid, MP 124° to 125°.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:35]([C@@H:32]3[CH2:33][CH2:34][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:31]3)=[O:36])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g, 8.24 mmol, Preparation #9) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g, 9.07 mmol, Peptech) in DCM (30 mL) was added EDC.HCl (1.90 g, 9.89 mmol). After about 4.5 h at ambient temperature, water (30 mL) was added and the layers were separated. The aqueous layer was then extracted with EtOAc (15 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with a gradient of 40-100% EtOAc in heptane to give tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (4.20 g, 97%): LC/MS (Table 2, Method a) Rt=2.27 min; MS m/z: 515 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=O)=[O:8].[Li]C(C)(C)C.C(=O)=O>C1COCC1.CCOC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[N:12]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]cnc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 136.8 %

Procedure:
The quinazoline 1 (1.5 g, 3.0 mmol) was dissolved in THF (150 mL). After cooling to −78° C., t-BuLi (1.7 M in heptane, 1.76 mL) was added dropwise. After stirring for 10 min at −78° C., CO2 (crushed) was added to the solution, then warmed up to RT and stirred for 30 min. Quenched the reaction with H2O (100 mL), diluted with EtOAc (100 mL), The organic layer was dried, concentrated, purified by flash chromatography (1%-10% MeOH/DCM) to obtain 2 (600 mg, 43% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:27]([OH:29])=O)=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:27]([C:25]2[CH:24]=[CH:23][C:18]3[NH:19][C:20](=[O:22])[CH2:21][C:15]4[CH:14]=[N:13][C:12]([NH:11][C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:30][C:16]=4[C:17]=3[CH:26]=2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCCN1CCCC1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCCN4CCCC4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described in Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and 3-(pyrrolidin-1-yl)propan-1-amine were converted to I-77 (6%) after purification by C-18 RP LC-MS chromatography. HRMS Calcd. for C28H32N6O4: 517.2563, Found 517.2552.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)[CH:14]=[N:15][C:16]=1[O:20][CH2:21][CH:22]([F:24])[F:23]
Reactant: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)F)c(Cl)c1
Reactant: O=COc1ccccc1
Product: O=C(Oc1ccccc1)c1nccc2c1CN(Cc1cnc(OCC(F)F)c(Cl)c1)C2=O
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (220 mg, brown solid) from 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-13) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C)C(=O)C>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=2)=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CNc1nccc(-c2cc(NC(=O)c3ccc(C(C)(C)C)cc3)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-amino-6-methoxy-2-naphthyl)-N-methylpyrimidin-2-amine (33) (252 mg, 0.900 mmol), N,N-dimethylacetamide (4 mL) was treated with N,N-diisopropylethylamine (0.9 mL, 5.2 mmol) followed by 4-(tert-butyl)benzoyl chloride (181 mg, 0.9 mmol) and stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate (150 mL) and water (120 mL). The aqueous layer was removed and the organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate, filtered, concentrated (rotary) and dried under high vacuum to afford the crude desired product, which was purified by reverse phase chromatography on preparative LC/UV/MS system using a mass triggered fractionation. Compound was eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 mL/min with acetonitrile/water gradient using 0.1% FA as a modifier. 4-tert-butyl-N-{7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}benzamide (184) was isolated as an off-white solid (95 mg). M.p.=231-232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 10.39 (s, 1H), 8.59 (s, 1H), 8.34-8.39 (m, 2H), 8.06 (m, 3H), 7.61 (d, J=6.7 Hz, 2H), 7.31 (m, 3H), 7.16 (s, 1H), 3.87 (s, 3H), 3.34 (br s, 3H), 1.36 (s, 9H); Experimental Elemental Analysis (0.23 equivalents of formic acid)=72.52% C, 6.15% H, 12.21% N; Calculated Elemental Analysis 72.50% C, 6.36% H, 12.42% N; LCMS (m/z): 442 [M+H].
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccc(Br)c1C(=O)Nc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Yield: 51.4 %

Procedure:
The title compound was prepared following the experimental procedure described in Preparation 9a from 810 mg (2.89 mmol) of 1-amino-3-bromo-N-phenyl-1H-pyrrole-2-carboxamide and 656 mg (3.47 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich). The crude product was purified by flash chromatography in hexane-ethyl acetate to afford 670 mg (49% yield) of the title compound.
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].CCN(CC)CC.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>ClCCl>[C:25]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([SiH2:7][O:6][CH2:5][CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:15][CH:16]=[CH2:17])=[CH:14][CH:13]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)Cl
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(CC=C)CO[SiH2]c1ccc(NC(=O)C=C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A solution of 4-(diallylethoxysilyl)aniline (153 mg, 0.62 mmol) and distilled dichloromethane (dist. CH2Cl2: 5 mL) was added with dist. Et3N (86 μL, 0.62 mmol), and then acryloyl chloride (50 μL, 0.62 mmol) was added dropwise slowly at 0° C. The mixture thus obtained was stirred under a nitrogen atmosphere at 0° C. for 8 hours. After that, the solvent in the mixture was distilled without being heated to obtain a residue. Subsequently, the residue thus obtained was separated and purified by PTLC (hexane/EtOAc=2/1) to obtain 1-acryloylamino-4-(diallylethoxysilyl)benzene (110 mg, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[N:11]=1
Reactant: COc1ccccc1CN
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: COc1ccccc1CNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 470 mg (3.43 mmol) of 2-methoxybenzylamine to give 37 mg (28% of theory) of the title compound.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[CH2:8]([O:12][C:13]1[CH:18]=[CH:17]C=CC=1)[CH:9]1[O:11][CH2:10]1>>[CH2:13]([O:12][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:18]1[O:7][CH2:17]1
Reactant: Oc1ccccc1
Reactant: c1ccc(OCC2CO2)cc1
Product: C(OCC1CO1)C1CO1

Procedure:
Such a mono(chlorohydrin ether) as that of formula V is then mixed with up to an equimolar amount of a bis(chlorohydrin ether) of a polyhydric phenol, and subjected to dehydrochlorination. The materials obtained, described as synthetic high molecular weight products of resinous character, are of a complex nature and generally solids of melting point 43° C. or more. Presumably, if, e.g., phenyl glycidyl ether were used, the product obtained on dehydrochlorination would contain, amongst other compounds, a glycidyl ether of a mono-secondary alcohol formed in the following manner ##STR3##
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]([Cl:22])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.CCO.[OH-].[K+]>O>[Cl:22][C:13]1[C:12]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:11][C:10]([CH:4]([CH2:5][CH:6]2[CH2:9][CH2:8][CH2:7]2)[C:3]([OH:33])=[O:2])=[CH:15][C:14]=1[O:16][CH2:17][C:18]([F:19])([F:20])[F:21]
Reactant: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 100.4 %

Procedure:
To a solution of the 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (8.0 g, 14.5 mmol) in a mixture of the EtOH (100 mL) and H2O (15 mL) was added potassium hydroxide (10 g, 178.5 mmol). The reaction mixture was refluxed for 3 h and the solvent evaporated. Then, 6 N HCl was added to adjust the pH to 3-5 and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4 and evaporated to give 2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid as a white solid (7.0 g, 90%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 6.98 (s, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.49 (t, J=7.7 Hz, 1H), 2.27-2.13 (m, 2H), 2.06-1.73 (m, 5H), 1.71-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 153.6, 142.1, 141.2, 138.0, 129.7, 125.0 (q, 3JCF=3.6 Hz), 124.9, 124.0 (q, 1JCF=262.5 Hz), 123.0 (q, 1JCF=277.6 Hz), 121.8, 114.3, 67.3 (q, 1JCF=36.0 Hz), 49.3, 40.3, 33.9, 28.3, 28.0, 18.5.