Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[CH:6][CH:7]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Fc1ccc(I)cn1
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Fc1ccc(C23CCCN2CCC3)cn1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 40.4 %

Procedure:
2-Fluoro-5-iodopyridine (200 μL, 0.90 mmol) was dissolved in Et2O and cooled to -78° C. A solution of 2.5M t-BuLi (1.2 mL, 1.98 mmol) in pentane was added, and the reaction was stirred for 2 minutes. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (375 mg, 1.80 mmol) was added, and the reaction mixture was allowed to stir for 10 minutes at -78° C. then allowed to warm to -20° C. The cold bath was removed, 2N HCl was added, and the mixture was extracted with Et2O. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2 Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (75 mg, 40%). 1H NMR (CDCl3, 300 MHz) δ1.58-1.73 (m, 2H), 1.79-2.05 (m, 6H), 2.64-2.73 (m, 2H), 3.12-3.19 (m, 2H), 6.82 (dd, J=8.4, 2.7 Hz, 1H), 7.90 (m, 1H), 8.30 (dd, J=1.4, 0.7 Hz, 1H); MS (CI/NH3) m/z: 207 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[C:4]([N:6](CC)[CH:7](OC)[C:8](C)(C)C)=[O:5].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[Br:43]CCBr>C1COCC1.CC(C)=O.Cl>[Br:43][C:19]1[C:2]([Cl:1])=[C:3]([C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][CH:18]=1)[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(OC)C(C)(C)C
Reactant: BrCCBr
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CC(C)=O
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(Br)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound of Example 201 (0.79 g, 2.2 mmol) and TMEDA (0.44 mL, 2.9 mmol) in THF (20 mL) at -78° C. was added a solution of 0.86 M s-BuLi in cyclohexane (3.3 mL, 2.9 mmol). The reaction was stirred at -78° C. for 30 min and 1,2-dibromoethane (0.26 mL, 3.0 mmol) was added. The reaction was stirred for 15 min at -78° C. and was quenched with sat NaHCO3. The mixture was extracted with ether, washed with brine, dried (MgSO4) and concentrated to afford a yellow oil. This oil was dissolved in a mixture of acetone (30 mL) and 6 N HCl (15 mL) and was stirred overnight. The mixture was concentrated, extracted with ether, the organic layers washed with brine, dried (MgSO4) and concentrated to afford the title compound as a clear oil. The crude product was purified by RC (ethyl acetate/hexanes) and was recrystallized from pentane (-78° C.) to afford 76 mg of a white solid (10% yield). m.p. 105-106° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].C[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[C:13](C)[N:12]=1>>[N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].[N:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[CH:11]=1
Reactant: Cc1cc(C)c(C)nc1C
Agent: Cc1cnc(C)c(C)c1
Product: Cc1cncc(C)c1

Procedure:
Into a 1-liter electromagnetic agitation type autoclave equipped with a reflux condenser were charged 321 g of 3,5-lutidine and 64 g of Raney cobalt, and the air in the vessel was replaced with hydrogen gas, after which the internal temperature was raised to 240° C. Next, 570 g of methanol was continuously introduced thereinto under pressure by means of a constant volume delivery pump over a period of 7 hours. During the introduction of methanol, the produced gas was intermittently liberated outside the reaction system so as to keep the internal pressure of the autoclave in the range of 45 to 60 kg/cm2. After the reaction was completed, the autoclave was cooled to room temperature, and the contents were taken out. The catalyst was removed by filtration, after which 30 g of sodium hydroxide was added to the filtrate, and the resulting mixture was separated by using a separating funnel to obtain 400 g of an oily substance. When the oily substance obtained was distilled by using a Dixon packed tower, there were obtained 32 g of 3,5-lutidine of 99% purity as measured by gas chromatography at a tower top temperature of 90° to 93° C./50 mmHg, 314,4 g of 2,3,5-collidine of 99.3% purity as measured by gas chromatography at a tower top temperature of 102° to 103° C./50 mmHg, and 13.9 g of 2,3,5,6-tetramethylpyridine of 99% purity as measured by gas chromatography at a tower top temperature of 112° C./50 mmHg. The yield of the product 2,3,5-collidine obtained from 3,5-lutidine used as a starting material was 86%, and that of 2,3,5,6-tetramethylpyridine obtained therefrom was 3.4%. The selectivities of the above-mentioned products were 96.3% and 3.7%, respectively.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15](Br)[CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=3)[CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCCCCCc1cc(Br)c2ncccc2c1
Product: CCCCCCc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1

Procedure:
6-hexyl-8-bromoquinoline and 3-nitrobenzene boronic acid can be combined to form 6-hexyl-8-(3-nitrophenyl)quinoline,
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:20]1[CH2:28][CH2:27][CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23]>>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([N:20]1[CH2:28][CH2:27][CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
Cbz-L-LeuOH (0.01 mol) was coupled to L-ProOMe (0.01 mol) to form Cbz-L-Leu-L-ProOMe which was then deesterified to yield Cbz-L-Leu-L-ProOH, using the procedure outlined in Example 8 for the preparation of Cbz-L-Asn-L-(O-t-butyl)-ThrOH.
Reaction SMILES: [OH:1][N:2]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:10][C:9](=[O:17])[C:3]21[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[OH:1][N:2]1[C:11]2([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[N:10]([C:25](=[O:26])[NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9](=[O:17])[C:3]21[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: O=C1NC2(CCCCC2)N(O)C12CCCCC2
Reactant: O=C=Nc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)N1C(=O)C2(CCCCC2)N(O)C12CCCCC2
Reaction time: 18 h

Procedure:
3.6 Parts of 7-oxyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one (prepared from 7,14-diazadispiro[5.1.5.2]pentadecan-15-one by oxidation with hydrogen peroxide and sodium tungstate), 2.1 parts of phenyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 75 parts of dry benzene were heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residue allowed to stand in 100 parts of water for 18 hours. The mixture was extracted thoroughly with chloroform and the extract washed with brine and dried over magnesium sulphate. Evaporation in vacuo afforded a solid material which was chromatographed on an alumina column to yield 7-oxyl-14-phenylcarbamoyl-7,14-diazadispiro[5.1.5.2]-pentadecan-15-one as pale red crystals of melting point 125° to 128°C. This material had the following elemental analysis by weight:
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl>[OH-].[Na+]>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:13])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)COc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1ccc(O)cc1
Temperature: 90 °C

Procedure:
(4-Hydroxy-phenoxy)-acetic acid methyl ester 11 (20 grams, 109.89 mmol) is added to 10% sodium hydroxide solution (100 mL) and heated to 90° C. on water bath for 6 hours. The reaction mixture is cooled to room temperature, and the pH is adjusted to 2 with distilled HCl. Crude 12, is filtered, dried, and can be recrystallised in appropriate solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=1[Cl:24]>>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([F:1])[CH:3]=2)=[C:15]([Cl:24])[C:16]=1[N+:21]([O-:23])=[O:22]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Product: N#Cc1ccc(-c2ccc(N)c([N+](=O)[O-])c2Cl)cc1F

Procedure:
The title compound was prepared according to Preparation 92 using 3-fluoro-4-cyanophenylboronic acid and 4-bromo-3-chloro-2-nitroaniline. The residue was purified using silica gel column chromatography eluting with 10-50% EtOAc in heptanes to afford a yellow solid (2.45 g, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[F:24])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4F)c3)csc12

Procedure:
3-[3-(2-Fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and 2-fluorobenzoyl chloride (Aldrich) following the procedure described in Example 10 as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:20])=[O:19].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Reactant: NC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc(NC(=O)COc2ccc(Br)cc2Cl)c1
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of 4-bromo-2-chloro-phenol (2.0 g, 9.64 mmol) and anhydrous potassium carbonate (4.0 g, 28.92 mmol) in dry DMF (30 ml) was heated at 60° C. for 1 h under Ar atmosphere. The mixture was then cooled to room temperature and ethyl chloroacetate (1.24 ml, 11.57 mmol) was added through septum using syringe. The mixture was stirred overnight at room temperature and poured into water with stirring. Stirring continued for 10 min, and then partitioned between ethyl acetate and water. The organic phase washed with brine, dried (anhydrous MgSO4), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) to give (4-Bromo-2-chloro-phenoxy)-acetic acid ethyl ester as a colorless oil (2.98 (2.83) g, >100% yield). To (4-bromo-2-chloro-phenoxy)-acetic acid (132.8 mg, 0.5 mmol), 3-amino-benzamide (102.2 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=10:1) to give 3-[2-(4-bromo-2-chloro-phenoxy)acetyl-amino]-benzamide as a white solid (181.4 mg, 94.6% yield).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:22]=1[C:23]([N:25]([CH2:35][CH3:36])[CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[O:24])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.C(=O)(O)[O-].[Na+]>Cl.C(OCC)(=O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:47]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:22]=1[C:23]([N:25]([CH2:35][CH3:36])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCN(CCC(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN(CCC(=O)O)C(=O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionate (13.3 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (2 ml), and the mixture is stirred at room temperature for 4 hours. Thereto are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionic acid (12 mg). MS (m/z): 780 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:9][CH2:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCCl)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of 4-aminophenol (250 g, 2.29 mol, 1 equiv) in CH2Cl2(2L) and saturated NaHCO3 (2L) was stirred for 5 min at 25° C., then 3-chloropropanoyl chloride (314 g, 2.52 mol 1.1 equiv) was added dropwise and the reaction was stirred for an additional 3 h at 25° C. The solids were filtered and dried under high vacuum to afford 3-chloro-N-(4-hydroxyphenyl)propanamide was used to the next step directly. (250 g, crude). 1H NMR (400 MHz, DMSO) δ, 2.96-2.99 (m, 2 H), 4.06-4.10 (m, 2 H), 6.88-6.92 (m 2 H), 7.57-7.60 (m, 2 H), 9.38-9.39 (br, 1 H), 10.1 (br, 1 H).
Reaction SMILES: C(O[C:4]([CH2:6][C:7]([O:9][C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:12][CH:11]=1)=[O:8])=[O:5])C.[NH2:32][C:33]1[CH:34]=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>C1(C)C(C)=CC=CC=1>[Cl:39][C:38]1[CH:37]=[CH:36][C:35]([C:40]([F:42])([F:43])[F:41])=[CH:34][C:33]=1[NH:32][C:4]([CH2:6][C:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)=[O:8])=[O:5]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)OCC)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A solution of the product from (c) (47 g, 0.112 mol) and 3-amino-4-chlorobenzotrifluoride (21.9 g, 0.112 mol) in xylene (450 ml) were heated to reflux for 5 h. Over the final hour, the volume of the mixture was reduced to 200 ml by distillation. After cooling to about 80° C., the solution was poured into petrol (b.p. 60°-80° C. (1 liter) with rapid stirring. A pale yellow solid was collected by filtration and then recrystallized from petrol (b.p. 60°-80° C.) to give an off white solid (40.5 g, 63%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].CC(C)=O>II.C(#N)C>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: II
Solvent: CC#N
Solvent: CC(C)=O
Product: C#Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
51.0 g of the same p-vinylphenol fraction as used in Example 1, obtained by vacuum flash distillation was placed in a 300-ml flask together with 51.0 g of acetone. To the resulting mixture being stirred and cooled to 0° C. was dropwise added 1.0 ml of an acetonitrile solution containing 0.02 g of iodine. A polymerization reaction was conducted for 1 hour at 0° C. to obtain 8.3 g of a poly(p-vinylphenol). The polymer had a Mw of 13,800, a Mn of 11,200, a light transmittance at 248 nm, of 76.3% and a light transmittance at 450 nm, of 95.0%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:25]OC(=O)C1C=CC(NC2N=CC(Br)=CN=2)=CC=1.B(O)(O)C1C=CC(OC)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:25][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:12]2[N:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(Nc2ncc(Br)cn2)cc1
Reactant: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)cc3)nc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1
Temperature: 80 °C

Procedure:
4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid can be prepared by the following procedure. To a solution of 4-(5-bromo-pyrimidin-2-ylamino)-benzoic acid methyl ester (0.3 mmol) (from Example 3f) in DMF (1.5 mL) are added 4-methoxy boronic acid (0.3 mmol), aq K2CO3 (0.68 mmol) and Pd(PPh3)4 (0.16 mmol). The reaction mixture is evacuated twice and heated at 80° C. for 30 min. After this time the reaction mixture is diluted with a sat. aq NH4Cl and extracted with DCM (3×30 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated to afford 4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid methyl ester that upon trituration with MeOH gives an orange solid (95%). MS (m/z) (M+1)+ 336.1. This solid is suspended in a 3:2:1=THE:MeOH:H2O solution (3 mL) and 6N LiOH (0.15 mL) added and stirred at rt for 12 h. At this point the solvent is removed and the residue is dissolved in water and extracted with DCM (3×30 mL). The mixture is adjusted to pH˜2 and extracted with a 3:1=DCM:IPA mixture (5×30 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated to afford 4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid as an orange powder (100%) which is used without further purification. 1HNMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.87 (s, 2H), 7.95-7.87 (m, 4H), 7.71 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 3.81 (s, 3H). MS (m/z) (M+1)+ 322.1.
Reaction SMILES: [Na].Cl.[C:3]1([CH2:9][C:10]([NH2:12])=[NH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13]1([CH2:19][C:20](=O)[CH2:21][C:22](OCC)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:3]1([CH2:9][C:10]2[N:12]=[C:20]([CH2:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:21]=[C:22]([OH:23])[N:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1cc(Cc2ccccc2)nc(Cc2ccccc2)n1
Reaction time: 120 h
Yield: 34.3 %

Procedure:
To a solution of sodium (1.84 g, 80 mmol) in ethanol (200 ml) was added phenylacetamidine hydrochloride (16.2 g, 95.0 mmol) and ethyl 4-phenylacetoacetate (15 g, 72.9 mmol). The mixture was heated under reflux with stirring for 5 days followed by cooling and evaporation in vacuo. Water (150 ml) was added to the residue causing a solid to precipitate which was filtered off and washed thoroughly with water and diethyl ether. Recrystallisation of the solid from a chloroform/hexane mixture afforded 6.9 g 2,4-di(phenylmethyl)-6-hydroxypyrimidine as a white solid. m.pt., 158°-160° C., M+ found: 276.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:14][C:15]=1[CH3:16]
Reactant: CCOC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of ethyl {3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetate (10.00 g), 2N aqueous sodium hydroxide solution (40 mL), tetrahydrofuran (100 mL) and ethanol (20 mL) was stirred overnight at room temperature. The reaction mixture was acidified by adding hydrochloric acid and concentrated. The residue was extracted with an ethyl acetate/tetrahydrofuran (1:1, v/v) mixed solvent. The organic layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from methanol-diethyl ether to give {3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetic acid as a white solid (7.92 g, yield 85%). melting point: 176-177° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:22])=[C:17]([CH:19]([OH:21])[CH3:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:22])=[C:17]([CH:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[CH3:20])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)O
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.46 mmol), 4-methanesulfonyl-phenol (0.08 g, 0.46 mmol) and PPh3 (0.14 g, 0.55 mmol) in THF (5 mL) was added DEAD (0.1 g, 0.55 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.79 (2H, m), 6.94 (2H, m), 5.59 (1H, q, J=6 Hz), 4.2-4.04 (2H, m), 3.04-2.94 (1H, m), 2.98 (3H, s), 2.86-2.72 (2H, m), 2.39 (3H, s), 2.04-1.96 (2H, m), 1.67 (3H, d, J=6 Hz), 1.66-1.58 (2H, m), 1.42 (9H, s).