Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[SiH:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[C:28]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]=1[OH:40])[C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]=1[OH:25].C(N(CC)CC)C>>[C:32]([C:30]1[CH:29]=[C:28]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]2[O:40][SiH:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:25][C:12]3[C:13]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16][C:11]=3[CH2:10][C:26]=2[CH:31]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: Cl[SiH](Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[SiH](c1ccccc1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Yield: 64.3 %

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 17.7 grams (0.1 mole) of dichlorophenylsilane, 42.5 grams (0.1 mole) of 2,2'-methylenebis(4,6-di-t-butylphenol) and 20.2 grams (0.20 mole) of triethylamine. Recrystallization twice from acetonitrile-toluene yields 34.0 grams (64% yield) of product as an off white powder, mp 153°-156° C.; IR: 2200 cm-1SiH.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([Cl:18])=[O:17])[CH2:14][CH2:13]1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCC(Cl)(Cl)Cl>[ClH:18].[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([C:7]2[CH:8]=[CH:9][C:10]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[CH:6]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCNCC1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Product: O=C(c1ccc2ccccc2c1)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 99 g of naphthalene (0.75 mole) and 96 g of isonipecotic acid chloride hydrochloride (0.5 mole) in tetrachloroethane is added over a period of 10 minutes 200 g (1.5 moles) of aluminum chloride. The reaction mixture is allowed to stand at room temperature for 10 minutes, then decomposed by pouring it over ice water, made basic with a 50% NaOH solution, and extracted with diethyl ether. The ether layer is dried over magnesium sulfate, filtered, and treated with ethereal HCl. The resulting oil is dissolved in warmed methanol, treated with charcoal, filtered and diluted with butanone. The methanol is removed by distillation, adding more butanone as needed. The solution is cooled overnight, and the resulting solid filtered off and recrystallized from methanol-butanone to give the desired product. M.P. 251°-253° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][CH:20]=O>CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:19]=[CH:20][N:17]=2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(Oc2ccccc2)cn1
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(Nc3nccs3)nc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
8.4 (5-Phenoxy-pyridine-2-yl)-thiourea (0.3 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred 2 h at 70° C. After cooling to RT the precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. (5-Phenoxy-pyridine-2-yl)thiazole-2-yl-amine is obtained as colourless powder in a yield of 66%; mp. 161.4-162.4° C.; HPLC (method C): 1.69 min; LC-MS (method A): 1.559 min, 270.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.248 (s, 1H), 8.114 (d, 1H, J=2.7 Hz), 7.523 (dd, 1H, J=9.0 Hz, J=2.7 Hz), 7.387-7.355 (m, 3H), 7.151 (d, 1H, J=9.0 Hz), 7.107 (t, 1H, J=7.1 Hz), 6.997-6.967 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24](Cl)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:33]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[H-].[Na+].O>CN(C=O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24]([O:41][CH2:40][CH2:39][N:33]6[CH2:38][CH2:37][O:36][CH2:35][CH2:34]6)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(OCCN3CCOCC3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (100 mg) and 2-morpholin-4-yl-ethanol (250 μL) in dry DMF (1 mL) was added NaH (100 mg, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. To this was added water (20 mL) and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-(2-morpholin-4-yl-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (42 mg). LCMS (m/z): 552.8.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Na]>ClCCl.C(O)(=O)C.FC(F)(F)C(O)=O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(F)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Fc1ccc(NC2CCNCC2)cc1

Procedure:
Was synthesised in the same way as (A) from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol), 4-fluoro-phenylamine (1.0 g, 9.0 mmol) and sodium triacetoxyborhydride (5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.1 g, 63%
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.C1(N=C=NC2CCCCC2)CCCCC1.C[C@H]1[C@@]2(O)O[C@H](C[C@H](OC)C(C)=CC=CC=C[C@@H](C)C[C@@H](C)C([C@H](OC)[C@H](O)C(C)=C[C@@H](C)C(C[C@@H]([C@@H](C[C@H]3C[C@@H](OC)[C@H](O)CC3)C)OC([C@H]3N(C(C2=O)=O)CCCC3)=O)=O)=O)CC1.CN(C1C=CC=CN=1)C>CN(C)C=O.C(Cl)Cl>[C:6]1(=[O:8])[O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCCC(=O)O1
Reaction time: 2 h

Procedure:
Rapamycin 42-ester with adipic acid was prepared by a variation of the method of Example 2. Adipic anhydride was prepared by combining 146 mg adipic acid in 1.0 mL dimethylformamide with 200 μL dicyclohexylcarbodiimide and incubating at room temperature 2 h. 300 μL of the supernatant of this reaction was added to 90 mg rapamycin and 45 mg dimethylaminopyridine dissolved in 200 μL methylene chloride. After 5 min the mixture was centrifuged to sediment precipitated material. The supernatant was partitioned between 3 mL water with 100 μL acetic acid and 2×1 mL methylene chloride. The organic layers were combined, dried with anhydrous sodium sulfate and the solvent evaporated. The residue was dissolved in 1.0 mL methanol and 0.5 mL ethanol, cooled in ice, and precipitated by adding 5 mL water. This was centrifuged, the supernatant discarded and the residue dried in a vacuum desiccator, yielding 78 mg white powder.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:20]N(C)C=O.CI>C(N(CC)CC)C>[CH3:19][CH:13]1[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([S:1][CH3:20])=[N:3][CH:4]=[N:5]3)=[CH:10][CH:9]=2)=[N:17][NH:16][C:15](=[O:18])[CH2:14]1
Reactant: CC1CC(=O)NN=C1c1ccc2c(S)ncnc2c1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CI
Product: CSc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To 0.36 g of Compound 56 obtained in Example 18 were added 10 ml of dimethylformamide, 0.2 ml of triethylamine and 0.1 ml of methyl iodide. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated. Thereafter, water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.3 g (79%) of 4,5-dihydro-5-methyl-6-(4-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (Compound 57).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[OH:4].[H-].[Na+].[NH2:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=1>C1COCC1>[Cl:30][C:25]1[CH:26]=[C:27]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[C:2]([F:18])([F:19])[F:1])[N:28]=[C:23]([NH2:22])[N:24]=1
Reactant: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 72.2 %

Procedure:
2,2,2-Trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol (0.15 g, 0.563 mmol) was treated with NaH (60% in mineral oil, 45 mg, 1.12 mmol) in dry THF (5 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (92 mg, 0.5633 mmol) was added and the mixture was stirred at 50° C. for 6 hours. The mixture was quenched with water and extracted with methylenechloride (2×). The organics were combined, washed with water, then brine, dried over MgSO4, and concentrated to give 0.16 g of 4-chloro-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-2-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][CH2:18][CH2:19][C@@H:13]3[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.C(OCC)(=O)C>CN(C)C=O.ClCCl>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][CH2:18][CH2:19][C@@H:13]3[CH2:12]2)=[O:10])=[CH:3][C:2]=1[NH:1][S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(C(=O)N2CCN3CCC[C@@H]3C2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)c(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (R)-(3-amino-4-fluorophenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanone (79 mg, 0.3 mmol) and sodium carbonate (64 mg, 0.6 mmol) in N,N-dimethylformamide (1 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (88 mg, 0.36 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 18 hours. Then ethyl acetate was added, and the mixture was washed with water (2×10 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (methanol/dichloromethane=1:15) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25 (m, 1H), 1.60-2.20 (m, 6H), 2.70-3.10 (m, 5H), 4.35-4.55 (m, 1H), 7.22 (m, 3H), 7.82 (m, 1H), 8.00 (m, 3H); MS (ESI) m/z 472 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.C(N(C(C)C)CC)(C)C.OP([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncnc(O)c2c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 L reactor was charged with 4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (155.1 g, 0.70 mol) and toluene (2.7 L). Phosphorous oxychloride (128.8 g, 78 mL, 0.84 mol) was then added followed by the addition of diisopropylethylamine (94.2 g, 127 mL, 0.70 mol). The reaction mixture was stirred for 5 min at room temperature and then heated at reflux for 20 h. HPLC analysis indicated complete disappearance of starting material. The reaction mixture was then cooled to 0° C. and cold K2HPO4 solution (527 g in 2.4 L of water) was added at a rate to maintain the internal temperature of the reaction mixture below 5° C. The final pH of the mixture was 8. The mixture was then stirred at between 0° C. to 5° C. for 20 min and then at room temperature for 1 h. The organic phase was separated and washed with K2HPO4 solution (85 g in 405 mL of water) and water (345 mL) and then filtered and concentrated in vacuo until yellow solids began to precipitate. Dimethyl formamide (1 L) was added and the remaining toluene was removed in vacuo (bath temperature=38° C., pressure=9 Torr). After concentration, approximately 4% toluene was observable by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Reactant: BrCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCBr

Procedure:
8-(4-Bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Example 11, Step 1) and 1,4-dibromobutane following the procedure outlined in Example 11, Step 2. MS (ESI): 485.8.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2sccc2c1O
Temperature: 140 °C

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43 a, 165 mg, 0.5 mmol), phenylboronic acid (94 mg, 0.75 mmol), tetrakis(triphenylphosphine) palladium(0) (59 mg, 0.05 mmol), potassium carbonate (208 mg, 1.5 mmol), and anhydrous 1.4-dioxane (3 ml) was heated in a microwave oven at 140° C. for 15 min. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a yellowish oil (95 mg); MS-(+)-ion: MS-(+)-ion: M+1=328.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([CH:14]1[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1)[C:20]1[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[N:24][CH:25]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=414.1, tR (minutes, Method F)=2.54
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[CH:20][C:15]=2[O:14][CH:13]=1)=O)C.[OH-].[Na+]>C1COCC1>[CH2:22]([O:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH2:10][OH:9])=[CH:13][O:14][C:15]=2[CH:20]=1)[CH3:23]
Reactant: CCOC(=O)c1coc2cc(OCC)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc2c(CO)coc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1M LiAlH4-solution in THF (47.6 ml, 47.6 mmol) is diluted with 200 ml of THF and cooled to 0° C. 6-Ethoxy-benzofuran-3-carboxylic acid ethyl ester (27a) (5.6 g, 23.8 mmol) is dissolved in 100 ml of THF and added drop wise within 30 min. After completed addition the mixture is allowed to stir at 0° C. for 2 h. Then the reaction mixture is cooled to −15° C. and 10 ml of a 1M NaOH solution is added very slowly. Then the mixture is filtrated over celite, washed with THF and evaporated under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:9]2)[N:5]=[CH:4][N:3]=1.B([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:30][CH:29]([CH2:28][C:27]1[CH:34]=[CH:35][C:24]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH2:9]3)[N:5]=[CH:4][N:3]=2)=[CH:25][CH:26]=1)[C:31]([OH:33])=[O:32]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Clc1ccc(C2CCCN(c3ncnc(Cl)n3)C2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(Cc1ccc(-c2ncnc(N3CCCC(c4ccc(Cl)cc4)C3)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 5.8 %

Procedure:
A microwave vial was charged with 2-chloro-4-[3-(4-chlorophenyl)-piperidin-1-yl]-[1,3,5]triazine (62 mg, 0.2 mmol), 4-borono-L-phenylalanine (60 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.6 ml; 1M) was added to the solution, followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 5.1 mg of 2-amino-3-(4-{4-[3-(4-chlorophenyl)-piperidin-1-yl]-[1,3,5]triazin-2-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3Cl) δ 8.58 (d, 2H), 8.05 (d, 2H), 7.47 (m, 5H), 4.96 (m, 1H), 4.23 (m, 2H), 3.21-3.44 (m, 4H), 2.37 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.CC1N=C(C2C=CC=CC=2)SC=1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:25][C:24]2[S:23][C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:21][C:20]=2[CH3:19])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccccc2)sc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cc1nc(-c2ccccc2)sc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2sc(-c3ccccc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-(4-methyl-2-phenyl-thiazol-5-yl)-ethanol (prepared from (4-methyl-2-phenyl-thiazol-5-yl)-methanol [PCT Int. Appl. (2002), WO 02/80899 A1] according to the reaction sequence described in example 104 a] to c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield [rac]-2-ethoxy-3-{2-methyl-4-[2-(4-methyl-2-phenyl-thiazol-5-yl)-ethoxy]-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [Br:1][CH:2]([F:14])[C:3]([F:13])([F:12])[O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+]>O>[Br:1][CH:2]([F:14])[C:3]([F:13])([F:12])[O:4][C:5]1[CH:11]=[CH:10][C:8]([OH:16])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(OC(F)(F)C(F)Br)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(OC(F)(F)C(F)Br)cc1
Temperature: 10 °C

Procedure:
40 g of 4-(2-bromo-1,1,2-trifluoroethoxy)-aniline were added dropwise, at 10° C., to 400 ml of 2.5N sulfuric acid, after which 11 g of sodium nitrite in 30 ml of water were added dropwise at 0° C., and the mixture was stirred for a further hour at 10° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([F:23])=[C:7]([O:12][C:13]2[C:14]([Cl:22])=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[C:6]([F:23])=[C:7]([O:12][C:13]2[C:14]([Cl:22])=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1Cl
Yield: 92.6 %

Procedure:
3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.565 g, 1.521 mmol) was dissolved in THF (5 mL) and was treated successively with triphenylphosphine (0.598 g, 2.281 mmol) and water (0.137 g, 7.60 mmol) at 25° C. for 3 days with stirring. The reaction mixture was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc (to remove triphylphosphine oxide) followed by a gradient of 100% EtOAc to 10% CH3OH/DCM to give the desired product, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.487 g, 1.409 mmol, 93% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (d, J=2.20 Hz, 1H), 7.48-7.58 (m, 2H), 7.19 (d, J=1.83 Hz, 1H), 3.77 (s, 2H), 1.94 (br. s., 2H). LC-MS (ES+) m/z 344.89, 346.89, 348.89 [M+H].
Reaction SMILES: [NH3:1].CO.[C:4]([C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]=[C:21]([C:23]([O:25]C)=O)[CH:20]=[C:19]([CH:27]=[CH2:28])[N:18]=3)=[CH:13][CH:12]=2)=[CH:8][C:7]=1[C:31]([F:34])([F:33])[F:32])#[N:5]>CO>[C:4]([C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]=[C:21]([C:23]([NH2:1])=[O:25])[CH:20]=[C:19]([CH:27]=[CH2:28])[N:18]=3)=[CH:15][CH:16]=2)=[CH:8][C:7]=1[C:31]([F:33])([F:34])[F:32])#[N:5]
Reactant: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Reactant: N
Solvent: CO
Product: C=Cc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Temperature: 25 °C

Procedure:
In a 50-mL vial with a screw-top septum, methyl 2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate was dissolved in MeOH (2 mL) and stirred at room temperature. To the solution was added 7N NH3/MeOH (5 mL) and the reaction mixture was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure and purified using Combiflash with a gradient of methanol (30% max) in chloroform to provide 2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxamide (270 mg) as a white solid. LC/MS: m/z=411 [M+H]+.