Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:31][CH3:32])=[CH:7][CH:6]=2.Br[CH2:34][CH2:35][O:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[F:44].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:20][CH2:19][N:18]([CH2:34][CH2:35][O:36][C:37]3[C:38]([F:44])=[CH:39][CH:40]=[CH:41][C:42]=3[F:43])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:31][CH3:32])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(Cl)c(CCCC3(C(=O)OCc4ccccc4)CCNCC3)c2c1
Reactant: Fc1cccc(F)c1OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)OCc4ccccc4)CCN(CCOc4c(F)cccc4F)CC3)c2c1
Temperature: 75 °C
Yield: 87.6 %

Procedure:
A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with three times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 7 to 17 were combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate were obtained in the form of a thick yellow oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(C(=O)CCl)c(N(C)C=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)COC(=O)c2ccccc2)c(N(C)C=O)c1
Temperature: 25 °C

Procedure:
A solution of benzoic acid (30.3 g) and triethylamine (50.1 ml) in dichloromethane (150 ml) was added dropwise at 0° over a period of 15 minutes to the solution of 2'-(2-chloroacetyl)-5'-methyl-N-methylformanilide obtained above. The resultant solution was allowed to warm to ambient temperature and then heated under reflux overnight. After cooling the reaction mixture was washed with water (2×200 ml), dried over magnesium sulphate and evaporated to give crude 2-[4-methyl-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[C:14]1([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[N:35][CH:36]=3)=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:37][C:34]3[N:35]=[CH:36][C:31]([NH:30][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[N:21][N:22]=4)=[CH:32][CH:33]=3)=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cn3)ccnc2c1
Temperature: 130 °C
Reaction time: 3.5 h

Procedure:
A pyrex reaction tube was charged with 8-chloro-3-methoxy-1,5-naphthyridine (50 mg, 0.26 mmol), 5-(4-phenylphthalazin-1-ylamino)pyridin-2-ol (80 mg, 0.26 mmol), cesium carbonate (249 mg, 0.76 mmol) and DMSO (2 mL). The tube was sealed and the reaction mixture was heated to 130° C. After 3.5 h, an aliquot was analyzed by LCMS, and the desired product was determined to be the major peak. The reaction mixture was diluted with DMSO and purified by Gilson HPLC {5-65% (0.1% TFA in CH3CN) in H2O over 20 min}. The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with DCM. The organic portion was dried with Na2SO4, filtered, and concentrated to afford material that was further purified by silica gel chromatography, 90/10/1 CH2Cl2/MeOH/NH4OH. This provided N-(6-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-3-yl)-4-phenylphthalazin-1-amine as pure material. MS [M+H]=473.0@1.48 minutes. Calc'd for C28H20N6O2: 472.5.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([O-:11])=[O:10]>CCOC(C)=O>[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[N:14]=[C:4]=[O:3])([O-:11])=[O:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=C=Nc1ccccc1[N+](=O)[O-]

Procedure:
Method a (from 2-nitroanilines): To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0° C. was added a solution of the 2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 2-nitrophenylisocyanate as a yellow solid. This material was refluxed in a mixture of excess tert-BuOH in CH2Cl2 for 2.5 h. Removal of the solvent left an orange solid which was purified by silica gel column chromatography with hexane/EtOAc to give the (2-nitro-phenyl)-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH2:19][CH2:20][CH3:21])[C:10]=1[CH2:22]O)([OH:8])[C:4]([F:7])([F:6])[F:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O>ClCCl>[CH3:18][O:17][CH2:16][O:15][C:12]1[C:11]([CH2:19][CH2:20][CH3:21])=[C:10]2[C:9](=[CH:14][CH:13]=1)[C:3]([C:4]([F:6])([F:5])[F:7])([C:2]([F:1])([F:24])[F:25])[O:8][CH2:22]2
Reactant: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCCc1c(OCOC)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-[2-(hydroxymethyl)-4-(methoxymethoxy)-3-propylphenyl]propan-2-ol (1.29 g, 3.43 mmol) and triphenylphosphine (1.98 g, 7.55 mmol) in dichloromethane (15 mL), diethyl azodicarboxylate (2.2 mol/L toluene solution, 4.67 mL, 10.27 mmol) was added under ice-cold conditions and the mixture was stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.14 g, 93%) was obtained as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[C:13]([NH2:17])=[N:14][O:15][N:16]=3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:20](I)[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH2:20]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[C:12]1[C:13]([NH2:17])=[N:14][O:15][N:16]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: Nc1nonc1-c1nc(-c2ccccc2)c[nH]1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(-c2ccccc2)nc1-c1nonc1N
Yield: 19 %

Procedure:
Synthesis of 4-(4-phenyl-1H-imidazol-2-yl)-1,2,5-oxadiazol-3-amine (50 mg, 0.22 mmol) was dissolved in DMF and NaH (15 mg, 0.7 mmol) was added. The reaction mixture became dark red. Isobutyl iodide (60 mg, 0.33 mmol) was added and the reaction mixture heated to 120 CC in the microwave for 5 minutes. The reaction mixture was concentrated to an oil which was purified by RPHPLC (CH3CN/H2O, 0.1% TFA) to give the product, 12 mg, 0.042 mmol, 19% yield. HPLC Method B Rt 4.50 min, MH+ 284.30. 1H NMR (500 MHz, CDCl3) δ 7.71 (m, 2H), 7.34 (m, 2H), 7.28 (s, 1H), 7.23 (m, 1H), 4.19 (d, J=7.4 Hz, 2H), 2.12 (m, 1H), 0.92 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[O:5][C:6]1[CH:34]=[CH:33][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23]CC4C=CC=CC=4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:31]#[N:32])=[CH:8][CH:7]=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[O:5][C:6]1[CH:34]=[CH:33][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:31]#[N:32])=[CH:8][CH:7]=1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1O

Procedure:
The product from step (1) (7.2 g, 14.3 mmole) trifluoroacetic acid (40 ml) and thioanisole (8.38 ml, 71.5 mmole) was refluxed in a nitrogen atmosphere for 3 hours. After cooling the trifluoroacetic acid was removed by rotary evaporation and the oily residue was stirred with ice and water and basified with aqueous ammonia (S.G. 0.880). The resulting suspension was filtered and the solid was washed successively with water, ethyl acetate and diethyl ether and then dried to give 4-(4-(2-methoxyphenoxy)-anilino)-3-cyano-6-methoxy-7-hydroxyquinoline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][N:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[N:14]1[CH:18]=[N:17][N:16]=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(C1C=CC(NN2C=NN=C2)=CC=1)#N.CN([CH:49]=[O:50])C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][C:29]=1[O:50][CH3:49])[CH2:12][N:13]([C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=1)[N:14]1[CH:15]=[N:16][N:17]=[CH:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(c2ccc(C#N)cc2)n2cnnc2)cc1OCc1ccccc1
Yield: 44 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using NaH (60% dispersion in oil, 0.22 g, 5.4 mmol), 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (1.0 g, 5.68 mmol) and 4-methoxy-3-benzyloxybenzyl bromide[Meyers, 1989] (1.66 g, 5.4 mmol) in anhydrous DMF (5 mL) to give 4-[(3-benzyloxy-4-methoxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as an off-white solid (0.97 g, 44%) after recrystallisation; mp. 138-141° C.; δH (400 MHz, CDCl3) 3.89 (s, 3H), 4.72 (s, 2H), 5.12 (s, 2H), 6.59 (AA′BB′, 2H), 6.62 (d, J=2, 1H), 6.64 (dd, J=7.8, 2, 1H), 6.79 (d, J=7.8, 1H), 7.28-7.34 (m, 5H), 7.57 (AA′BB′, 2H), 7.74 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 412 (100, [M+H]), 343 (51), 227 (72%); HPLC: tR=2.21 min (94%); HRMS (FAB+): Found 412.1774 C24H22N5O2 requires 412.1776.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]3[CH:45]=[CH:46][C:36]([F:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(/C=C/c2ccc(F)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), (E)-4-fluorostyrylboronic acid (49.7 mg, 0.299 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 20-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a light yellow solid (32 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=16.17 Hz, 1H), 2.00-2.21 (m, 1H), 3.55-3.71 (m, 2H), 3.79-3.93 (m, 2H), 3.93-4.10 (m, 1H), 4.33-4.46 (m, 2H), 4.54 (d, J=8.84 Hz, 1H), 7.15 (d, J=5.05 Hz, 1 H), 7.28 (t, J=8.84 Hz, 1H), 7.58-7.74 (m, 3H), 7.93 (br s, 3H), 8.15 (d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20F2N4O2, 387. found, 387.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.FC(F)(F)S(O[CH2:45][CH:46]([F:48])[F:47])(=O)=O.C(N(CC)CC)C>C1COCC1>[F:48][CH:46]([F:47])[CH2:45][N:29]1[CH2:30][CH2:31][CH:26]([N:25]([CH3:32])[C:23]([N:11]2[CH2:12][C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[CH:14][C:10]2([CH2:9][OH:8])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CC(F)F)CC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To 87 mg (0.16 mmol) of amine 7-2 in THF in a sealed tube was added 41 mg (0.19 mmol) of 2,2-difluoroethyl trifluoromethane sulfonate and 67 μL (0.48 mmol) of triethylamine. After stirring 2.5 h at 70° C., the mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was dissolved in 5 mL CH2Cl2 and 1 mL of trifluroacetic acid was added. After stirring for 30 min at room temperature, the solvents were removed by rotary evaporation, the residue was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with MeOH/CHCl3 to provide 10-1 as a white solid. Data for 10-1: 1HNMR (500 MHz, CDCl3) δ 7.7-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.8 (m, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.7 (m, 1H), 3.0 (m, 2H), 2.9 (s, 3H), 2.75 (m, 2H), 2.3 (m, 2H), 1.9 (m, 2H), 1.6 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H29F4N3O2: 492.2269. Found: 492.2250.
Reaction SMILES: [SH2:1].[NH2:2][C:3](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C.N1C=CC=CC=1>>[NH2:2]/[C:3](/[C:4]([CH3:7])([CH3:5])[CH3:6])=[C:8](\[C:9]#[N:10])/[C:11](=[S:1])[NH2:12]
Reactant: S
Reactant: CC(C)(C)C(N)=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)/C(N)=C(/C#N)C(N)=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With cooling, 1.52 g (4.50 mmol) of hydrogen sulphide are introduced as a gas into a mixture of 1.6 g (1.40 mmol) of (1-amino-2,2-dimethylpropylidene)propanedinitrile, 1.41 g (1.40 mmol) of triethylamine and 2.21 g (2.80 mmol) of pyridine. For 1 h, nitrogen is then passed through the reaction mixture, and the reaction mixture is then added to ice-water and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a stirred solution of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (20) in THF (4 ml) were added 4-chlorobenzoic acid (147 mg), N-methylmorpholine (0.27 ml) and TBTU (401 mg). The reaction mixture was heated to 50° C. and stirred for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (SiO2; gradient: EtOAc/heptane) to afford (S)-4-{2-[4-(4-chloro-benzoylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a white solid (254 mg, 89%). MS (ISP): 478.3 ([{37Cl}M+NH4]+), 476.3 ([{35Cl}M+NH4]+), 405.4 ([{37Cl}M+H—C4H8]+), 403.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([OH:27])[CH:26]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([O:27][CH2:1][CH3:2])[CH:26]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (0.461 g, 1.758 mmol) is added to a mixture of 3-bromo-5-hydroxy pyridine (0.3 g, 1.724 mmol) in THF (10 ml). Ethanol (0.103 ml) is added the reaction mixture is cooled to 0° C. (ice-bath). DEAD (0.277 ml, 1.758 mmol) is finally added and the mixture is warmed to room temperature and stirred overnight. The crude material is purified by flash chromatography by wet loading onto a 50 g silica column eluting with 3:1 iso-hexanes:EtOAc to afford the title compound as a yellow oil, [MH+ 201.88].
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].CN(C=O)C.N1([C:21]([CH:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[CH:30][CH:29]=[N:28]4)[N:25]=[CH:24]2)=[O:22])C=CN=C1>C(O)(=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:21]([CH:23]1[C:36](=[O:37])[C:35]2[C:26](=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[N:28]3)[N:25]=[CH:24]1)=[O:22]
Reactant: O=C1c2ccc3cccnc3c2N=CC1C(=O)n1ccnc1
Reactant: COCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COCCOCCOC(=O)C1C=Nc2c(ccc3cccnc23)C1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (3.15 g, 60%) was added in portions to a mixture of 2-(2-methoxyethoxy)ethanol (15 ml) and DMF (200 ml). The mixture was stirred for approximately 30 minutes until effervescence ceased. 3-(Imidazol-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline (21.05 g) was added and the mixture stirred for 18 hours. The mixture was acidified to pH 5-6 with acetic acid, and evaporated to dryness under reduced pressure. Water (50 ml) was added and the mixture extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica using dichloromethane, followed by a 24:1:0.1 mixture of dichloromethane methanol : triethylamine as eluant. The product so obtained was triturated with ethyl acetate to give 3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline in 68% overall yield, mp 164-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH:17]=[CH2:18])[CH:10]=1.N1C=CC=CC=1.Cl[C:34]([O:36][CH3:37])=[O:35]>ClCCl>[CH3:37][O:36][C:34](=[O:35])[NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C@@H:15]([NH:19][C:20]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:16][CH:17]=[CH2:18])[CH:10]=2)=[C:2]([NH2:1])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(N)cc2N)ccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2N)ccn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a cooled (−78° C.) clear, brown solution of 1E (2.63 g, 7.42 mmol) and pyridine (0.600 ml, 7.42 mmol) in dichloromethane (74.2 ml) was added dropwise over 30 min methyl chloroformate (0.516 ml, 6.68 mmol). The reaction was stirred at −78° C. After 1.5 h, the reaction was quenched with sat. NH4Cl and the reaction was allowed to warm to rt. The reaction was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM (1×). The combined organic layers were washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue dissolved in DCM (˜10 mL) and then hexane (˜300 mL) was added to give a brown suspension with brown gummy sticky substance at the bottom. The mixture was sonicated to give a mostly clear solution with the brown substance at the bottom. The solution decanted and the bottom substance rinsed with hexane, dried to give 1F (2.7 g, 88%) as a slightly brown foam. MS (ESI) m/z: 413.2 (M+H)+.
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].C[CH:20](C)[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1C)O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=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][CH:21]([C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)=[N:25][CH:24]=2)[CH3:20])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)s2)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 [rac]-1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-ethoxy-3-(2-methyl-4-{1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless liquid.