Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O>[N:12]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc(C(F)(F)F)n1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
A mixture of 82.5 grams (g) of 2-fluoro-6-(trifluoromethyl)pyridine (0.5 mole), 65 g of sodium azide (1.0 mole) and 400 milliliters (ml) of dimethylsulfoxide (DMSO) was heated to a temperature of 80° C. for 18 hours. The mixture was allowed to cool and then poured into 1500 ml of ice water. This resulting mixture was then extracted 4 times with 300 ml of pentane each time. The pentane extracts were combined, washed with 500 ml of a saturated NaCl solution and dried with MgSO4. The pentane was then carefully evaporated leaving 67 g of the desired 2-azido-6-(trifluoromethyl)pyridine as a light yellow oil having an RI of 1.4771 @25° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>O>[CH:1]1([CH2:7][N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(cyclohexylmethyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-propanoate (0.031 g, 0.057 mmol) in TEF (2.0 mL) were added water (2.0 mL) and lithium hydroxide (0.006 g, 0.26 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 2M HCl and extracted with ethyl acetate (4×25 mL). The combined organic phase was washed with brine (25 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.027 g (93%) of a colourless oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.C(OC[CH2:13][CH2:14][NH2:15])=C.C=O.C1(C)C=CC=CC=1>O>[O:5]1[C:4]2[CH:3]=[CH:1][CH:8]=[CH:7][C:6]=2[CH:13]=[CH:14][NH:15]1
Reactant: C=COCCCN
Reactant: Oc1cccc(O)c1
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Temperature: 25 °C
Yield: 125.2 %

Procedure:
A 500 mL flask was charged with resorcinol (33 g, 300 mmol), 3-amino-1-propanol vinyl ether (61 g, 600 mmol), and paraformaldehyde (38 g, 1260 mmol). Approximately 200 g of toluene was added and the mixture was heated to reflux. Reflux continued until water ceased to collect in the trap (about one hour). The reaction mixture was then cooled to room temperature. A large volume of solid byproduct formed in the reaction vessel. The toluene solution was decanted from the solid, and the remaining solid was washed with extra toluene. All of the toluene fractions were combined in a separatory funnel. The toluene solution was washed with a 5% NaOH solution, followed by a saturated NaCl solution. The toluene solution was dried with magnesium sulfate, and filtered over a small bed of neutral alumina. Removal of the solvent under reduced pressure produced about 50 g of an orange colored liquid (46% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:39])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]5[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]5)[CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([OH:47])[CH:46]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:39])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]5[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]5)[CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:43]3[CH:44]=[C:45]([OH:47])[CH:46]=[C:41]([F:40])[CH:42]=3)[C:3]=12
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1)n1nc(I)c2c(N)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 73.7 %

Procedure:
3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1H-isochromen-1-one (Intermediate D8, 1.14 g, 1.788 mmol), (3-fluoro-5-hydroxyphenyl)boronic acid (0.558 g, 3.58 mmol), K2CO3 (0.494 g, 3.58 mmol) and PdCl2(dppf) (0.196 g, 0.268 mmol) were reacted in dioxane (30 ml) overnight at 120° C. The reaction was diluted with DCM (100 ml), filtered to remove solids, and the filtrate evaporated under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G SNAP with a gradient of DCM and MeOH to give the title compound (819 mg, 73.7%) as brown pale solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:12]=[CH:11][N:10]=2)=CC=1.CCOC(C)=O>CO.C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)n2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Nc1nccc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)n1
Yield: 64.2 %

Procedure:
The title compound was prepared from 1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (Example 15, 20 mg, 0.039 mmol) using a similar procedure described for Example 16. Flash chromatography on SiO2 using EtOAc then 1-2% MeOH in CH2Cl2 as eluents gave the title compound (10 mg, 62%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.01 (s, 1H), 10.52 (s, 1H), 8.20 (d, 1H, J=6.0 Hz), 7.70 (dd, 1H, J=12.1, 2.0 Hz), 7.36-7.30 (m, 6H), 7.16 (dd, 2H, J=8.8, 8.8 Hz), 6.45 (d, 1H, J=6.1 Hz), 3.73 (s, 2H); MS(ESI+) m/z 400.09 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:14]=[C:13]([O:25][CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[N:7][CH:8]=1.[P:30]([O:37]CC)([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33].CO.C(OCC)(=O)C>CN(C=O)C>[CH2:32]([O:31][P:30]([CH2:2][C:3]1[CH:8]=[N:7][C:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:14]=[C:13]([O:25][CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[CH:5][CH:4]=1)(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(CBr)cn2)c1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(NC(=O)c2cc(OCCc3ccsc3)cc(OC(C)C)c2)nc1)OCC
Yield: 16.6 %

Procedure:
N-(5-Bromomethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (0.46 g, 0.97 mmol) was dissolved in DMF (5 mL). Triethyl phosphite (0.51 mL, 2.91 mmol) was added and the reaction mixture was subjected to microwave radiation at 180° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure and partitioned in EtOAc (20 mL) and water (20 mL). The organic layer was rinsed with water (10 mL), and then a saturated sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated to dark brown oil. After chromatography on silica gel with a gradient from 50-100% ethyl acetate-hexanes to 10% methanol-ethyl acetate, {6-[3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-ylmethyl}-phosphonic acid diethyl ester (86.0 mg, 16.6% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.25 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 4.70 (m, 1H), 4.25 (t, 2H), 3.95 (m, 4H), 3.25 (d, J=12.0 Hz, 2H), 3.05 (t, 2H), 1.25 (s, 6H), 1.15 (m, 6H); LCMS (m/z): 533.2 [C26H33N2O6PS+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC>[CH2:1]([O:8][C:9]1[C:15]([CH3:16])=[CH:14][C:12]([NH:13][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCC(=O)O
Reactant: Cc1cc(N)cc(C)c1OCc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCC(=O)Nc1cc(C)c(OCc2ccccc2)c(C)c1

Procedure:
1.0 g of 4-benzyloxy-3,5-dimethylaniline and 30 ml of nonanoic acid are stirred at 150° C. for 3 hours. To the reaction mixture is added 100 ml of ether, and the mixture is washed with an aqueous 10 % sodium hydroxide and water, and dried followed by evaporation of the solvent. The residue is purified by silica gel column chromatography [Solvent:chloroform-ethanol (10:1)], and from the eluate is obtained 260 mg of N-(4-benzyloxy-3,5-dimethylphenyl)nonaneamide as an oily product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.18 mL (48.0 mmol) benzyl chloroformate in 50 mL DCM was added dropwise to 12.3 g (45.7 mmol) tert-butyl 4-piperidin-4-yl-piperazine-1-carboxylate and 8.2 mL (50 mmol) N-ethyldiisopropylamine in 200 mL DCM while cooling with ice and the reaction mixture was stirred overnight at RT. It was washed with 200 mL of 15% K2CO3 solution, the organic phase was separated off and dried over Na2SO4. After elimination of the desiccant and solvent the residue was further reacted without any further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19].Br>CCCCCCC>[Br:19][C@@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrP(Br)Br
Agent: Br
Solvent: CCCCCCC
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 179.8 %

Procedure:
Under an argon atmosphere, a suspension of (S)-1-[3,5-bis(trifluoromethyl)-phenyl]ethanol (1.0 g, 3.87 mmol, >99.5% ee) in heptane (2 mL) was added dropwise with phosphorus tribromide (0.52 g, 1.94 mmol) at 0 to 5° C., and the mixture was stirred at 0 to 5° C. for 30 minutes. The reaction mixture was added dropwise with hydrogen bromide (30% solution in acetic acid, 0.76 mL, 3.87 mmol) at 0 to 5° C., and the mixture was stirred at 10° C. for 17 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (15 mL×2). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL×1) and then with saturated brine (15 mL×1), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 8 g; developing solvent, n-hexane) to obtain 1.12 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.O[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCC1CCN(c2cc(Cl)nnc2Cl)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCC2CCN(c3cc(Cl)nnc3Cl)CC2)cc1
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a 50 mL dry three-necked flask, 0.554 g (0.002 mol) of self-made 2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethanol, 0.20 g (0.002 mol) of p-hydroxybenzonitrile, 0.612 g of triphenylphosphine were added, 15 mL of anhydrous tetrahydrofuran was added under conditions of ice bath and nitrogen gas protection, then 0.35 mL of diethyl azodiformate (DEAD) dissolved in 5 mL of anhydrous tetrahydrofuran, was added dropwise into the flask. After the dropwise addition, the temperature was elevated to room temperature, the agitation was kept overnight. On the next day, the solvent was removed by evaporation using a rotation evaporator, the residue was poured into 100 mL of water, extracted for three times by using total 150 mL of dichloromethane, the extract solutions were combined together, dried over anhydrous Na2SO4, concentrated, and separated by column chromatograph (eluent, petroleum ether:ethyl acetate:methanol=10:3:0.1) to obtain 0.26 g of 4-{2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethoxy}-benzonitrile, a white solid. Yield: 34.0%, m.p. 138˜139° C. 1HNMR (400MHz, CDCl3) δppm: 1.49˜1.55(m, 2H), 1.83˜1.86(m, 3H), 1.91˜1.94(dbrs, 2H), 2.82˜2.87(dt, 2H, J=11.4Hz), 3.76˜3.79(dbrs, 2H), 4.08˜4.11(t, 2H, J=5.8Hz), 6.85(s, 1H), 6.94˜6.96(d, 2H, J=8.8Hz), 7.58˜7.61(d, 2H, J=8.8Hz), 7.40(s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([S:30]([CH2:32][CH3:33])=[O:31])[C:24](C(F)(F)F)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[ClH:34]>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([S:30]([CH2:32][CH3:33])=[O:31])[C:24]([Cl:34])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(=O)CC)cc3n2COCCOC)c1
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)CC)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.191 g, 0.420 mmol) in ethanol (2 mL) was added 4M HCl in dioxane (2 mL). The reaction mixture was stirred at 23° C. for 2 h. The resulting precipitate was collected and rinsed with diethyl ether to yield the titled compound (0.103 g, 67% yield). MS (ESI/CI): mass calcd. for C15H15ClN4O3S, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.02 (d, J=0.6 Hz, 1H), 8.40 (d, J=0.6 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.17 (dq, J=14.6, 7.3 Hz, 1H), 2.84 (dq, J=14.6, 7.4 Hz, 1H), 1.32 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 4-fluorobenzaldehyde (0.93 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.2 g of product m.p. 185-186° C., 1H-NMR (CDCl3) δ: 2.43 (d, J=1.2 Hz, 3H), 2.52 (m, 1H), 4.79 (d, J=1.2 Hz, 2H), 6.17 (d, J=1.2 Hz, 1H), 6.96-7.66 (m, 8H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH2:11]([O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([O:17][C@H:18]([CH3:22])[C:19]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCO[C@H](C)C(=O)Cl
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Product: CCCCCCO[C@H](C)C(=O)O[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Using trans-4-hydroxycyclohexane carboxylic acid (1.01 g, 7 mmol) and (R)-2-n-hexyloxypropanoyl chloride (1.35 g, 7 mmol), the reaction was carried out in the same manner as described in Example 4, (1), to give the title compound as a pale yellow oil; yield: 750 mg.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:24]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]=1)[C:14]([O:16][C@H:17]([CH3:20])[CH2:18][OH:19])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:24]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]=1)[C:14]([O:16][C@H:17]([CH3:20])[CH2:18][O:19][C:1](=[O:3])[CH3:2])=[O:15])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@H](CO)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Acetyl chloride (2.3 mL, 33.1 mmol) and (1R)-2-hydroxy-1-methylethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (17) (11.8 g, 22.1 mmol) were dissolved in 400 mL of anhydrous dichloromethane. A solution of pyridine (2.7 mL, 33.1 mmol) in dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The product was extracted with dichloromethane, washed with 5% NaHCO3, 10% citric acid, and dried over Na2SO4. After concentration the resulting residue was further dried under vacuum. The crude product (18) (12.9 g, 100% yield) was isolated as a foamy solid. 1H NMR (400 MHz, CDCl3): δ 1.15 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.03 (s, 3H), 2.95 (dd, J=14.0, 6.8 Hz, 1H), 3.01 (dd, J=14.0, 6.8 Hz, 1H), 3.99 (dd, J=12.0, 6.4 Hz, 1H), 4.12 (dd, J=12.0, 3.2 Hz, 1H), 4.50 (dd, J=14.0, 6.8 Hz, 1H), 4.93 (d, 1H, NH), 5.07 (m, 1H), 5.10 (s, 4H), 6.65 (dd, J=8.0, 2 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.28-7.46 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:14])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[OH-:15].[Na+:16]>O>[C:2]([NH:6][C:5](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O-:3])=[O:14])(=[O:15])[CH3:1].[Na+:16]
Reactant: CC1=NC(=Cc2ccccc2)C(=O)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC(=Cc1ccccc1)C(=O)[O-]
Reaction time: 2 h

Procedure:
In a 100-ml tightly-sealed glass vessel were charged 9.36 g of 2-methyl-4-benzylidene-5-oxazolone and 30 ml of water. Then, 5.3 g of 45% sodium hydroxide solution was added thereto and the resulting mixture was stirred at 40°-45° C. for two hours. The 2-methyl-4-benzylidene-5-oxazolone was hydrolyzed to form an aqueous homogeneous solution of sodium α-acetylaminocinnamate. The solution had a pH in excess of 12. 0.2 g of 5%-palladium-carbon was then added to the solution. After the gas phase in the vessel was purged with nitrogen and then with hydrogen, the reaction mixture in the vessel was subjected to catalytic reduction at 40°-45° C. under atmospheric pressure. The time required for the reduction was approximately four hours. After completion of the reduction, the reaction mixture was treated in the same manner as in Example 1 to obtain 9.91 g of N-acetylphenylalanine as a white crystal. Its melting point was 149.5°-150.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:17].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:17][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=3)=[CH:7][C:2]=2[Cl:1])=[CH:21][CH:20]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Reactant: OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(F)cc(Oc2ccc(OCc3ccc(Cl)cc3)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A mixture of 0.95 g of 2-chloro-4-(3,5-difluorophenoxy)phenol, 0.54 g of p-chlorobenzyl alcohol, 1.01 g of triphenylphosphine, 0.65 g of diethylazadicarboxylate and 90 ml of tetrahydrofuran was stirred at room temperature. After 48 hours, the reaction mixture was concentrated, and 50 ml of diethyl ether was added thereto. The precipitate were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to give 0.87 g of 4-chloro-1-[2-chloro-4-(3,5-difluorophenoxy)phenoxy]methylbenzene. Yield, 62%. m.p.: 95.3° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:10]/[CH:11]=[C:12](\[CH2:18][CH2:19][CH2:20][F:21])/[C:13]([O:15]CC)=[O:14])=O)(C)(C)C.Cl>O>[NH2:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10]/[CH:11]=[C:12](\[CH2:18][CH2:19][CH2:20][F:21])/[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)/C(=C/C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCF
Agent: Cl
Solvent: O
Product: N[C@@H](C/C=C(\CCCF)C(=O)O)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (1e) (80.0 mg, 0.20 mmol) and 4 N aqueous hydrochloric acid (1 mL) was heated to reflux for 4 h. The mixture was then cooled to r.t., diluted with water (5 mL) and lyophilised. The crude product was purified by preparative HPLC (XBridge C18, 5 μm 150×19 mm, acetonitrile/water (0.1% TFA) gradient, 21 mL/min). Yield: 12.0 mg, 0.04 mmol, 19%.