Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22].[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:22][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:13][CH2:14][C:15]=2[C:5]=1[O:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[F:23]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1F
Yield: 81.5 %

Procedure:
Dissolve 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.297 mmol) in DCM (5 mL). Add 2-fluorobenzoyl chloride (39 μL, 0.326 mmol), triethylamine (62 μL, 0.445 mmol) and stir at ambient temperature for 72 h under nitrogen atmosphere. Dilute with DCM, add 1M aqueous HCl and extract the aqueous phase with DCM. Dry the combined organic extracts over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3 and 2:1) to give 7-chloro-6-[2-(2-fluorobenzoylamino)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (111 mg, 82%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[Si:35]([O:42][C:43]([C@@H:46]1[CH2:51][CH2:50][C@H:49](O)[CH2:48][CH2:47]1)([CH3:45])[CH3:44])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[Si:35]([O:42][C:43]([C@H:46]1[CH2:47][CH2:48][C@H:49]([O:34][C:31]2[CH:32]=[CH:33][C:28]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[CH2:1][CH3:2])=[CH:29][CH:30]=2)[CH2:50][CH2:51]1)([CH3:45])[CH3:44])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(O[C@H]3CC[C@H](C(C)(C)O[Si](C)(C)C(C)(C)C)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.58 g), cis-4-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)cyclohexanol (1.05 g) and triphenylphosphine (1.01 g) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (2.0 mL, 1.9 M toluene solution), and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 54%).
Reaction SMILES: [NH2:1][C@H:2]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.[NH:31]([N:43]=[N+:44]=[N-:45])[C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(=O)OCC>[NH:31]([N:43]=[N+:44]=[N-:45])[C@H:32]([C:40]([NH:1][C@H:2]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:8][CH:9]=1)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=NN[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-]
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
H-Phe(4-CH2NHBoc)-Leu-OMe 80 (68 mg, 161 μmol, 1 equiv.) was dissolved in DCM (5 ml) and N3-Phe-OH (37 mg, 193 μmol, 1.2 equiv.), HBTU (79 mg, 209 μmol, 1.3 equiv.) and DiPEA (67 μl, 403 μmol, 2.5 equiv.) were added and the mixture was stirred for 90 minutes before being washed with 1M HCl (2×), sat aq. NaHCO3 (3×) and dried over Na2SO4. Column chromatography (10% EA:tol->35% EA:tol) yielded the title compound (71 mg, 119 μmol, 74%). 1H NMR (400 MHz, CDCl3): δ ppm 7.40-7.20 (m, 5H), 7.17 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.9 Hz, 2H), 6.97 (d, J=8.1 Hz, 1H), 6.34 (d, J=7.5 Hz, 1H), 4.93 (s, 1H), 4.67 (dd, J=14.3, 7.1 Hz, 1H), 4.51 (td, J=8.2, 5.4 Hz, 1H), 4.26 (d, J=5.2 Hz, 2H), 4.16 (dd, J=8.2, 4.2 Hz, 1H), 3.70 (s, 3H), 3.24 (dd, J=14.1, 4.1 Hz, 1H), 3.08-2.82 (m, 3H), 1.62-1.46 (m, 3H), 1.45 (s, 9H), 0.88 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ ppm 172.71, 169.82, 168.38, 155.80, 137.63, 135.83, 135.00, 129.51, 129.42, 128.60, 127.81, 127.24, 79.36, 65.13, 54.03, 52.25, 50.80, 44.37, 41.36, 38.33, 37.89, 28.33, 24.70, 22.58, 21.91.
Reaction SMILES: Cl.Cl.[CH:3]1([C@H:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[NH2:7])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Br[C:28]1[C:29]2[CH2:37][N:36]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)[CH2:35][CH2:34][C:30]=2[N:31]=[CH:32][N:33]=1.O>C(#N)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([N:36]2[CH2:35][CH2:34][C:30]3[N:31]=[CH:32][N:33]=[C:28]([NH:7][C@H:6]([CH:3]4[CH2:5][CH2:4]4)[C:8]4[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=4)[C:29]=3[CH2:37]2)=[N:39][CH:40]=1
Reactant: N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1ccc([C@H](Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)C2CC2)cn1
Temperature: 180 °C
Yield: 30.7 %

Procedure:
To a stirred solution of (R)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methanamine dihydrochloride (53 mg, 0.184 mmol) and N,N-diisopropylethylamine (60 uL, 0.4 mmol) in acetonitrile (1.2 mL) was added 4-bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (30 mg, 0.092 mmol). The reaction mixture was heated in microwave reactor at 180° C. for 8 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to obtain a brown oil which was purified using HPLC (semi-prep 30-80% water/acetonitrile) to give a light brown solid (13 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]1.F[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10]1
Reactant: Fc1cnccn1
Reactant: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC1=N[C@](CF)(c2cc(Oc3cnccn3)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a microwave vial were added N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (95 mg, 0.229 mmol), 2-fluoro-pyrazine (24.74 mg, 0.252 mmol), cesium carbonate (90 mg, 0.275 mmol) in DMSO (459 μL). The vial was heated in microwave instrument at 100° C. for 30 min. After cooling to room temperature, water was added to the reaction mixture and precipitate was observed. After stirring for 10 min, the precipitate was collected by filtration, washed with water and hexane, dried in vacuum oven at 60° C. for 1 h to provide N-((4S,6S)-4-(2-fluoro-5-(pyrazin-2-yloxy)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (85 mg, 0.173 mmol, 75% yield) as off-white solid. MS m/z=493 [M]+. Calculated for C23H17F5N4O3: 492.4.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.O>CN1CCCC1=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1C
Temperature: 160 °C
Reaction time: 8.5 h
Yield: 69.6 %

Procedure:
In 25 mL of N-methyl-2-pyrrolidinone were dissolved 17.0 g of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 7.39 g of ethyl 2-(6-chloro-3-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, and stirred at 160° C. for 8.5 hours. After cooling, a water was added and extracted with ethyl acetate. The extract was washed with a saturated brine solution and dried over magnesium sulfate. Following to concentration under reduced pressure. The residue was subjected to silica gel column chromatography to be eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated to yield 10.4 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily material. In 100 mL of ethanol was dissolved this oily material, and 18.3 mL of a 5N aqueous sodium hydroxide solution was added thereto and heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with diisopropyl ether. The aqueous layer was adjusted to pH 5 by the addition of 5N hydrochloric acid. The crystals formed were collected by filtration, recrystallized from methanol-water (10:1), and dried to yield 4.09 g (of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](N)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:12][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O>[F:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1
Reactant: F[B-](F)(F)F
Reactant: COc1cc(N)cc(OC)c1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COc1cc(F)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a mixture of 3,5-dimethoxybenzenamine (6.12 g, 40.0 mmol) and tetrafluoroboric acid (8% solution, 70 mL) was added dropwise a solution of sodium nitrite (2.84 g, 41.2 mmol) in water (10 mL). After stirring at room temperature for 30 min, the reaction mixture was filtered. The solid was collected and washed with water (2×10 mL) and dried under high vacuum. The resulting red solid was suspended in dry hexane (50 mL) and heated to reflux for 2 hr. The mixture was filtered and the filtrate was concentrated to give the crude product as a yellow oil (3.03 g, Yield: 48.5%). MS (ESI) m/z=157 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=O)=[CH:4][CH:3]=1.[CH3:14]OC(OC)N(C)C.[NH:22]([C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH2:23].[OH-].[Na+]>Cl.O>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:22]1[C:9](=[O:11])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][NH:23]1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Reactant: NNc1ncccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c(-c2ccc(Cl)cc2)c[nH]n1-c1ncccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.4 %

Procedure:
19.9 g (0.1 mole) of ethyl 4-chloro-phenylacetate are heated at 100° C. with 23.8 g (0.2 mole) of dimethylformamide dimethyl acetal for 5 hours. All the volatile constituents are then distilled off at this temperature under a waterpump vacuum. The oily residue, which essentially consists of ethyl α-dimethylaminomethylene-4-chlorophenylacetate, is dissolved, without further purification, in 140 ml of ethanol. 11 g (0.1 mole) of 2-hydrazinopyrimidine and 10 ml of concentrated hydrochloric acid are added. The mixture is heated under reflux for 5 hours, cooled to room temperature and, after addition of 9 g of concentrated sodium hydroxide solution, stirred at room temperature for 5 hours. After neutralization with dilute hydrochloric acid, the mixture is diluted with 1 liter of water. The crystals which have separated out are filtered off with suction, washed with water and dried in air. 7.2 g (26.4% of theory) of 1-pyrimid-2-yl-4-(4-chloro-phenyl)pyrazolin-5-one are obtained. Melting point: 190° to 191° C. (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([CH2:16][CH2:17][CH3:18])[NH:20][C:21]2=[N:22][N:23]([CH3:26])[CH:24]=[C:25]12
Reactant: Cn1ccc(N)n1
Reactant: CCCC(=O)C(=Cc1ccccc1Cl)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2Cl)c2cn(C)nc2N1

Procedure:
A solution of ethyl 3-ketohexanoate (7.5 g), 2-chlorobenzaldehyde (6.6 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 ml) was heated under reflux for 5 hours, and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. A solution of ethyl 2-(2-chlorophenyl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture, 2.8 g), 3-amino-1-methylpyrazole (0.25 g) and p-toluenesulfonic acid (25 mg) in toluene (5 mL) and dimethylsulfoxide (0.5 mL) was heated under reflux for one day. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent (ethyl acetate-methanol (10:1))) to give the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O[N:25]([CH:34]=C=O)[C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27](O)=[O:28])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl>CN(C)C=O.O1CCOCC1>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:27](=[O:28])[C@@H:26]([NH:25][CH3:34])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: CC(C)C[C@@H](C(=O)O)N(C=C=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN[C@@H](CC(C)C)C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 54F and (5)-2-(tert-butoxy-carbonyl(methyl)amino)-4-methylpentanoic acid (51.8 mg, 0.211 mmol) in anhydrous N,N-dimethylformamide (2.5 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.288 mmol) and 4-methylmorpholine (0.042 mL, 0.384 mmol). The resulting mixture was stirred at room temperature for 90 minutes and then was partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of 1,4-dioxane (1 mL) and hydrogen chloride (4 N in 1,4-dioxane, 1 mL, 4.00 mmol), and the resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 solution and dichloromethane (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane. The title compound was obtained as a colorless solid (53 mg, 71%). 1H NMR (300 MHz, CDCl3) δ ppm 0.87-1.03 (m, 10 H), 1.23-1.52 (m, 2 H), 1.76-2.06 (m, 4 H), 2.17-2.49 (m, 6.5 H), 2.74-2.96 (m, 1 H), 2.98-3.10 (m, 1 H), 3.12-3.26 (m, 0.5 H), 3.36-3.52 (m, 1 H), 3.73 (dd, J=9.83, 6.78 Hz, 1 H), 3.88 (d, J=13.22 Hz, 0.5 H), 4.00 (d, J=12.55 Hz, 0.5 H), 4.66 (d, J=13.56 Hz, 0.5 H), 4.81 (d, J=11.87 Hz, 0.5 H), 5.31-5.42 (m, 1 H), 7.92-7.97 (m, 1 H), 8.00-8.06 (m, J=7.80 Hz, 1 H); MS (ESI) m/z 388 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:13]([OH:26])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[O:27]1[CH:31]=[CH:30][CH2:29][CH2:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1([N:13]([O:26][CH:28]2[CH2:29][CH2:30][CH2:31][O:27]2)[C:14](=[O:25])[CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1(N(OC2CCCO2)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1

Procedure:
To a solution of 4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (70 g, 192.1 mmol) in dichloromethane (1500 ml) under argon atmosphere was added 2,3-dihydro-furan (29.1 ml, 26.9 g, 384.1 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (1.94 g, 19.2 mmol). The reaction mixture was stirred at reflux for 7 hours, filtered and concentrated. The residue was triturated with hexane, filtered and the solid dried in vacuo. Yield: 70.0 g of 1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (compound P3ii.6) as a solid, mp 107-109° C. This material was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:21])([F:20])[CH2:18]I.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:18][C:17]([F:21])([F:20])[F:16]
Reactant: FC(F)(F)CI
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 10 h
Yield: 87.3 %

Procedure:
To a solution of 2-Methoxy phenol (IX) (5 g, 0.04 moles) in N-methylpyrrolidone (50 ml) were added, potassium carbonate (7.8 g, 0.06 mole) and 2,2,2-trifluoroethyl iodide (33.8 g, 0.16 mole) under stirring. The reaction mixture was stirred vigorously at 120° C. for 10 hours. Water (150 ml) was added to the reaction mixture and the mixture was extracted in Toluene (250 ml). Organic layer was washed with 1 N Sodium hydroxide solution (150 ml), followed by brine wash. The extract was dried over sodium sulphate. The solvent was evaporated under reduced pressure to give 7.2 g of (X) as oil. Purity (by GC)=94%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl.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.[Cu]I>[N+:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([O-:14])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#C[Si](C)(C)C)cc([N+](=O)[O-])c1
Yield: 88 %

Procedure:
A solution of methyl 3-bromo-5-nitrobenzoate (0.331 g, 1.27 mmol), (trimethylsilyl)acetylene (0.27 mL, 1.9 mmol), bis(triphenylphosphine)palladium(II) chloride (45 mg, 0.064 mmol), copper(I) iodide (19 mg, 0.10 mmol) and triethylamine (0.26 mL, 1.9 mol) in DMF (5 mL) was stirred at room temperature overnight. The solution was diluted with ethyl acetate and 1 N HCl. The aqueous layer was extracted with ethyl acetate once, and the combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the desired product (310 mg, 88%). LCMS for C13H16NO4Si (M+H)+: m/z=278.1.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 120 °C
Yield: 76 %

Procedure:
To N,N-dimethylformamide (50 ml) are added 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (3.04 g), 2-chloro-5-trifluoromethyl pyridine (1.70 g) and potassium carbonate (1.40 g), which is heated at 120° C. for 2 hours with stirring. After cooling to room temperature, the reaction solution is poured into water and extracted with ethyl acetate, and the layer is washed with water and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the crude solid is purified by silica gel column chromatography using mixed solution of hexane-ethyl acetate as eluent to give 3.30 g of desired compound (melting point: 116.0°-117.0° C.).