Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([CH3:10])=[CH:9][N:4]2[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[OH:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[S:6][C:5]3=[N:7][C:8]([CH3:10])=[CH:9][N:4]3[N:3]=2)[CH:16]=[CH:15][C:14]=1[OH:28]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Cc1cn2nc(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2nn3cc(C)nc3s2)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (1.53 g, 7.02 mmol, 1 eq) in dioxane (30 mL), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.76 g, 7.02 mmol, 1 eq) was added followed by 2M aq. Na2CO3 (15 mL, 30 mmol, 4.3 eq). The suspension was degassed (N2, 15 min) and equipped with an argon balloon. Pd(Ph3P)2Cl2 (1.23 g, 1.75 mmol, 0.25 eq) was quickly added, and the reaction flask was placed in a pre-heated bath (115° C.). After stirring at reflux temperature for 2 h the reaction mixture was cooled to RT and concentrated. The residue was taken in water and extracted with DCM; the organic phase was washed with water, dried and concentrated to give 2-methoxy-4-(6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)phenol as a crude product (brown solid, 3 g) that was used in the next step without further purification. HPLC-MS (10-95% B in 4 min +2 min 100% B, flow 0.5 mL/min, 50° C.): tR=3.27 min, [M+H]+ m/z 262.0
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[OH-].[Na+].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Temperature: 25 °C

Procedure:
The intermediate from step A (890 mg, mmol) was suspended in POCl3 (5 mL) and refluxed for 1 hour. The reaction was cooled to room temperature and poured into an erlenmeyer flask containing ice and 5 N NaOH (30 mL). The resulting mixture was extracted with ethyl acetate (3×). The organic layer was washed with saturated NaHCO3, saturated NaCl solution dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate-hexanes to afford the product as a white solid. 1H NMR (500 MHz, CDCl3): 9.19 (s, 1H), 8.33 (s, J=9.2 Hz, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.36 (dd, J=2.5, 9.1 Hz, 1H), 4.53 (q, J=7.1 Hz, 2H), 4.01 (s, 3H), 1.5 (t, J=7.4 Hz, 3H). LC-MS: 3.22 min; (M+H)=266.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[CH3:21])=O.[BH4-].[Na+].CCOC(C)=O.CCCCCC>C1COCC1.CO>[CH3:21][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Yield: 98.7 %

Procedure:
To a 0° C. solution of 3-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (300 mg, 1.02 mmol) in THF/MeOH (10/3 mL) is added portion-wise sodium borohydride (386 mg, 10.20 mmol) and heated to reflux. After 1 h TLC (20% EtOAc/hexane) indicates complete consumption of starting material. The reaction mixture is concentrated and the residue is partitioned between EtOAc (100 mL) and 0.2N HCl (20 mL). The aqueous layer is extracted with a second portion of EtOAc (50 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound (268 mg, 99%). 1NMR (400 MHz, CDCl3) δ ppm: 7.69 (s, 4H), 7.50-7.39 (m, 3H), 4.77 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:12]=2)=[N:8][CH:9]=1)[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[CH:25]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[CH:17]=[C:18]2[CH2:23][CH2:22][N:21]([C:31]([NH:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[O:32])[CH2:20][CH2:19]2)=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
To a solution of 5-ethoxy-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.22 g, 0.708 mmol) in DMSO (4 mL) was added phenyl pyridin-3-ylcarbamate (0.151 g, 0.708 mmol) followed by triethylamine (0.265 mL, 2.12 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (38% acetone, 62% hexane) to give the title compound (0.17 g, 55%). 1H NMR (500 MHz, CDCl3): δ 8.44 (d, J=1.8 Hz, 1H), 8.25 (d, J=4 Hz, 1H), 8.0 (s, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.23 (m, 3H), 6.97 (d, J=4.05 Hz, 3H), 692 (d, J=4 Hz, 2H), 6.86 (d, J=8.8, 1H), 6.38 (s, 1H), 4.03 (t, J=6.95, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.49 (t, J=5.6 Hz, 2H), 2.56 (t, J=5.7 Hz 2H), 2.43 (t, J=5.1 Hz, 2H), 1.40 (t, J=8.25 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 157.32, 155.27, 154.5, 151.85, 143.96, 141.15, 128.78, 137.64, 136.16, 133.59, 129.42, 127.40, 126.82, 124.83, 124.57, 123.58, 120.54, 118.31, 112.54, 64.62, 53.43, 45.71, 44.71, 41.01, 35.73, 29.14, 14.82; m/z (431.2, M+ H+); HPLC: 98.8%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:20]Br.O>CC(O)=O>[Br:20][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:5]=1
Reactant: BrBr
Reactant: Clc1nccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nc(Br)cnc1N1CCNCC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a mixture of 2-chloro-3-(1-piperazinyl)pyrazine (5.94 g, 30 mmol, from Example 90, Step 1) and Na2CO3 (6.0 g, 57 mmol) in AcOH (25 mL) was added a solution of Br2 (6.00 g, 38.0 mmol) in AcOH (25 mL) dropwise at room temperature. The reaction mixture was stirred overnight. Water (50 mL) was added and the solution was stirred for 30 min and then concentrated to a small volume. Water (20 mL) was added and the solution was basified to pH 9 by adding solid Na2CO3. The mixture was extracted with CH2Cl2 containing 10% MeOH. The combined extract was evaporated to dryness and the residue was recrystallized from MeOH to give 7.43 g (89%) of the title compound: mp 114-115° C. HRMS m/z calcd for C8H10BrClN4 (M)+ 275.9777, found 275.9765.
Reaction SMILES: C(OC([NH:11][CH:12]([CH3:23])[C:13](=[O:22])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:20][C:14]1([CH3:21])[C:13](=[O:22])[CH:12]([CH3:23])[NH:11][C:15]1=[O:16]
Reactant: CCOC(=O)C(C)(C)C(=O)C(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1NC(=O)C(C)(C)C1=O
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-oxopentanoate (10.5 g) in methanol (150 mL) was added 10% palladium carbon (containing 50% water, 5.0 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound as a colorless solid (yield: 4.00g, 87%).
Reaction SMILES: [CH3:1][C:2]([CH2:5][CH3:6])=[CH:3][CH3:4].[CH2:7]([CH:9]([CH2:13][CH2:14][CH2:15]C)[C:10]([O-:12])=O)C.[C]=O.[H][H]>>[CH3:1][C:2]([CH2:5][CH3:6])=[CH:3][CH3:4].[CH3:7][CH:9]([CH:13]([CH3:1])[CH2:14][CH3:15])[CH:10]=[O:12]
Reactant: [H][H]
Reactant: CCCCC(CC)C(=O)[O-]
Agent: CC=C(C)CC
Agent: [C]=O
Product: CCC(C)C(C)C=O
Reaction time: 7 h

Procedure:
400 g of 3-methyl-2-pentene as well as 40 mg Rh (in the form of 2-ethylhexanoate) were introduced into a high pressure vessel (volume 2.1 liters) and were reacted with an equimolar mixture of carbon monoxide and hydrogen at 90° C. and 260-270 bar. The reaction was completed in 7 hours, after which the pressure was relieved and the reactor allowed to cool. The composition of the crude reaction product was determined by a vacuum distillation and a gas chromatographic analysis. With a 99.9% 3-methyl-2-pentene conversion, 81.3% of isomeric C7 aldehydes was obtained as 2,3-dimethylpentanal (cf. Table 1, Exp. 1).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23]N)=[CH:18][N:17]=1.CCN(CC)CC>>[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23][NH:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][N:17]=1
Reactant: NCc1cnc(N)nc1N
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Nc1ncc(CNC(c2ccccc2)c2ccccc2)c(N)n1

Procedure:
W=CH2NH; X=CH; Z=non-linked hydrogens on each phenyl group; m=n=0) is prepared similarly to N-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)amino]benzhydrylamine as disclosed above by using benzhydrylamine (366 mg, 2.0 mmol), 2,4-diamino-5-aminomethylpyrimidine (278 mg, 2.0 mmol), mg, 2 mmol), and BH3.Et3N (75 mg, 6.6 mmol). The product can be purified by chromatography.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:12][CH:13]1[CH2:20][CH2:19][CH2:18][NH:17][C:15](=O)[CH2:14]1)(OCC)=[O:8].O>O1CCCC1>[OH:8][CH2:7][CH2:12][CH:13]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC1CCCNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1CCCNCC1

Procedure:
To a stirred slurry of lithium aluminium hydride (5.70 g) in dry tetrahydrofuran (100 ml) was added β-carbethoxymethyl-caprolactam (10.3 g) in dry tetrahydrofuran (150 ml) over a period of 30 minutes. The mixture was refluxed for 2.5 hours, cooled and treated very slowly with water. The precipitate was filtered off and the filtrate was evaporated to yield the title compound as a viscous oil, which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:44].[N:45]1([CH2:51][CH2:52][C:53](O)=[O:54])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.Cl>CCOCC.C(Cl)Cl>[ClH:44].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:53](=[O:54])[CH2:52][CH2:51][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.12 g. (8.2 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-p-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c] [1]benzopyran, prepared according to the method of Example 6, 1.77 g. (8.6 mmoles) of dicyclohexylcarbodiimide and 1.65 g. (8.5 mmoles) of β-piperidinopropionic acid hydrochloride (m.p. 216° - 220°, J. Am. Chem. Soc. 73, 3168 (1951) are combined with 125 ml. of methylene chloride and stirred at room temperature for about 20 hours. The reaction mixture is filtered and the methylene chloride removed using a rotary evaporator. The residue is treated with benzene and filtered to remove a small quantity of insoluble material. The benzene is evaporated and the dark, viscous residue is chromatographed using 100 g. of 60 - 100 mesh Florosil activated magnesium silicate and methanol/chloroform graded solvent mixtures. Chromatography yields an oil which is dissolved in ether and treated with a solution of ethereal HCl. The desired compound appears as crystals which are filtered and washed with additional ether to obtain the desired product.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:5][CH2:4][N:3]1[C@H](C1C=CC=CC=1)C>[C].[Pd].CO>[OH:10][C:7]([C@H:6]1[CH2:5][CH2:4][NH:3][C@H:2]1[CH3:1])([CH3:9])[CH3:8]
Reactant: C[C@@H](c1ccccc1)N1CC[C@H](C(C)(C)O)[C@@H]1C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1NCC[C@@H]1C(C)(C)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 126.9 %

Procedure:
A mixture of 2-[(2S,3S)-2-methyl-1-[(1S)-1-phenylethyl]pyrrolidin-3-yl]propan-2-ol (2.00 g) synthesized by a known method, 10% palladium-carbon (50% water-containing product, 172 mg) and methanol (30 ml) was stirred under a hydrogen atmosphere at room temperature for 60 hr. The catalyst was removed by filtration through celite, and the mother liquor was concentrated. The obtained oily substance was dissolved in methanol, oxalic acid dihydrate (510 mg) was added thereto, and the mixture was concentrated. The residue was crystallized from diethyl ether to give the title compound (1.47 g, 1/2 hydrate).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cn1cccc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cccn1C
Yield: 5.6 %

Procedure:
Using 1-methyl-1H-pyrrole-2-carboxylic acid (93 mg, 0.74 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (135 μL, 1.48 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 119, the title compound (15 mg, 6%) was obtained as a white powder.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([N:13]([CH3:15])[NH2:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[C:1]1([C:7]2[N:12]=[N:11][C:10]([N:13]([CH3:15])[NH:14][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(N)c1ccc(-c2ccccc2)nn1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NN(C)c1ccc(-c2ccccc2)nn1

Procedure:
A solution of 4.4 g. of 6-phenyl-3-(1-methylhydrazino)pyridazine, 3.4 g. of N,N-diisopropylethylamine and 50 ml. of dixane is prepared. To the solution is added 2.6 g. of ethyl chloroformate and the mixture is stirred for 2 hours. The solvent is removed under vacuum and to the residue is added ethanol and water. Filtration gives the product which is recrystallized from ethanol to give crystals, m.p. 129°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20](O)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]([O:41][C:42](=[O:65])[NH:43][C@@H:44]([C:54]1[S:55][C:56]([C@@H:59]([NH2:64])[C:60]([F:63])([F:62])[F:61])=[CH:57][CH:58]=1)[CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH:39]=[CH2:40].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:38]([O:41][C:42](=[O:65])[NH:43][C@@H:44]([C:54]1[S:55][C:56]([C@@H:59]([NH:64][C:20](=[O:21])[C@H:6]([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:5][C:3]([O:2][CH3:1])=[O:4])[C:60]([F:61])([F:62])[F:63])=[CH:57][CH:58]=1)[CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH:39]=[CH2:40]
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc([C@@H](N)C(F)(F)F)s1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc([C@@H](NC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (3.2 g, 10.6 mmol) in dichloromethane (70 mL) was cooled to −15° C., and then was added N-methylmorpholine (1.17 mL, 10.6 mmol) and isobutyl chloroformate and the mixture was stirred for 30 minutes. A solution of prop-2-en-1-yl[(1R)-1-{5-[(1S)-1-amino-2,2,2-trifluoroethyl]thiophen-2-yl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]carbamate (3.1 g, 7.07 mmol) and Hunig's base (1.48 mL, 8.48 mmol) in dichloromethane (70 mL) cooled to −15° C. was added to the mixed anhydride solution. The mixture was allowed to warm up to room temperature by stirring overnight. Sodium bicarbonate was added and the phases were separated using a phase separator and concentrated under reduced pressure. The crude was purified on silica gel using 10% to 60% ethyl acetate in hexane to provide the title compound as an oil. MS: m/z=742.2 (MNa+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:15][O:16][CH2:17][C:18]([N:8]1[C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:19]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCCN2
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COCC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (203 mg, 1.04 mmol) and 4-Dimethylaminopyridine (13 mg, 0.10 mmol) in Pyridine (3.5 mL) was treated with Methoxyacetyl chloride (0.15 mL, 1.6 mmol) was added to the vial and stirred at rt. After 4 h, the mixture was partitioned between EtOAc and water, separated and the org. layer was washed with 1N HCl. After washing with brine and drying, 2-Methoxy-1-(3-nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone was isolated following silica gel chromatography (0-100% EtOAc:Hex) as yellow solids (270 mg, 97%). 1H-NMR (CDCl3): 7.96 (m, 2H), 7.36 (m, 1H), 4.82 (m, 1H), 4.25 (m, 2H), 3.89 (m, 3H), 3.34 (s, 3H), 2.96 (m, 1H), 2.13 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH2:21][O:22][CH2:23][C:24](=[O:26])[NH2:25])=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:24]([CH2:23][O:22][CH2:21][C@@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]1)(=[O:26])[NH2:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COCC(N)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)COC[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(carbamoylmethyloxymethyl)pyrrolidine (0.60 g) in a mixture of trifluoroacetic acid (3 ml) and anisole (0.6 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4hydroxypyrrolidine. To a solution of the compound obtained above in a mixture of water (20 ml) and tetrahydrofuran (20 ml) was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.50 g) in tetrahydrofuran (5 ml) under icecooling with stirring, keeping the pH between 8.5-9.5 with 1N aqueous sodium hydroxide. The mixture was stirred at the same condition for 1 hour and extracted with ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 and then 2:98 V/V) to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.32 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C(#N)C>[CH2:24]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)=[O:8])[CH2:10][CH2:11]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
(3 g, 12.3 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride was suspended in acetonitrile (60 mL) and triethylamine (4.29 mL, 3-1 mmol), benzylbromide (1.61 mL, 14 mmol) and sodium iodide (2.8 g, 18 mol) were added. The mixture was stirred at 80° C. overnight and after cooling the mixture was filtrated, water was added and the aqueous phase was extracted with 100 mL of dichloromethane. The combined organic phases were dried with magnesium sulfate, filtrated concentrated and purified with column chromatography on silica using dichloromethane/Methanol (95/0.5) to yield 3.6 g, (12 mmol, 99% yield) of the title compound as a brown solid. MS (m/e): 298.4 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.[CH3:24][Zn]Cl>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:24])=[C:3]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[CH:4]=[CH:5]2
Reactant: C[Zn]Cl
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of methyl 4-(1-bromo-6-methoxynaphthalen-2-yl)benzoate (300 mg, 0.811 mmol) (see Example 12 step 1), MeZnCl (1.2 mL, 2.40 mmol, 2M in THF) and Pd(PPh3)4 (93.8 mg, 0.0811 mmol) in anhydrous THF (10 mL) was stirred at 60° C. under N2 atmosphere for 16 hours. After cooling to room temperature, the mixture was quenched with saturated aqueous NH4Cl (20 mL), extracted with EtOAc (20 mL×3). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (PE/EtOAc=300/1 to 200/1) to give the product (210 mg, yield 85%) as a solid.