Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:13]([CH2:20][C:21]([NH:23][C:24]1[NH:25][C:26](=[O:41])[C:27]2[N:28]=[CH:29][N:30]([C:39]=2[N:40]=1)[C@@H:31]1[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[CH2:32]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:37][CH2:36][C@H:35]2[O:38][C@@H:31]([N:30]3[C:39]4[N:40]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[NH:25][C:26](=[O:41])[C:27]=4[N:28]=[CH:29]3)[CH2:32][C@@H:33]2[OH:34])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 2-N-phenoxyacetyldeoxyguanosine for 16 hours in pyridine. After extraction with a dichloromethane/sodium bicarbonate mixture and evaporation to dryness, the product is taken up in chloroform and purified on a silica column (elution 4% methanol). The product is only slightly soluble in organic solvents.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].N(CCO)(CCO)CCO.C(OCC)(=O)C>C(O)C>[OH:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=CC(C)=CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCN(CCO)CCO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C=CC(C)=CCO
Yield: 71.2 %

Procedure:
27.5 g of ethyl 6-acetoxy-4-methyl-2,4-hexadienoate, 20 g of sodium carbonate and 2 ml of triethanolamine were heated to reflux for 3 hours in 250 ml of ethanol. After the addition of ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Distillation at 110° C./0.4 mmHg gave 15.7 g (71%) of ethyl 6-hydroxy-4-methyl-2,4-hexadienoate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[N:3][C:2]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([OH:44])=[C:30]([Cl:43])[CH:31]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, {6-chloro-4-[trans-4-(dimethylamino)cyclohexyl-amino]-1,5-naphthyridin-3-yl}(cyclopropyl)methanone (50 mg, 0.13 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 g, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (65 g, 84%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.43 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.11 (s, 2H), 5.64-5.54 (m, 1H), 3.51-3.44 (m, 1H), 2.91 (s, 6H), 2.93-2.89 (m, 1H), 2.63-2.56 (m, 2H), 2.32-2.24 (m, 2H), 1.87-1.68 (m, 4H), 1.33-1.18 (m, 4H).; ESI MS m/z 499 [M+H]+; HPLC>99% (AUC), tR=10.12 min.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH3:21])([CH3:20])[C:11]1([CH2:14][O:13][CH2:12]1)[C:10]2=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH3:21])([CH3:20])[C:11]1([CH2:14][O:13][CH2:12]1)[C:10]2=[CH2:1]
Reactant: CC1(C)Oc2ccc(Br)cc2C(=O)C12COC2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2OC(C)(C)C12COC2
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (8.13 g, 22.3 mmol) in THF (44 mL) was added n-butyllithium (1.65 M in n-hexane, 13.5 mL, 22.3 mmol) in a dry ice-acetone bath under argon atmosphere. The mixture was stirred for 60 minutes in an ice bath. To the mixture was added a mixture of 6-bromo-2,2-dimethyl-4H-spiro[chromene-3,3′-oxetan]-4-one (2.21 g, 7.44 mmol) and THF (11 mL) in an ice bath. The mixture was stirred for 1 hour at ambient temperature. The reaction was quenched by adding water in an ice-water bath. The mixture was partitioned between EtOAc-hexane (1:2) and water. The organic layer was washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated. Purification using silica gel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 20%) afforded 6-bromo-2,2-dimethyl-4-methylene-4H-spiro[chromene-3,3′-oxetane] (2.02 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][NH2:10])([CH3:3])[CH3:2].[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH:24]=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.[BH4-].[K+]>C1(C)C=CC=CC=1>[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24][NH:10][CH2:9][CH2:8][O:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=Cc1cccc(OC2CCCC2)c1
Reactant: CC(C)Oc1ccccc1OCCN
Agent: [BH4-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccccc1OCCNCc1cccc(OC2CCCC2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.5 g of 2-(2-isopropoxyphenoxy)ethylamine (2.56 mmol) and 0.49 [lacuna] of 3-cyclopentyloxybenzaldehyde (2.56 mmol) are mixed together in 20 ml of toluene. The solution is refluxed for 12 hours, while continuously removing the water formed. The toluene is then evaporated off, the residue is taken up in 20 ml of methanol and the solution is cooled to 0° C. 0.28 g of potassium borohydride (5.12 mmol) is added portionwise and the mixture is stirred for 3 hours at room temperature. The methanol is evaporated off, the residue is taken up in dichloromethane and the organic phase is washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. The title product is isolated by chromatography on a column of silica (eluent: 98/1.5/0.5 dichloromethane/methanol/aqueous ammonia). 0.77 g of the title product is obtained in the form of a pale yellow oil:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([N:10]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:33]([C:34]([O:36]C)=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:22])=[O:21])[CH3:11])=[O:9])[CH3:2].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([N:10]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:33]([C:34]([OH:36])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:22])=[O:21])[CH3:11])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@@H]1C(=O)N(C)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCC[C@@H]1C(=O)N(C)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 100 °C
Yield: 30.7 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-{N—[((R)-1-ethylpyrrolidine-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 155, 0.177 g) and lithium hydroxide monohydrate (0.136 g) in dioxane (5 mL) and water (2 mL) was stirred and heated at 100° C. for 19.5 hours. After cooling, the mixture was evaporated to dryness and the residue was acidified by addition of aqueous citric acid solution (10%). The resultant solid was collected by filtration, washed with water and dried under vacuum at 40° C. The solid was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-(2-{N—[((R)-1-ethylpyrrolidine-2-yl)carbonyl]-N-methylaminomethyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.053 g) as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][NH:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:27]=O.[Na]>C(O)C.[OH-].[Na+]>[CH3:27][N:15]1[CH2:16][C@@H:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][C@H:14]1[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:13]
Reactant: C=O
Reactant: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: CN1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine (26 mg, 0.072 mmol) in ethanol (EtOH; 1 mL) was added formaldehyde (37% in H2O; 150 μL) and sodium triacetoxyborohyrdide (46 mg, 0.216 mmol). After 18 h, the mixture was diluted with 1 M NaOH and, stirred for 1 h, and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. Purification by FCC provided the desired product (17 mg, 63%). MS (ESI): mass calcd. for C21H30FN3O2, 375.23; m/z found, 376.6 [M+H]+. 1H NMR (CDCl3): 6.97-6.91 (m, 2H), 6.80-6.73 (m, 2H), 4.77-4.70 (m, 1H), 3.85-3.53 (m, 4H), 3.37 (dd, J=10.7, 3.8 Hz, 1H), 3.15 (ddd, J=8.9, 8.8, 2.7 Hz, 1H), 2.88-2.78 (m, 1H), 2.66-2.57 (m, 1H), 2.51-2.44 (m, 3H), 2.40 (dd, J=10.9, 5.2 Hz, 2H), 2.35 (s, 3H), 2.16-2.07 (m, 1H), 2.06-1.98 (m, 2H), 1.91-1.78 (m, 4H), 1.71-1.56 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].[Cl-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:13][C:6]=1[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11]
Reactant: COC(=O)NCc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1F
Temperature: 90 °C
Reaction time: 48 h
Yield: 83.1 %

Procedure:
A mixture comprising 8.00 g of methyl N-(5-bromo-2-fluorobenzyl)carbamate, 4.50 g of trimethylsilylacetylene, 0.96 g of dichlorobis(triphenylphosphine)palladium, 0.47 g of copper(I) iodide and 30 ml of triethylamine, was stirred at 90° C. for 48 hours in an autoclave. This reaction solution was poured into a saturated sodium chloride aqueous solution and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7.09 g of methyl N-[2-fluoro-5-(trimethylsilylethynyl)benzyl]carbamate as a brown viscous liquid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].N([O-])=O.[Na+].[I-:14].[K+]>CS(C)=O.O.OS(O)(=O)=O.O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([I:14])=[C:3]([OH:9])[CH:4]=1
Reactant: [I-]
Reactant: Nc1ccc(Cl)cc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Oc1cc(Cl)ccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
2-Amino-5-chlorophenol (5.7 g, 40 mmol) is dissolved in DMSO/water/H2SO4 (200/60/140 mL) and cooled to 0° C. To this solution is added sodium nitrite (4.1 g, 60 mmol) in water (20 mL) and the mixture is stirred for 1 h at 0° C. To the mixture is added potassium iodide (19.9 g, 120 mmol) in water (20 mL) and the mixture is stirred at room temperature for 1 h. Another batch of potassium iodide (19.9 g, 120 mmol) in water (20 mL) is added and the mixture is stirred at room temperature for 1 h. The mixture is diluted with ethyl acetate, washed with water, saturated aqueous sodium sulfate, and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage™ Si65M, 20% ethyl acetate/hexane) to yield 8.09 g (79%) of the title compound as a pink solid. GCMS m/e 254 [M]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:29][C:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:12]3=[O:28])[CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:29][C:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:12]3=[O:28])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc([N+](=O)[O-])cnc3C2)c2cccnc21
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(N)cnc3C2)c2cccnc21
Reaction time: 4.5 h

Procedure:
A mixture of 10% Pd/C (20 mg) and (±)-3-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (117 mg, 0.284 mmol) was stirred vigorously in MeOH (5 mL) under an atmosphere of hydrogen (ca. 1 atm). After 4.5 h, the mixture was filtered through a pad of Celite, washing extensively with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=383 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53]([O:55][C:56](=[O:77])[CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:61][C:60]=1OS(C(F)(F)F)(=O)=O)[CH3:54].[NH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:53]([O:55][C:56](=[O:77])[CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:61][C:60]=1[N:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1)[CH3:54]
Reactant: C1COCCN1
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1N1CCOCC1
Reaction time: 12 h
Yield: 51.1 %

Procedure:
Palladium(II) acetate (1.4 mg, 0.006 mmole, 6 mol % eq), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7.5 mg, 0.012 mmole, 12 mol % eq), and cesium carbonate (50.3 mg, 0.155 mmole, 1.5 eq) were added into anhydrous toluene. 3-(4-tert-Butyl-2-trifluoromethanesulfonyloxyphenyl)acrylic acid ethyl ester (36.2 mg, 0.103 mmol, 1 eq) in toluene solvent was added by cannula. Morpholine (13.5 μl, 0.155 mmol, 1.5 eq) was added. The mixture was stirred for 12 hr in reflux. After confirming the completion of the reaction with TLC, the reaction mixture was filtered with celite. The filterate was concentrated in vacuo, and then the residue was purified with column chromatography(n-Hx:EA=12:1) to give title product (16.7 mg, 51.2%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13](OCC)=[N:12][S:11](=[O:18])(=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[CH3:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][CH2:43][NH2:44])=[O:40])[CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13]([NH:44][CH2:43][CH2:42][NH:41][C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=2)=[O:40])=[N:12][S:11](=[O:17])(=[O:18])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: Cc1cccc(NC(=O)NCCN)c1
Agent: O=C[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(NC(=O)NCCNC2=NS(=O)(=O)N=C2N[C@@H](Cc2ccc(O)cc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of N-(4-ethoxy-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-butyl ester from Step A (150 mg, 0.38 mmol) and the formate salt of 2-(3-methylphenylaminocarbonylamino)eth-1-ylamine from Step B (210 mg, 0.89 mmol) in ethanol (10 mL) was added triethylamine (133 mg, 1.44 mmol). The reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, 5% MeOH in EtOAc)to give N-[4-(2-(3-methylphenylamino-carbonylamino)eth-1-ylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]-L-tyrosine tert-butyl ester (130 mg, 91%). MS (+ESI, m/e) 545 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:7][CH2:8][O:9]CC1C=CC=CC=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][CH2:5][CH:6]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:7][CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCC(CCOCc1ccccc1)COC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCC(CCO)COC(C)=O
Yield: 91.6 %

Procedure:
To a solution of 2-acetoxymethyl-4-benzyloxy-but-1-yl acetate (55 g, 0.187 mol) in ethanol (250 ml) was added 10% palladium on carbon (2.5 g), and the mixture hydrogenated at atmospheric pressure and room temperature. When the theoretical hydrogen uptake had been achieved (18 hours), the reaction was stopped and filtered through Celite. Evaporation of the filtrate gave a colourless oil (35 g). This was purified by column chromatography on silica gel, elution with 2% methanol in chloroform affording 2-acetoxy-methyl-4-hydroxybut-1-yl acetate as a clear oil (32.9, 86%). δH (CDCl3) 1.61 (2H, q, CHCH2CH2), 2.04 (6H, s, 2×OCOCH3), 2.20 (1H, m, CH), 2.61 (1H, br s, D2O exchangeable, OH), 3.68 (2H, t, CH2OH), 4.04 (4H, d, 2×CH2OCOCH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2([OH:17])[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([CH2:8]O)[CH:7]=1.Cl>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:10]1([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)[O:17][CH2:8]2
Reactant: CN1CCC(O)(c2ccc(F)cc2CO)CC1
Agent: Cl
Product: CN1CCC2(CC1)OCc1cc(F)ccc12

Procedure:
Treatment of 4-(5-fluoro-α-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine with hydrochloric acid by the method described in Example 16d provides 1,3-dihydro5-fluoro-1'-methylspiro[isobenzofuran-1,4'-piperidine].
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:9]([N+:24]([O-:26])=[O:25])[CH:8]=1.S(OC)(O[CH3:31])(=O)=O.O>CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([N:11]([CH3:31])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[C:9]([N+:24]([O-:26])=[O:25])[CH:8]=1
Reactant: COCOc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.40 g (10.0 mmol)) in 15.0 ml of DMF, 4′-methoxymethoxy-2′-nitro-p-toluenesulfonanilide (3.00 g (8.51 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (1.0 ml (10.6 mmol)) was added and the mixture was stirred for 15 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) to give 2.91 g (93%) of the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccco2)CC1

Procedure:
t-Butyloxycarbonyl piperazine (2.0 g, 10.7 mmol) was reacted with furancarbonyl chloride (1.40 g, 10.7 mmol) by the method of Example 4. Following chromatography, a 2.25 g sample of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5](Cl)[C:6](=O)[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[S:28])=[CH:25][CH:24]=1>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[S:28][C:27]([C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:32])([F:21])[F:33])=[CH:31][CH:30]=2)=[N:29][C:6]=1[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(=O)CCCOCc1ccccc1
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCOCc1ccccc1
Yield: 66.5 %

Procedure:
To a solution of 1.15 g of 6-benzyloxy-2-chloro-3-oxo-hexanoic acid ethyl ester in 10 ml of ethanol was added 0.932 g of 4-(trifluoromethyl)thiobenzamide. The reaction mixture was refluxed overnight. The solvent was removed under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 90/ethyl acetate 10) to give 1.15 g of 4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a colorless liquid.
Reaction SMILES: Cl.CN.[F:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:12]2[C:8]([CH:9]=[C:10]([C:19]3[S:20][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:22][N:23]=3)[NH:11]2)=[CH:7][C:6]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1.O[N:40]1[C:44]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[F:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:12]2[C:8]([CH:9]=[C:10]([C:19]3[S:20][CH:21]([CH2:24][C:25]([NH:40][CH3:44])=[O:27])[CH2:22][N:23]=3)[NH:11]2)=[CH:7][C:6]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: On1nnc2ccccc21
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Temperature: 0 °C
Yield: 78.8 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (35 mg) and triethylamine (0.072 mL) in N,N-dimethylformamide (7 mL) were added {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (135 mg), 1-hydroxybenzotriazole (70 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give colorless crystals, which were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (109 mg, 79%) as colorless crystals. MS 537 (MH+). mp 151-152° C.