Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]1([C:24]#[C:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])=[O:9])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: O=C(C(=O)c1ccc(C#Cc2ccccc2)cc1)c1ccccc1

Procedure:
4-Bromobenzil (10.0 g, 0.0346 mol), phenylacetylene (3.88 g, 0.0380 mol), and (PPh3)2PdCl2 (0.121 g, 0.0002 mol) in diethylamine (950 mL) is stirred at ambient temperature for 72 hours, followed by concentration to dryness. The residue is then taken up in methylene chloride. Standard aqueous workup followed by recrystallization from 2-propanol gives the title compound.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3ccc(O)cc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccc(O)cc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To the title compound of Example 12 Step A (0.1 mmol, 50 mg) in 800 μL of dioxane was added LiOH (0.4 mmol, 10 mg) in 400 μL of H2O. The resulting solution was stirred at 40° C. overnight. The reaction mixture was taken up in aqueous pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford the acid as a white solid, which was used without further purification. (HPLC A: 1.97 min).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:30])#[N:25]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: N#Cc1cccc(C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C#N)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Cyano-benzoic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)=[O:3].[CH3:13][NH:14][NH2:15]>C(O)C>[CH3:13][N:14]([C:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([CH3:1])=[O:3])[CH:5]=1)=[S:12])[NH2:15]
Reactant: CC(=O)c1cccc(N=C=S)c1
Reactant: CNN
Solvent: CCO
Product: CC(=O)c1cccc(NC(=S)N(C)N)c1
Yield: 78.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 20.0 g (0.113 mole) of 3-methylcarbonylphenyl isothiocyanate and 5.21 g (0.113 mole) of methylhydrazine in 150 ml of ethanol yielded 19.9 g of 2-methyl-4-(3-methylcarbonylphenyl)-3-thiosemicarbazide as a solid, mp 125°-127° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:29][S:26]([C:23]([CH3:25])([CH3:24])[CH3:22])(=[O:28])=[O:27])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)C(C)(C)C)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 2-methyl-propane-2-sulfonic acid amide are processed according to the method described in Example 170 to give 2-methyl-propane-2-sulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9H), 3.78 (s, 3H), 4.43 (d, J=6.1 Hz, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.65 (t, J=6.2 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.06 (t, J=2.1 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 417.1150 [(M+H)+ Calcd for C20H21ClN4O2S: 417.1152].
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH:12][CH2:13][C:14]([C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)=[O:15])=[CH:6][C:5]=1[O:31][CH2:32][CH3:33].[C:35](OC([O-])=O)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>O1CCCC1>[Br:10][C:8]1[CH:9]=[C:4]([C:3]([NH:2][CH3:1])=[O:34])[C:5]([O:31][CH2:32][CH3:33])=[CH:6][C:7]=1[CH2:11][N:12]([CH2:13][C:14]([C:16]1[CH:17]=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:19]([OH:26])=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)=[O:15])[C:35](=[O:36])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOc1cc(CNCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Br)cc1C(=O)NC
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: C1CCOC1
Product: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC(C)(C)C)c(Br)cc1C(=O)NC
Yield: 94.8 %

Procedure:
After dissolving the N1-methyl-5-bromo-4-[({2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-oxoethyl}amino)methyl]-2-ethoxybenzamide (1.75 g) in tetrahydrofuran (20 ml), tert-butyl dicarbonate (770 mg) was added. The mixture was heated to reflux for 2 hours, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.97 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[Cl:15][C:16]1[CH:21]=[C:20]([N:4]2[C@@H:3]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]([CH3:14])([CH3:1])[O:6][C:5]2=[O:7])[CH:19]=[CH:18][N:17]=1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Reactant: Clc1cc(I)ccn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccnc(Cl)c2)[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To a microwave vial were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (1 g, 5.23 mmol), 2-chloro-4-iodopyridine (1.878 g, 7.84 mmol) (commercially available from Frontier Scientific, Inc., Logan Utah), and dioxane (10.46 mL). Tribasic potassium phosphate (5.55 g, 26.1 mmol) and copper (I) iodide (0.996 g, 5.23 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were then added to the vial. The vessel was purged with argon and then N,N′-dimethylethylenediamine (1.126 mL, 10.46 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) was added. The vessel was then irradiated at 140° C. for 40 minutes, and LC-MS indicated complete conversion to the desired product. After cooling to room temperature, the reaction mixture was passed through a syringe filtered, and the material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-3-(2-chloropyridin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one. m/z (ESI) 303.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:25]([CH2:24][CH2:23][Cl:22])(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 5-(tert-butoxycarbonylamino)pentylamine (1.00 g, 4.94 mmol) and triethylamine (689 μL g, 4.94 mmol) in dichloromethane (22 mL) at 0° C. was added 2-chloro-1-ethanesulfonyl chloride (470 μL, 4.50 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give the title compound (100% yield), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[CH:13]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].[Al].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: Cn1ccc2cc(NC(=O)OC3CCCC3)ccc21
Agent: O=C([O-])O
Agent: [Al]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
A solution of 5-(cyclopentyloxycarbonyl)amino-1-methylindole (AA) (1.3 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (1.3 g.) in N,N-dimethylformamide (25 ml.) was stirred and heated at 100° C., under a nitrogen atmosphere, while protecting the reaction vessel from light with aluminum foil, for 24 hours. The cooled mixture was poured onto saturated aqueous sodium bicarbonate solution (300 ml.), extracted with ethyl acetate (3×100 ml.), the combined extracts washed with brine (50 ml.), dried (MgSO4), and evaporated. The product was isolated by flash chromatography on silica gel (3.5 cm. diameter column) to give the title compound (P) (0.98 g., 45%), identical with that obtained in Example 8.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)[CH:16]=2)[C:11]2[N:31]=[CH:32][CH:33]=[CH:34][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].Cl>CN(C)C=O>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)[CH:16]=2)[C:11]2[N:31]=[CH:32][CH:33]=[CH:34][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Yield: 81.9 %

Procedure:
A mixture of 2-benzyl-4-[3-(4-methoxycarbonylphenyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and lithium bromide (0.30 g) in N,N-dimethylformamide (3 ml) was stirred under reflux for 4 hours. The mixture was cooled and poured into dilute hydrochloric acid with stirring. The resultant precipitate was collected and washed with water to give 2-benzyl-4-[3-(4-carboxyphenyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (119 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=2)[N:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:24][C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[N:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: ClCc1cccc(Oc2ccnc(Cl)c2)n1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(OCc2cccc(Oc3ccnc(Cl)c3)n2)cc1
Yield: 69.8 %

Procedure:
A mixture of 2-(chloromethyl)-6-[(2-chloro-4-pyridyl)oxy]pyridine (1.66 g, 6.5 mmol), 4-fluorophenol (0.89 g, 8 mmol), and potassium carbonate (1.1 g, 8 mmol) in N,N-dimethylformamide (5 mL) is refluxed for 90 minutes, cooled, and diluted with a 1:1 hexane/ethyl acetate solution (100 mL). The organic mixture is then filtered through a layer of silica gel using a 1:1 hexane/ethyl acetate solution as eluent. The resultant solution is concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 8:2 hexane/ethyl acetate solution gives the title product as colorless crystals (1.5 g, 70%, mp 103° C.).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CCN(CC)CC>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CBr
Yield: 60.5 %

Procedure:
This novel compound was prepared as follows: Bromoacetyl bromide (4.25 g; 21 mmol) was added dropwise to a solution of dioctadecylamine (10 g; 19 mmol) and Et3N (2.13 g; 21 mmol) in CHCl3 (400 mL). After 4 h at room temperature the reaction solution was washed with H2O, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (n-hexane/Et2O=8/2 (v/v) to give the desired product (7.5 g; 11.5 mmol). Yield 61%. K.F.: <0.1%; The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the postulated structure
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22]>C(Cl)Cl.C(OCC)C>[ClH:22].[ClH:22].[CH3:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH:19]=[CH:18][N:17]=1
Reactant: Cc1nccc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nccc(N2CCC(N)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of [1-(2-methyl-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (818.7 mg, 2.8 mmol) in CH2Cl2 (14 mL) was added at room temperature under stirring a 2 M HCl solution in diethyl ether (7 mL) and was stirred at room temperature over the weekend. The solvent was removed under reduced pressure and the residue was treated twice with diethyl ether. The title compound was obtained after removal of the solvent under reduced pressure as a light brown solid (869 mg, 100%)
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.Cl[C:58]([O:60][CH:61]([CH3:63])[CH3:62])=[O:59].ClC([O-])=O>>[CH:61]([O:60][C:58]([N:27]1[C@H:26]([C:24](=[O:25])[NH:23][C@H:6]([C:5]([OH:56])=[O:4])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])=[CH:12][CH:13]=2)[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28]1)=[O:59])([CH3:63])[CH3:62]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: O=C([O-])Cl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)OC(C)C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was reacted with isopropyl chloroformate according to General Procedure G (with excess of chloroformate). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (4 mg). LCMS (m/z): 841.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@@H:5]([NH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[C:6]([O:8][CH3:9])=[O:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:14]([O:13][C:11]([NH:10][C@H:5]([CH2:4][CH2:3][NH:2][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[C:6]([O:8][CH3:9])=[O:7])=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOC(=O)N[C@H](CCN)C(=O)OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N[C@H](CCNS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of methyl 4-amino-2(R)-(N-butyloxycarbonylamino)butyrate hydrochloride (2.28 g, 8.5 mmol) and p-toluenesulfonyl chloride (1.62 g, 8.5 mmol) in 10 mL CHCl3 cooled in an ice bath was added diisopropylethylamine (4.5 mL, 26 mmol). The mixture was stirred at room temperature overnight and concentrated. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 40% ethyl acetate/hexane gave 2.16 g (66%) product. 1H-NMR: d (CDCl3) 7.75 (d, 2H ); 7.26 (d, 2H); 5.72 (t, 1H); 5.22 (d, 1H); 4.32 (m, 1H); 3.72 (s, 3H); 3.18 (m, 1H); 2.82 (m, 1H); 2.41 (s, 3H); 2.10 (m, 1H); 1.60 (m, 1H); 1.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][C:17]=3[O:27][CH3:28])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[O:27][CH3:28])=[CH:29][CH:30]=2)=[O:10])=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methoxyphenyl)acetate (0.065 g, 0.143 mmol) in methanol/THF (1:1, 3 ml) was added NaOH (0.100 ml, 0.500 mmol). After 5 minutes, reaction was quenched with 10 ml of 2N HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 0.5% methanol/dichloromethane (containing 0.5% AcOH) to 7.5% methanol/dichloromethane containing (0.5% AcOH) to provide 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methoxyphenyl)acetic acid (0.041 g, 65.1% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.37-8.41 (bt, NH), 7.70 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.6 Hz, 2H), 3.64 (s, 2H), 3.56 (t, J=6.8 Hz, 2H), 2.88 (t, J=7.4 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH:9]1C1C=CC=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:23][OH:24]>[OH-].[OH-].[Pd+2]>[CH3:23][O:24][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:1]=1[N:8]1[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1
Reactant: CO
Reactant: COc1ccccc1C1CC(=O)C=CN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: COc1ccccc1N1CCC(O)CC1

Procedure:
To a solution of N-benzyl-2,3-dihydro-2-(2-methoxyphenyl)4-pyridone (5.5 g, 18.77 mmol) (which was prepared by the procedures of Yamamoto et al., Tetrahedron, 1993, 49, 1749) in methanol (80 mL) was added Pd(OH)2 (1.7 9) and the resulting suspension was hydrogenated (50 psi) for 20 hours. Pd-C was then filtered off and the crude reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel flash chromatography (5% MeOH-0.5% NH3 .diamond-solid.H2O-94.5% CH2Cl2) to afford the title compound as a solid (1.5g). 13C NMR (CDCl3, 100 MHz) ) δ:156.5, 131.4, 128.1, 126.9, 120.8, 110.3, 69.6, 55.3, 53,8, 45.1, 41.7, and 35.6.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31](O)[C@H:30]([OH:34])[C@@H:29]3[OH:35])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:36][OH:37]>[Pd]>[OH:35][C@H:29]1[C@@H:30]([OH:34])[C@H:31]([O:37][CH3:36])[CH2:32][C@@H:28]1[O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C[C@@H](O)[C@H](O)[C@@H]3O)c3ccccc3n2)CC1
Reactant: CO
Agent: [Pd]
Product: CO[C@@H]1C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,2S,3S,4R)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]quinazoline [cf. Example 33(4)] (1.00 g) in methanol (15 ml) is added 10% palladium/carbon (200 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 3 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure, and the residue is dissolved in ethanol (35 ml) and thereto is added fumaric acid (242 mg). The precipitated crystals are dissolved by adding water to the mixture. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure, and the resulting residue is recrystallized from water-ethanol to give 4-[(1S,2S,3S,4R)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline 1/2 fumarate (390 mg) as crystals.