Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C(F)(F)F)cn4)CC2)C3)CC1
Temperature: 25 °C

Procedure:
A mixture of (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned; 110 mg}, 2-chloro-5-trifluoromethyl-pyrimidine (76 mg), K2CO3 (100 mg), and dimethyl sulfoxide (1.5 mL) is stirred at 110° C. for 3 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 30:70→10:90) to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](O)=[C:23]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=3)[C:24](=[O:28])[NH:25]2)=[CH:20][C:19]=1[N+:38]([O-:40])=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:22]1[C:21]2[C:26](=[CH:27][C:18]([Cl:17])=[C:19]([N+:38]([O-:40])=[O:39])[CH:20]=2)[NH:25][C:24](=[O:28])[C:23]=1[C:29]1[CH:30]=[C:31]([CH3:36])[CH:32]=[C:33]([CH3:35])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of (S)-2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.864 g in 38 mL dry tetrahydrofuran) was added 1.56 g of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one [see Example 9] followed by 1.19 g of triphenylphosphine and the mixture stirred at room temperature. To this was added 0.72 mL of diethyl azodicarboxylate (DEAD) and stirring was continued for 64 hours. At this time the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound, 1.56 g.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[OH-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])=[CH:14][CH:13]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
Twenty-five grams of 4-(2-naphthyloxy)aniline were dissolved in 200 ml of toluene, and 100 ml of 40% aqueous sodium hydroxide solution and 12 g of N,N-dimethylcarbamyl chloride were added thereto. The reaction mixture was heated under reflux for 10 hours, and its temperature was cooled to room temperature. The toluene layer was washed with water, and the solvent was removed under reduced pressure. The residue was recrystallized from ethanol to obtain 18 g of N'-[4-(2-naphthyloxy)phenyl]-N,N-dimethylurea as white needles. M.P., 156°-157° C.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([C@@H:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][N:19]3C(OC(C)(C)C)=O)=[O:17])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[ClH:37]>CCOC(C)=O>[ClH:37].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([C@@H:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][NH:19]3)=[O:17])=[CH:11][N:10]=[CH:9]2)=[CH:35][CH:36]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NCCc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide (0.25 g, 0.52 mmol) in EtOAc (15 mL) was cooled to -20° C. The solution was saturated with HCl gas and stirred at 0° C. for 0.5 hr and 25° C. for an additional 0.5 hr. The reaction was evaporated in vacuo to obtain the title compound which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13](Cl)(=[O:15])=[O:14])([O-:3])=[O:2].[NH2:17][C:18]1[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=1>C(Cl)Cl>[CH3:23][N:21]1[CH:22]=[C:18]([NH:17][S:13]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14])[CH:19]=[N:20]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Cn1cc(N)cn1
Solvent: ClCCl
Product: Cn1cc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1
Temperature: -5 °C

Procedure:
2,4-Dinitrobenzenesulphonyl chloride (3.1 g) was added dropwise to a stirred solution of 4-amino-1-methylpyrazole (2.55 g) in methylene chloride (50 ml) that had been cooled to −5° C. The resultant mixture was stirred at this temperature for 5 minutes. The mixture was washed in turn with water, a 5% aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulphate and filtered. There was thus obtained a solution of N-(1-methylpyrazol-4-yl)-2,4-dinitrobenzenesulphonamide; Mass Spectrum: M+H+ 328.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:38]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:39])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)NCc3ccccc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH:5](=[N:3][CH2:2][CH2:1][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCN=Cc1ccccc1)c1ccccc1

Procedure:
A mixture of ethylene diamine (12.02 g; 0.2 mole) and benzaldehyde (42.44 g; 0.4 mole) in toluene (200 ml) was refluxed for 4 hours using a Dean-Stark trap. The toluene was then removed under vacuum. The residual oil crystallized on cooling. The resulting product was dried in a vacuum oven for 24 hours at room temperature and had a melting point of 52°-54°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([C:17]#[N:18])(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:18]=[C:17]([C:14](=[O:16])[CH3:15])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1oc(-c2ccc(F)cc2)ns1
Reactant: CC(=O)C#N
Solvent: Cc1ccccc1
Product: CC(=O)c1nc(-c2ccc(F)cc2)ns1
Reaction time: 3 h

Procedure:
In still a further embodiment, 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone may be prepared according to the methodology and reagents of Scheme 16A. In this embodiment, a 1,3,4-oxathiazol-2-one ring fragment is generated and subsequently converted to a 1,2,4-thiadiazole ring fragment during the preparation of 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone. Specifically, 4-fluoro-benzamide is reacted with chlorocarbonylsulfenyl chloride to provide 5-(4-fluorophenyl)-1,3,4-oxathiazol-2-one. In one embodiment, the reaction is performed in toluene. In another embodiment, the reaction is performed at elevated temperatures of about 80° C. for about 3 hours. 5-(4-Fluorophenyl)-1,3,4-oxathiazol-2-one is then reacted with acetyl cyanide to provide 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone. In one embodiment, this reaction is performed in 1,2-dichlorobenzene. In another embodiment, this reaction is performed at elevated temperatures of about 160° C. for about 20 hours. 1-(3-(4-Fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone is then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:6])[CH2:4][CH3:5].C(N(CC)CC)C.Br[CH2:15][CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH:23]([NH:35][C:36](=[O:40])[O:37][CH2:38][CH3:39])[CH:24]2[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:19][CH:18]=1>CN(C=O)C>[CH2:38]([O:37][C:36](=[O:40])[NH:35][CH:23]1[CH2:22][CH2:21][C:20]2[C:25](=[CH:26][C:17]([CH2:16][CH2:15][S:6][CH2:3][CH2:4][CH3:5])=[CH:18][CH:19]=2)[CH:24]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH3:39]
Reactant: CCCS
Reactant: CCOC(=O)NC1CCc2ccc(CCBr)cc2C1Cc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCSCCc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(NC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (4.73 mg, 0.177 mmol) in 3 ml dry DMF under N2 was added 1-propanthiol (0.012 ml, 0.133 mmol, dissolved in 1 ml dry DMF). The reaction was stirred at room temperature for 2 h, followed by addition of triethylamine (0.019 ml, 0.133 mmol) and ethyl 7-(2-bromoethyl)-1-(3-chlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (40 mg, 0.089 mmol, dissolved in 2 ml dry DMF). The mixture was stirred at room temperature over night, the solvent evaporated, the residue re-dissolved in ethyl acetate, washed with water, citric acid, NaHCO3 and brine and filtered. The solvent was evaporated to obtain 31 mg of an off white solid which was used without further purification.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21])=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].ClCCl.O1CCCC1>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21]
Reactant: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1N

Procedure:
(2S, 3S)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate salt was prepared from (2S,3S)-3-t-butyloxycarbonylamino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Robl, et al., Bioorg. & Med. Chem. Lett. 1994, 4, 1789–1794) by treatment with a solution of trifluoroacetic acid—dichloromethane—tetrahydrofuran (1:10:10) at room temperature, followed by solvent evaporation and coevaporation with tetrahydrofuran under vacuum.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([CH3:14])[CH:16]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=CCOCc1ccccc1
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc([C@@H](CC=O)COCc2ccccc2)c2ccccc21
Yield: 87.2 %

Procedure:
Prepared according to the general procedure from 4-benzyloxy-but-2-enal (286 mg, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidm-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.85 mL) and isopropanol (0.15 mL) at −83° C. for 18.5 h to provide, after silica gel chromatography (50:50 Et2O/hexanes), the title compound as a colorless oil (134 mg, 84% yield, 96% ee). IR (film) 3056, 2957, 2894, 2830, 2722, 1717, 1618, 1600, 1582, 1550, 1478, 1451, 1370, 1331, 1309, 1272, 1223, 1173, 1110, 1070, 1024, 772, 740, 714 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.77 (dd, J=2.1, 2.1 Hz, 1H, CHO), 8.04 (d, J=7.2 Hz, 2H, ArH), 7.75 (d, J=8.1 Hz, 1H, ArH), 7.61-724 (m, 5H, ArH), 7.17 (ddd, J=1.5, 6.6, 8.1 Hz, 1H, ArH), 6.96 (s, 1H, NCH), 4.73 (dd, J=5.1, 11.1 Hz, 1H, CH2O). 4.42 (dd, J=8.7, 11.1 Hz, 1H, CH2O), 4.12 (m, 1H, ArCH), 3.76 (s, 3H, NCH3), 3.06 (ddd, J=2.1, 6.3, 16.8 Hz, 1H, CH2CO); 2.96 (ddd, J=2.7, 8.4, 16.8 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 201.5, 166.4, 137.1, 133.1, 129.9, 129.6, 128.5, 126.8, 126.4, 122.1, 119.3, 119.0, 112.9, 109.6, 68.1, 46.5, 33.0, 31.2; HRMS (CI) exact mass calcd for (C20H19NO) requires m/z 321.1365, found m/z 321.1354. [α]D=−2.0 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (4:96 ethanol/hexanes, 1 mL/min); S isomer tr=42.9 min and R isomer tr=53.2 min.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30](=[CH2:32])[CH3:31].OS(O)(=O)=O>ClCCl>[C:30]([O:27][C:26](=[O:28])[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])([CH3:32])([CH3:31])[CH3:29]
Reactant: O=C(O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 84.4 %

Procedure:
A solution of 150 mg (0.389 mmol) of 8-(9-Fluorenylmethoxycarbonylamino)-3,6-dioxaoctanoic acid, 546 mg (9.73 mmol) isobutylene, and 4.3 μL of 95-98% H2SO4 was stirred at r.t. for 3 days. For workup the reaction solution was diluted with dichloromethane and washed with sat. bicarbonate solution. After drying over sodium sulfate the solvent was removed and the residue obtained purified by chromatography on silica gel with a cHex EtOAc gradient providing 145 mg (84.4%) of the title compound. ESI MS: 464.12 [M+Na]+.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH2:7][NH:8][CH:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH:11]1[CH:15]2[CH2:16][CH2:17][CH:12]1[CH2:13][CH2:14]2)C>C(#N)C>[CH3:21][O:20][C:18](=[O:19])[CH:9]([N:8]1[CH2:7][C:6]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:5][C:4]1=[O:3])[CH2:10][CH:11]1[CH:12]2[CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17]2
Reactant: CCOC(=O)C=C(CNC(CC1C2CCC1CC2)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)C(CC1C2CCC1CC2)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 150 °C
Yield: 47.2 %

Procedure:
A solution of 4-(2-bicyclo[2.2.1]hept-7-yl-1-methoxycarbonyl-ethylamino)-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (83 mg, 0.19 mmol) in acetonitrile (2 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 150° C. for 6 h. The mixture was concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (4 g column, 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) which afforded 3-bicyclo[2.2.1]hept-7-yl-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (35 mg, 23%, over two steps) as a yellow oil.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4]([O:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]2)=[N:3][CH:2]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(Cl)(Cl)Cl.Br[C:60]1[CH:61]=[C:62]([C:68]([F:71])([F:70])[F:69])[C:63]([O:66][CH3:67])=[N:64][CH:65]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:67][O:66][C:63]1[N:64]=[CH:65][C:60]([N:9]2[CH2:8][CH2:7][C:6]3[N:1]=[CH:2][N:3]=[C:4]([O:11][C@H:12]4[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]4)[C:5]=3[CH2:10]2)=[CH:61][C:62]=1[C:68]([F:71])([F:69])[F:70]
Reactant: COc1ncc(Br)cc1C(F)(F)F
Reactant: CCC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)N1CC[C@H](Oc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
Temperature: 150 °C
Yield: 33.3 %

Procedure:
1-[(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one (47.8 mg, 0.173 mmol), X-Phos (28 mg, 0.059 mmol) and Pd2(dba)3.CHCl3 (17.90 mg, 0.017 mmol) were combined and flushed with argon during several min before addition of degassed dioxane. 5-Bromo-2-methoxy-3-trifluoromethyl-pyridine (intermediate 1) (54.5 mg, 0.213 mmol) and Cs2CO3 (113 mg, 0.346 mmol) were then added to the reaction mixture and the resulting mixture flushed with argon and heated at 150° C. for 30 min. in a sealed tube. The reaction mixture was cooled to rt, filtered over Hyflo and evaporated. Purification by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions over PL-HCO3 MP gave 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one (26 mg, 33% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.94-1.00 (m, 3H) 2.05-2.17 (m, 4H) 2.95-3.0 (m, 2H) 3.45-3.97 (m, 9H) 4.07-4.11 (m, 2H) 5.58-5.72 (m, 1H) 7.81-7.86 (m, 1H) 8.18-8.23 (m, 1H) 8.62 (s, 1H). MS: [M+H]+=452.2, Rt(1)=1.74 min.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:4].[Li+].[OH-]>CO>[CH2:25]([N:6]1[CH2:7][CH:8]([N:10]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C1CC(N(Cc2ccccc2)C(=O)OC(C)(C)C)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CC(C(=O)O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-4-[tert-butoxycarbonyl-(benzyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (11) in CH3OH is added LiOH, and the solution is stirred overnight at rt. After removal of solvent, the residue is dissolved in water, acidified until PH=5, and then extracted with EA, and concentrated to afford the product 1-benzyl-4-[tert-butoxycarbonyl-(benzyl)-amino]-pyrrolidine-2-carboxylic acid (12).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:26][CH2:25][C:24]2[C:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=3[S:29][C:23]=2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[N:41]=[C:40]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([CH:49]3[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51][CH2:50]3)=[CH:45][CH:44]=2)[C:39](=[O:62])[N:38]([CH3:63])[CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:36]2[N:41]=[C:40]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([CH:49]4[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]4)=[CH:47][CH:48]=3)[C:39](=[O:62])[N:38]([CH3:63])[CH:37]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[C:22](=[O:34])[C:23]2[S:29][C:28]3[CH2:30][CH2:31][CH2:32][CH2:33][C:27]=3[C:24]=2[CH2:25][CH2:26]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCNCC4)cc3)n2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 125.4 %

Procedure:
A 10 mL microwave vial with a magnetic stirrer was charged with 111a (173 mg, 0.36 mmol), 121a (139 mg, 0.3 mmol), 1M sodium carbonate solution (1.2 mL, 1.2 mmol) and 1,2-dimethoxyethane (3 mL). After bubbling nitrogen through the resulting suspension for 10 min, tetrakis(triphenylphosphine)-palladium(0) (18 mg, 0.015 mmol) was added. The reaction mixture was heated at 130° C. for 15 minutes in the microwave reactor. After this time, ethyl acetate (15 mL) and water (10 mL) were added, and the layers were separated. The aqueous layer was extracted with Ethyl acetate (2×20 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, ethyl acetate/hexanes) to afford compound 121b as yellow oil (240 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OC1CCOCC1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2C1CCOCC1

Procedure:
Compound IIe was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and tetrahydro-2H-pyran-4-ol following the general procedure for the Mitsunobu reaction.