Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]=1[CH3:12])[NH:5][CH:6]1C[CH2:7]1.C(NC1C([N+]([O-])=O)=CC(C)=C(C)C=1[N+]([O-])=O)(C)C.C(NC1C([N+]([O-])=O)=CC(C)=C(C)C=1[N+]([O-])=O)C=C.C(NC1C([N+]([O-])=O)=CC(C)=C(C)C=1[N+]([O-])=O)CCC.C(NC1C([N+]([O-])=O)=CC(C)=C(C)C=1[N+]([O-])=O)(CC)C.CC1C([N+]([O-])=O)=C(C([N+]([O-])=O)=CC=1C)NC(CC)CC.C(C(NC1C([N+]([O-])=O)=CC(C)=C(COC)C=1[N+]([O-])=O)CC)C.C(C1C=C([N+]([O-])=O)C(N)=C([N+]([O-])=O)C=1)C.CC(NC1C([N+]([O-])=O)=CC(C(C)C)=C(CN)C=1[N+]([O-])=O)C.[N+](N([N+]([O-])=O)C1C=CC=CC=1)([O-])=O>>[CH2:6]([NH:5][C:4]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[C:3]=1[N+:16]([O-:18])=[O:17])[CH3:7]
Reactant: Cc1cc([N+](=O)[O-])c(NC2CC2)c([N+](=O)[O-])c1C
Agent: C=CCNc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: CC(C)Nc1c([N+](=O)[O-])cc(C(C)C)c(CN)c1[N+](=O)[O-]
Agent: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Product: CCNc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
3,4-dimethyl-2,6-dinitro-N-(cyclopropyl)-aniline; N-isopropyl-3,4-dimethyl-2,6-dinitroaniline; N-allyl-3,4-dimethyl-2,6-dinitroaniline; N-n-butyl-3,4-dimethyl-2,6-dinitroaniline; N-sec-butyl-3,4dimethyl-2,6-dinitroaniline; 3,4-dimethyl-2,6 -dinitro-N-3-pentylaniline; (1-ethylpropyl)-3-(methoxymethyl)-4-methyl-2,6-dinitroaniline; (1-methylpropyl)-3-ethoxymethyl)-4-ethyl-2,6-dinitroaniline; (1-methylethyl)-3-(aminomethyl)-4-isopropyl-2,6-dinitroaniline and (1-ethylpropyl)-3-[(dimethylamino)methyl]-4-dinitroaniline. 2,6:dinitroaniline.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]([CH2:31][C@H:32]1[O:34][CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]([CH2:33][C@H:32]([OH:34])[CH2:31][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: CC(C)Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Oc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reaction time: 60 h
Yield: 79.1 %

Procedure:
Under nitrogen, to a solution of N-benzyl-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (258 mg) and (2S)-3-phenoxy-1,2-epoxypropane (138 mg) in dichloromethane (5 ml) was added ytterbium(III) trifluoromethanesulfonate (52 mg) at room temperature, and the mixture was stirred at the same temperature for 60 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 5:1) to give (2S)-1-[N-benzyl-N-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-amino]-3-phenoxy-2-propanol (303 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.[NH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH2:21][CH2:20]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: c1ccc2c(c1)NCCN2
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Product: O=C(c1cncnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Yield: 20 %

Procedure:
The title compound was prepared in analogy to Example 77, from 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76, intermediate a) and 1,2,3,4-tetrahydroquinoxaline (commercially available, CAS RN 3476-89-9). The compound was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (10:90 to 98:2) to give 16 mg (20%) of the desired compound. MS (ESI): m/z=401.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1I.[C:13]1([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Li+].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:11][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1)[NH:1][C:20]([Si:21]([CH3:24])([CH3:22])[CH3:23])=[C:19]2[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)C#Cc1ccccc1
Reactant: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)c1[nH]c2c([N+](=O)[O-])cc(Cl)cc2c1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
2-Amino-5-chloro-3-nitro-phenyliodide (1.5 g, 4.90 mmol) obtained in Step 1 and 1-phenyl-2-trimethylsilylacetylene (4.3 g, 24.50 mmol) were dissolved in DMF (50 mL), and thereto palladium acetate (0.11 g, 0.5 mmol), lithium chloride (0.21 g, 4.90 mmol) and triethylamine (2.48 g, 24.50 mmol) were added. The mixture was heated under stirring for 3 hours at 100° C. At the end of reaction, added water and extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give 5-chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.05 g, Yield 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([F:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:38])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.C1(C)C=CC=CC=1>CN(C)C=O.N1C=CC=CC=1>[C:28]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:30](=[O:38])[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:22]([F:27])[CH:21]=1)#[N:29]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)ccnc2cc1OCc1ccccc1
Reaction time: 2 h
Yield: 56 %

Procedure:
The 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline (9.45 g) synthesized in Production Example 8 was dissolved in dimethylformamide (70 ml) and pyridine (5.9 ml), and the mixture was cooled to 0° C. under a nitrogen atmosphere. After adding phenyl chlorocarbonate (3.4 ml), the mixture was stirred for 2 hours. Water was added to the reaction solution, and the precipitated crystals were filtered out and triturated in tetrahydrofuran and toluene to obtain 6.93 g of the title compound as light brown crystals (56% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]([O:14]CC)=[O:13].O>CN(C=O)C>[CH:3]1([O:9][CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COC1CCCCC1
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
To a solution of compound NaH (719 mg, 29.94 mmol) in DMF (10 mL) was added cyclohexanol (1 g, 9.98 mmol) at 0° C. After stirring for 5 minutes, ethyl 2-bromoacetate (2 g, 11.98 mmol) was added and the mixture stirred for another 16 h. Once complete, the mixture was treated with water (50 mL) and washed with ethyl acetate (2×20 mL). The water layer was treat with 2N HCL until pH 3. The water layer was extracted with ethyl acetate (2×20 ml) and the combined organic layers washed with brine (30 mL), dried over Na2SO4 and concentrated to give the desired product (500 mg, 27.8%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][CH3:18]>>[CH3:18][O:17][CH2:16][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COCCBr
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COCCn1ccc2ccc(C(=O)OC)cc21
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield (79 mg, colorless syrup) from methyl 1H-indole-6-carboxylate (200 mg, 1.14 mmol) and 1-bromo-2-methoxyethane (190 mg, 1.37 mmol) by the similar manner in Step-1 of Intermediate-9.
Reaction SMILES: C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(N(C)C(NCCCCCCC)=O)C=2)=CC=1)C(O)=O)(=O)C1C=CC=CC=1.[C:45]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C@@H:60]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([N:79]([CH3:93])[C:80]([NH:82][C:83]3[CH:92]=[CH:91][C:90]4[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=4)[CH:84]=3)=[O:81])[CH:74]=2)=[CH:69][CH:68]=1)[C:61]([O:63]CC)=[O:62])(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Li+]>>[C:45]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C@@H:60]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([N:79]([CH3:93])[C:80]([NH:82][C:83]3[CH:92]=[CH:91][C:90]4[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=4)[CH:84]=3)=[O:81])[CH:74]=2)=[CH:69][CH:68]=1)[C:61]([OH:63])=[O:62])(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(N(C)C(=O)Nc3ccc4ccccc4c3)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CN(C(=O)Nc1ccc2ccccc2c1)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Yield: 96.5 %

Procedure:
In a manner similar to the preparation of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2), using 0.66 g (1.02 mmol) of ethyl (S)-2-(2-benzoylphenylamino)-3-[3′-(1-methyl-3-naphthalen-2-ylureido)biphenyl-4-yl]propionate and 50 mg (1.19 mmol) of lithium hydroxide, 0.61 g of (S)-2-(2-benzoylphenylamino)-3-[3′-(1-methyl-3-naphthalen-2-ylureido)biphenyl-4-yl]propionic acid is obtained with a 96% yield.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH2:20])[CH3:19]>CN(C)C=O>[CH2:18]([NH:20][C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19]
Reactant: CCN
Reactant: CC(C)c1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCNc1nc2ccccc2n2c(C(C)C)nnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A slurry of 1.0 g. (0.004 mole) of 4-chloro-1-isopropyl-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 6) in N,N-dimethylformamide (15 ml.) was saturated with monoethylamine gas and stirred at room temperature for 4 hours. The precipitate was separated by filtration and washed with N,N-dimethylformamide to afford 220 mg. (22% yield) of 4-ethylamino-1-isopropyl[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 209°-211° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.O>[N:34]([CH2:13][C:10]1[CH:11]=[CH:12][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[N:9]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccn(-c2ccc(I)cc2)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: [N-]=[N+]=NCc1ccn(-c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
A mixture of 1-(4-iodophenyl)-3-methyl-1H-pyrazole (0.98 g, 3.45 mmol), NBS (0.80 g, 4.49 mmol) and AIBN (0.17 g, 1.03 mmol) in CCl4 (15 mL) was heated at reflux for 5 hrs. After being cooled to room temperature, it was filtered. The filtrate was concentrated in vacuo. The residue was dissolved in DMF (8 mL), NaN3 (0.400 g, 6.15 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with hexane, then with 4-6% EtOAc in hexane to give 3-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[O:8])=[CH:5][CH:4]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2N)cc1

Procedure:
Using a procedure similar to Example 1C except starting with N-(4-methoxybenzoyl)-2-nitroaniline in ethyl acetate, the title compound was obtained as a white solid (99%); MS(FD): 242.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[PH2](O)=O.ClC(C)C(O)=O.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][CH:19]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(O)cc1
Reactant: C=Cc1ccccc1
Agent: CC(Cl)C(=O)O
Agent: O=[PH2]O
Product: Cc1ccc(O)c(C(C)c2ccccc2)c1

Procedure:
The reaction was similarly carried out as Example 10 except that into a mixture of 32 g of p-cresol, 4 g of hypophosphorous acid and 6 g of α-chloropropionic acid was poured 36 g of styrene to give only 2-(α-methylbenzyl)-4-methylphenol, but not to detect other tert-butylated compounds.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH3:39][C:40](=[CH2:42])[CH3:41].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([O:16][C:40]([CH3:42])([CH3:41])[CH3:39])[CH2:13][N:12]1[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Tert-Butyletherification: To a solution of (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (14.8 g) in dichloromethane (140 ml) were added boron trifluoride ethyl etherate (3 ml) and isobutylene (cooled and liquefied at −30° C., 170 ml) at −30° C. The turbid reaction mixture was stirred at −20° C. for 2 h, poured onto a saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:4 and 1:2 as eluents to obtain (2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (16.4 g) as a glassy syrup, MS: 467 (M).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8](=[C:11]([S:14][CH3:15])SC)[C:9]#[N:10])=O.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([NH:29][C:30]([NH2:32])=[NH:31])=[O:28])=[CH:25][CH:24]=1)[CH3:21].C(N(CC)CC)C>CN(C=O)C>[C:9]([C:8]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:31][C:30]([NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH3:21])=[CH:34][CH:33]=2)=[N:32][C:11]=1[S:14][CH3:15])#[N:10]
Reactant: CSC(SC)=C(C#N)C(=O)c1ccco1
Reactant: COCCN(C)Cc1ccc(C(=O)NC(=N)N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc(SC)c(C#N)c(-c3ccco3)n2)cc1

Procedure:
From 2-(furan-2-carbonyl)-3,3-bis-methylsulfanyl-acrylonitrile, N-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzoyl)-guanidine and triethylamine in DMF. ES-MS m/e (%): 438 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH:33]([Mg]Br)=[CH2:34].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH:33]=[CH2:34])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A stirred suspension of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (75.4 mg, 0.168 mmol) in THF (1.6 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Vinylmagnesium bromide (1.6 ml, 1.600 mmol) was added to the reaction mixture slowly. The reaction mixture was stirred at 0° C. for 20 min, then at room temperature for 1.5 h. The reaction mixture was added via pipette to saturated aqueous NaHCO3 (20 ml) before being partitioned between EtOAc (40 ml) and water (20 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×20 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient, followed by a 100% acetonitrile+0.05% TFA. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C26H22ClN3O4 475.13 observed m/e: 476.18 (M+H)+ (Rt 1.21/2 min).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1ncccc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 2-fluoro-3-(pyridin-4-yl)pyridine (1.0080 g, 5.787 mmol), 4-aminophenol (0.7102 g, 5.793 mmol), and cesium carbonate (2.387 g, 6.945 mmol) in dimethyl sulfoxide at 90° C. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (3×10 mL), satd sodium chloride solution (3×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(pyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[CH2:20][CH2:19][C:18](=[N:21][O:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[CH2:17][CH2:16]2)=[CH:10][C:9]=1[F:37])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:32]1[CH:31]=[N:30][C:29]([N:26]2[CH2:25][CH2:24][CH:23]([O:22][N:21]=[C:18]3[CH2:19][CH2:20][N:15]([C:11]4[C:12]([F:14])=[CH:13][C:8]([CH2:7][C:6]([OH:38])=[O:5])=[C:9]([F:37])[CH:10]=4)[CH2:16][CH2:17]3)[CH2:28][CH2:27]2)=[N:34][CH:33]=1)[CH3:36]
Reactant: CCc1cnc(N2CCC(ON=C3CCN(c4cc(F)c(CC(=O)OC(C)(C)C)cc4F)CC3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCC(ON=C3CCN(c4cc(F)c(CC(=O)O)cc4F)CC3)CC2)nc1
Yield: 100 %

Procedure:
Compound 77d (141 mg) was dissolved in DCM (2 mL) and TFA (2 mL) and stirred at r.t. for 1 h. The solvent was removed in vacuo, DCM and 1M HCl were added and the organic phase was separated, dried over MgSO4 and concentrated to give (4-{4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-piperidin-1-yl}-2,5-difluoro-phenyl)-acetic acid 77e (126 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=1[F:27].[CH2:28]1[O:30][CH2:29]1>C1COCC1>[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[C:16]([CH2:28][CH2:29][OH:30])[C:15]=1[F:27]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1CCO
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (6.2 mL, 44 mmol) in THF (200 mL) was treated with n-butyllithium (17.4 mL, 44.0 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (4.8 g, 17 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, ethylene oxide (10 mL, 200 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude product was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound: LC-MS: m/z 319.98 (M+H)+.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].ClC(OCC)=O.C(=O)([O-])O.[Na+]>O>[N:4]([CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12])=[C:1]=[S:3]
Reactant: S=C=S
Reactant: CN1CCCC1CCN
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCCC1CCN=C=S
Temperature: 0 °C
Yield: 43.2 %

Procedure:
A mixture of carbon disulfide (0.996 mL, 16.57 mmol) in water (5 mL) was cooled to 0° C. Then 2-(2-aminoethyl)-1-methylpyrrolidine (2.4 mL, 16.57 mmol) was added over 45 minutes. The resulting mixture was maintained at 0° C. for an additional 30 minutes and then the cooling was discontinued. Next, ethyl chloroformate (1.58 mL, 16.57 mmol) was added over a 1 h period. The resulting mixture was maintained at room temperature for an additional 30 minutes and then made basic with saturated sodium hydrogen carbonate in water. The mixture was extracted with diethyl ether (2×50 mL). The extracts were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by vacuum distillation to give 1.22 g of 2-(2-isothiocyanatoethyl)-1-methylpyrrolidine.