Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:29][C:30](O)=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:30](=[O:31])[CH2:29][C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH:26]([CH3:27])[CH3:28])[N:17]=2)=[O:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2cc(F)ccc21
Reactant: CNC
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(5-fluoro-1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 3 of Example 25) and dimethylamine.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.FC(F)(F)C(O[C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36])=O.N1C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Yield: 90 %

Procedure:
4-(2-Fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and pentafluorophenyl trifluoroacetate were reacted in the presence of pyridine in THF as for example 4, step A. The crude residue was purified by flash chromatography on silica gel (60% EtOAc/Hexane) to give 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (90%). 1H NMR [400 MHz, (CD3)2SO] δ 9.02 (s, 1H), 8.60 (s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.20 (dd, J=11.6, 1.1 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 5.24 (d, J=1.6 Hz, 1H), 3.48 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[N:7].[Na].[CH3:9][OH:10]>>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6](=[NH:7])[O:10][CH3:9]
Reactant: CO
Reactant: COCOCC#N
Agent: [Na]
Product: COCOCC(=N)OC

Procedure:
Obtained using the procedure described in section a of Example 2, starting with 286.8 g (2.84 moles) of methoxymethoxyacetonitrile [prepared according to D. J. Loder and W. M. Bruner, U.S. Pat. No. 2,398,757; C.A. 1946, 40, 3774] and 6.5 g (0.284 gram-atom) of sodium in 1430 ml of methanol. Reaction time: 2 days. Yld: 302.6 g (80%), b.p.15 16°-65° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)S(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].[N:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[N:33]/[CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[N:28][CH:27]=1>CN(C=O)C.[OH-].[Na+]>[C:20]1([C:9]2[N:7]=[CH:8][N:33]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)[C:32]=2[C:29]2[CH:30]=[CH:31][N:26]=[CH:27][N:28]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(/N=C/c2ccncn2)CC1
Reactant: [C-]#[N+]C(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccc3)c2-c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of potassium carbonate (107 mg, 0.774 mmol), 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (C21, see Organic Syntheses; Wiley & Sons: New York, 2004; Collect. Vol. 10, p. 692) (0.209 g, 0.770 mmol) and tert-butyl 4-{[(1E)-pyrimidin-4-ylmethylene]amino}piperidine-1-carboxylate (C13) (582 mg, 2.00 mmol) in DMF (3 mL) was stirred for 18 hours at room temperature, then diluted with aqueous sodium hydroxide solution (1 N, 50 mL). The mixture was extracted with ethyl acetate, and the combined organic layers were washed with aqueous lithium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluants: 50%, then 75% ethyl acetate in heptane) provided the product as a cream-colored solid. Yield: 267 mg, 0.658 mmol, 85%. APCI m/z 406.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.82-1.92 (m, 2H), 2.17 (br d, J=12 Hz, 2H), 2.77-2.86 (m, 2H), 4.26-4.34 (m, 2H), 4.93 (tt, J=12, 4 Hz, 1H), 7.20 (dd, J=5.3, 1.5 Hz, 1H), 7.32-7.36 (m, 3H), 7.42-7.45 (m, 2H), 7.80 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 9.28 (d, J=1.3 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>CO>[CH2:1]([NH:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCN
Solvent: CO
Product: CCCCCCCCCCCCNCC(O)CO
Temperature: 70 °C
Yield: 59 %

Procedure:
The procedures of Ulsperger et al., J. Prakt. Chemie, Vol. 27, pp. 195-212 (1965), the disclosures of which are hereby incorporated herein by reference in their entirety, were substantially followed. Specifically, 18.54 g laurylamine (0.1M) and 7.4 g glycidol (0.1M) were mixed in 150 ml methanol at 60° C. for 5 hours. The mixture was refluxed for 1 hour at 70° C. The methanol was then removed by rotary evaporation. The product was a solid, 15.3 g (59% yield). After recrystallization from hexane, LDP, was recovered as a white crystal, m.p. 75°-76° C. (m.p. 76°-76.5° C., lit.).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][OH:22])[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[C:11]=2[O:22][CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)c(Br)c1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(F)c(Br)c2OCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of N-benzyl-3-bromo-2,4-difluoro-N-(2-hydroxyethyl)benzamide (4.57 g, 12.3 mmol) in N,N-dimethylformamide (60 ml) was added under ice-cooling sodium hydride (60%, 593 mg, 14.8 mmol), and the mixture was stirred for 2 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (3.23 g, 75.0%) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[Cl:23][C:24]1[CH:25]=[C:26]([NH2:38])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.Cl.N1C=CC=CC=1>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:38][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH:16]4[CH2:20][CH2:19][O:18][CH2:17]4)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:21]#[N:22])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 85 °C
Yield: 73.9 %

Procedure:
To a single-neck reaction flask (500 ml) were added 4-chloro-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile (5 g, 15.649 mmol), 3-chloro-4-(pyridin-2-yl-methoxy)benzenamine (4.037 g, 17.214 mmol) and pyridine hydrochloride (421 mg). To the flask was added isopropanol (150 ml). The mixture was stirred and refluxed for 2 hr at the temperature of 85° C. The reaction was stopped and cooled to the room temperature. The resultant mixture was filtered in vacuo. The filter cake was washed with mother liquor and dried in vacuo to give a yellow solid (5.988 g). Yield: 73.9%.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH:30]2[CH2:32][CH2:31]2)[N:29]=1>>[CH:30]1([C:28]2[N:29]=[C:25]([NH:24][C:1]([C:4]34[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]5[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]5[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]3)[CH2:8][CH2:9]4)=[O:3])[S:26][CH:27]=2)[CH2:32][CH2:31]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nc(C2CC2)cs1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(C4CC4)cs3)(CC1)CC2
Yield: 62.6 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-cyclopropylthiazole (47.7 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-cyclopropylthiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (43.1 mg).
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14]
Reactant: CCC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C(=O)O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A mixture of 4-(dihydroxyboranyl)benzoic acid (25.7 mg, 0.155 mmol), (cis)-1-acetyl-6-bromo-N-phenyl-2-propyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 86) (40 mg, 0.103 mmol), tetrakis(triphenylphosphine)palladium(0) (11.93 mg, 10.33 μmol) and potassium carbonate (42.8 mg, 0.310 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuo. Purification of the residue by MDAP (modifier:formic acid) gave 4-[(cis)-1-acetyl-4-(phenylamino)-2-propyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (19 mg, 0.044 mmol, 43%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:30][S:31](C)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[S:31][CH3:30])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Product: CSc1cc(-n2ccccc2=O)ccc1-n1cnc(CNC(=O)c2ccc(Cl)s2)c1

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 21 prepared in Example 11 (96 mg, 0.22 mmol) and NaSMe (68 mg, 0.97 mmol) in DMSO (2 mL) was heated at 80° C. for 1 h. The mixture was purified by HPLC to give 5-chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (16 mg). MS 457.0 and 459.0 (M+H, Cl pattern)
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=12.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[C:18]1([N:9]2[C:8]3[C:3](=[O:2])[NH:4][CH:5]=[CH:6][C:7]=3[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1nccc2c(-c3ccccc3)nn(-c3ccccc3)c12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]ccc2c(-c3ccccc3)nn(-c3ccccc3)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of 7-methoxy-1,3-diphenyl-1H-pyrazolo[3,4-c]pyridine (75 mg) in acetonitrile (10 mL) were added sodium iodide (75 mg) and chloro(trimethyl)silane (216 mg), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give the title compound (45 mg).
Reaction SMILES: [C:1]([C:3]1[CH:46]=[CH:45][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([NH:30]S(C(C)(C)C)=O)[C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(NS(C(C)(C)C)=O)C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#N>>[NH2:30][CH:10]([C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)[C:8]1[NH:7][C:6]2[CH:45]=[CH:46][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NS(=O)C(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: COc1cc(C)c2[nH]ccc2c1C(N)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(1,1-dimethylethylsulfinamido)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(1,1-dimethylethylsulfinamido)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate following the same procedure as described in Example 36-E. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (br. s., 1H) 7.91 (s, 1H) 7.57 (d, J=8.08 Hz, 1H) 7.47 (dd, J=8.34, 1.52 Hz, 1H) 7.19 (t, J=2.78 Hz, 1H) 6.74 (s, 1H) 6.23 (dd, J=3.03, 2.02 Hz, 1H) 5.80 (s, 1H) 3.71 (s, 3H) 2.44 (s, 3H). HRMS calcd. for C19H17N5O (M+H)+ 332.1506. found 332.1507.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14](OC)[O:15][CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[CH2:3][N:2]([CH3:1])[CH2:13][CH:14]2[O:15][CH3:16])([O-:12])=[O:11]
Reactant: COC(CN(C)Cc1ccc([N+](=O)[O-])cc1)OC
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: COC1CN(C)Cc2ccc([N+](=O)[O-])cc21
Reaction time: 18 h

Procedure:
A mixture of 0.83 g of N-methyl-N-(4-nitrophenylmethyl)-2,2-dimethoxy-ethylamine and 3.0 ml trifluoromethanesulphonic acid is prepared in a dry ice/ethanol cooling bath, slowly brought to ambient temperature and stirred for 18 h. Then it is poured onto ice water, made alkaline with 2N NaOH, extracted 3× with EtOAc, the organic phases are dried with Na2SO4, concentrated and purified by repeated chromatography.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)(Cl)=O.[CH3:15][O:16][NH:17][CH3:18].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:17]([O:16][CH3:15])[CH3:18])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cccc(I)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(I)c1
Temperature: 0 °C
Yield: 62.9 %

Procedure:
A solution of 3-Iodo-benzoic acid (5.0 g, 20.15 mmol), thionyl chloride (3.6 g, 30.2 mmol), and DMF (10 mL) in CH2Cl2 (100 mL) was heated to reflux for 3 h. The reaction was then concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL). O,N-Dimethylhydroxylamine hydrochloide (2.16 g, 22.2 mmol) was added and the solution was cooled to 0° C. N,N-diisopropylethylamine (2.6 g, 20.2 mmol) was added drop wise. The reaction was warmed to room temperature. After 4 h the reaction was quenched with water, the layers were separated and the aqueous layer was extracted with CH2Cl2 (1×). The combined organic layers were dried over Na2SO4. Purification by flash column chromatography (hexanes/ethyl acetate 6:4) afforded the title compound as a white solid (3.69 g, 63%). MS: 291.8 (MH+); HPLC Rf: 4.87 min. (HPLC method 4).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1>CN(C)C1C=CN=CC=1.CC(O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C@H:2]([OH:1])[CH2:3][N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: N#Cc1ccc([C@H]2CO2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Temperature: 55 °C

Procedure:
(S)-4-(Oxiran-2-yl)benzonitrile (10.00 g, 68.9 mmol), (S)-ethyl piperidine-3-carboxylate (10.83 g, 68.9 mmol) and iPrOH (100 mL) was charged into a round bottom flask under N2. After heating at 55° C. for 4 hours, 4-dimethylaminopyridine (1.683 g, 13.78 mmol) was then added. The reaction mixture was then heated to 50° C. for an additional 12 hours. At this time HPLC indicated the starting material was completely converted to the desired product. The reaction mixture was then cooled to room temperature. EtOAc (120 ml) was added, followed by 100 ml of water. The organic layer was separated, extracted with EtOAc (2×100 mL) and concentrated under vacuo to give a crude product. The crude product was recrystallized from EtOH/EtOAc/H2O (3/2/2) (8 ml/1 g) to give a crystalline off-white solid 14A-alt (15 g, 72% yield, 99.6% e.e.). The absolute and relative stereochemistry was determined by single X-ray crystallography employing a wavelength of 1.54184 Å. The crystalline material had an orthorhombic crystal system and unit cell parameters approximately equal to the following:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[Cl:14])=[N:5][N:6]=1.BrC1S[C:19]([N:21](C)[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=NN=1>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]([N:21]([CH3:19])[CH:22]3[CH2:23][C:24]([CH3:30])([CH3:31])[NH:25][C:26]([CH3:29])([CH3:28])[CH2:27]3)=[N:6][N:5]=2)=[C:8]([Cl:14])[CH:9]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: Clc1cc(Br)ccc1-c1nnc(Br)s1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN(c1nnc(-c2ccc(Br)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C

Procedure:
A stirred solution of 2-bromo-5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazole (700 mg, 1.975 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (1009 mg, 5.92 mmol) in NMP (4 mL) was heated to 120° C. for 3 hours. The reaction mixture was allowed to cool to room temperature then diluted with DCM (100 mL) and washed with saturated NaHCO3(aq) (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to a brown liquid. The crude material was purified by silica flash chromatography, running a gradient from 0-10% [2M NH3 in MeOH]/DCM over 30 minutes, collecting at 320 nm to afford the title compound as a light brown glass-like solid (750 mg, 86% yield). LC-MS: Rt 1.10 min; MS m/z 445.1 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=8.59 Hz, 1H), 7.93 (d, J=2.02 Hz, 1H), 7.70 (dd, J=8.59, 2.02 Hz, 1H), 4.36 (tt, J=12.38, 3.28 Hz, 1H) 3.01 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=2)[CH:13]=[CH:12][C:11]=1[OH:25].C(Cl)Cl.[O:29]1C[CH2:32][CH2:31][CH2:30]1.C(Cl)(=O)C=C>O.C(N(CC)CC)C>[C:30]([O:25][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)(=[O:29])[CH:31]=[CH2:32]
Reactant: Oc1ccc(-c2cc3ccccc3s2)cc1-c1cc2ccccc2s1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(-c2cc3ccccc3s2)cc1-c1cc2ccccc2s1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
1.31 g of the thus obtained 2,4-bis(2-benzothiophenyl)phenol is placed in a round bottom flask; 20 mL of methylene chloride and 2 mL of tetrahydrofuran are added to form a transparent solution; after ice cooling the flask, 0.44 g of triethylamine is added; 0.39 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=90/10 (volume ratio)) to concentrate a component having an Rf of 0.20, thereby obtaining 1.0 g (yield: 66%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 6.06 (dd=1.2 & 10.8 Hz, 1H), 6.38 (dd=10.8 & 17.2 Hz, 1H), 6.64 (dd=1.2 & 17.2 Hz, 1H), 7.31 to 7.40 (m, 5H), 7.59 (s, 2H), 7.70 to 7.85 (m, 5H), 8.05 (d=2.4 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][C:5]=1[Cl:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][C:5]=1[Cl:16]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)c(Cl)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 2-chloro-4-trimethylsilanylethynyl-benzoic acid methyl ester (4.52 g, 12.0 mmol, 1.0 equiv; 70% purity) in THF (50 mL) was as added a 1 M solution of tetrabutylammonium fluoride in THF (14.4 mL, 14.40 mmol, 1.20 equiv; [CAS RN 429-41-4]) and the reaction mixture stirred at rt over night. The crude reaction was extracted from a sat. solution of NH4Cl (50 mL) with ethyl acetate (3×50 mL) and the combined organic phases dried over Na2SO4. Purification of the crude reaction product by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a mixture of dichloromethane/methanol (4:1) provided 1.12 g (48%) of the title compound as a slightly orange solid. MS (ISN): 195.1 [M+H]+.