Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18](COCC[Si](C)(C)C)[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCN(Cc4ccccc4)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@@H]4CCN(Cc5ccccc5)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a 20 ml vial containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (51 mg, 0.085 mmol) dissolved in THF (1 ml) was added TBAF (1.0 M in THF, 1.0 ml, 1.0 mmol). The vial was backfilled with nitrogen then sealed and placed in heat block at 80° C. for 3 h. The reaction was cooled to room temperature, quenched with acetone (2 ml) and sat'd NaHCO3 (20 ml). The mixture was stirred for 1 h then extracted with EtOAc and the organics washed with brine. The aqueous was again extracted with EtOAc and the organics washed with brine. The organics were combined, dried over MgSO4, filtered and concentrated. The crude was dissolved in MeOH and EtOAc, supported on Celite, and purified by flash chromatography (4 g silicycle) with 0% to 10% MeOH in dichloromethane to 10% MeOH in EtOAc. The appropriate fractions were combined and concentrated. The solid was triturated with dichloromethane, Et2O, and hexanes to isolate 11 mg (29%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide as a white solid. LC-MS (M+H)+=470; 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (br. s., 1H), 9.10 (s, 1H), 8.34-8.54 (m, 3H), 7.68 (dd, J=9.8, 1.8 Hz, 1H), 7.11-7.26 (m, 5H), 6.97 (td, J=9.1, 1.9 Hz, 1H), 4.60 (br. s., 1H), 4.16 (s, 3H), 3.61 (s, 2H), 2.82-2.97 (m, 1H), 2.58-2.75 (m, 2H), 2.29-2.44 (m, 2H), 1.75 (br. s., 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]#[C:13][Si](C)(C)C)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]=12)#[CH:13]
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(F)cc3)c2c1O
Reactant: NCC(=O)O
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(F)cc3)nsc12

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(4-fluoro-phenyl)-4-hydroxy-7-trimethylsilanylethynyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 370.1 (M−1).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].S(F)([F:11])(=O)=O.[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>C(#N)C>[F:11][CH:5]1[CH2:4][NH:3][C@H:1]([C:13]([OH:14])=[O:16])[CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(F)F
Reactant: CCN(CC)CC
Agent: [K+]
Solvent: CC#N
Product: O=C(O)[C@@H]1CC(F)CN1
Reaction time: 20 h

Procedure:
13.0 mL of acetonitrile, 3.50 g (34.59 mmol, 3.46 eq) of triethylamine, and 1.60 g (9.92 mmol, 0.99 eq) of triethylamine tris(hydrogen fluoride) complex, followed by lowering the inside temperature to −40° C. and then bubbling 2.00 g (19.60 mmol, 1.96 eq) of sulfuryl fluoride from a cylinder. The inside temperature was returned to room temperature, and stirring was conducted for 20 hours. Conversion of the reaction was found by gas chromatography measurement to be 100%. The reaction-terminated liquid was poured into a potassium carbonate aqueous solution [prepared from 6.30 g (45.58 mmol, 4.56 eq) of potassium carbonate and 100.0 mL of water], followed by extraction two times with 100.0 mL of ethyl acetate. The recovered organic layer was concentrated under reduced pressure, followed by vacuum drying, thereby obtaining a crude product of 4-fluoroproline derivative represented by the following formula,
Reaction SMILES: [CH3:1][C:2]([S:10][CH2:11]Cl)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[P:13]([S-:19])(=[S:18])([O:16][CH3:17])[O:14][CH3:15].[Na+]>CC(C)=O>[P:13]([S:19][CH2:11][S:10][C:2]([CH3:9])([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[S:18])([O:16][CH3:17])[O:14][CH3:15]
Reactant: CC(C)(SCCl)c1ccccc1
Reactant: COP(=S)([S-])OC
Agent: [Na+]
Solvent: CC(C)=O
Product: COP(=S)(OC)SCSC(C)(C)c1ccccc1
Reaction time: 8 h

Procedure:
To 0.078 mole of chloromethyl α,α-dimethylbenzyl sulfide in 100 ml. of acetone is added 15.3 grams (0.078 mole) of sodium O,O-dimethyl phosphorodithioate followed by stirring overnight. The reaction mixture is maintained at a temperature of 25° C. to 30° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:20])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[C:10](C)[N:9]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:45][C@H:46]1[CH2:48][C@H:47]1[C:49](O)=[O:50].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:45][C@H:46]1[CH2:48][C@H:47]1[C:49]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][N:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:20])[CH:17]=2)=[O:50]
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Cc1c(F)cncc1-c1cc2cnc(N)cc2c(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)[C@@H]3C[C@@H]3F)cc2cn1
Temperature: 70 °C
Yield: 44.1 %

Procedure:
A mixture of 7-(5-fluoro-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-amine (80 mg, 0.30 mmol), HATU (246 mg, 0.63 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (62 mg, 0.60 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.19 mmol) in DMF (2 mL) was heated at 70° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (45 mg, 43%). 1H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 9.31 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H), 8.07 (s, 1H), 4.98 (m, 1H), 2.90 (s, 3H), 2.36 (s, 3H), 2.30 (m, 1H), 1.78-1.66 (m, 1H), 1.28-1.17 (m, 1H). LCMS (Method G): RT=7.78 min, M+H+=355.0.
Reaction SMILES: C([C:7]1([CH2:26]CCCCC)[C:19]2[CH:18]=[C:17](B(O)O)[CH:16]=C[C:14]=2[C:13]2[C:8]1=[CH:9][C:10](B(O)O)=[CH:11][CH:12]=2)CCCCC.Br[C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[N:37][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.C1(C)C=CC=CC=1>[N:37]1[CH:38]=[C:33]([C:11]2[CH:10]=[CH:9][C:8]3[C:7]4[C:19](=[CH:18][C:17]([C:33]5[CH:34]=[CH:35][C:36]([C:39]6[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=6)=[N:37][CH:38]=5)=[CH:16][CH:26]=4)[C:14]([CH2:26][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH2:19][CH2:18][CH3:17])[C:13]=3[CH:12]=2)[CH:34]=[CH:35][C:36]=1[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCCCCCC1(CCCCCC)c2cc(B(O)O)ccc2-c2ccc(B(O)O)cc21
Reactant: Brc1ccc(-c2cccnc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(-c3ccc(-c4cccnc4)nc3)ccc2-c2ccc(-c3ccc(-c4cccnc4)nc3)cc21
Temperature: 25 °C
Yield: 32.8 %

Procedure:
Into a flask, 0.6 g of 9,9-dihexyl-fluorene-2,7-diboronic acid, 0.5 g of 5-bromo-2,3′-bipyridine, 115 mg of Pd(PPh3)4, 1.27 g of tripotassium phosphate, and 20 ml of toluene were put, and the solution was stirred at reflux temperature for 6.5 hours under argon atmosphere. After heating, the reaction liquid was cooled to room temperature, and washed by a saturated sodium chloride aqueous solution. The organic layer was concentrated in an evaporator, and the concentrates were purified by activated alumina column chromatography. The concentrates were recrystallized in a heptane/ethyl acetate mixed solvent, and thus 150 mg of 2,7-bis(2,3′-bipyridine-5-yl)-9,9-dihexylfluorene was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([O:21]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1>C(O)(=O)C.O.C1COCC1>[CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([OH:21])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
At 20°, 390 mg. of (5Z,13E)-(15R)-16,16-dimethyl-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated for 16 hours with 10 ml. of a mixture of glacial acetic acid/water/THF (65/35/10); the mixture is evaporated under vacuum and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 305 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[CH2:9]([Br:14])[CH2:10][CH2:11][CH2:12][CH3:13].C1(C)C=CC=CC=1>C(#N)C>[Br-:14].[CH2:9]([N+:6]1[CH:7]=[CH:8][N:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=CCn1ccnc1
Reactant: CCCCCBr
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=CCn1cc[n+](CCCCC)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
1-Allylimidazole (1.0 mL: 0.009 mol) was ice-cooled, and pentyl bromide (3.43 mL: 0.28 mol) was added thereto dropwise. After the dropwise addition, the temperature was gradually increased to 25° C., and subsequently stirring was carried out continuously for 24 hours. The product was a pale brown viscous liquid. This was added dropwise to 100 mL of toluene, and a viscous liquid that separated out was recovered and dried. The same procedure was repeated once more. The viscous liquid thus obtained was made into an acetonitrile solution, active carbon that had been heated and vacuum-dried was added thereto, and stirring was carried out for about 24 hours. After the acetonitrile was distilled off, the viscous liquid was recovered with dichloromethane, and the solvent was distilled off. The 1-pentyl-3-allylimidazolium bromide thus obtained was a liquid at room temperature, the amount collected was 2.16 g (yield; 90%), the glass transition temperature (Tg) was −61.3° C., and the ionic conductivity at 30° C. was 0.244 (mS/cm). The results are given in Table 1. The structure was confirmed by 1H-NMR measurement. The results are shown below.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1cccs1
Product: O=C(CNC(=O)c1cccs1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and thiophene-2-carboxylic acid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.[H][H]>[Ni]>[CH3:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Ni]
Product: CCCCCCCCCCCCCCC
Temperature: 240 °C
Reaction time: 12 h

Procedure:
1000 g of 1-hexadecanol (Lorol C 16 from Cognis) were initially charged in a stirrable pressure vessel with 10 g of a nickel catalyst (Ni-5249 P from Engelhard; Ni content=63% by weight) and heated to 240° C. Subsequently, over a period of 12 h, hydrogen was added through a sparging tube at a pressure of 20 bar and the reaction gases were simultaneously discharged through a valve in the reactor lid. Thereafter, the product was cooled, discharged and filtered. This reaction product was fractionated in a distillation to give pure pentadecane and then deodorized with nitrogen. This gives a colorless, liquid and low-odor product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.O[C:15]1[C:20]([N+]([O-])=O)=[CH:19][C:18]([C:24](=[O:26])[CH3:25])=[CH:17][C:16]=1OC.[CH3:29]CC(C1C=CC=CC=1)=O.Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:25][C:24]([C:18]2[CH:19]=[CH:20][C:15]([CH3:29])=[CH:16][CH:17]=2)=[O:26])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: COc1cc(C(C)=O)cc([N+](=O)[O-])c1O
Reactant: CCC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1

Procedure:
A solution containing 5.49 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 5.37 g of 4,-methylacetophenone in 50 ml of tetrahydrofuran was added a catalytic amount of gaseous hydrogen chloride and refluxed for 4.5 h. The solvent was evaporated in vacuo and the residue crystallized from ether-petroleum-ether, yield 1.85 g (21%), m.p. 184°-186° C.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[O:22]1CCOCC1>O.CCOC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=[O:22]
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(C(Br)Br)cc2n1
Reactant: C1COCCO1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2ccccc2)c2ccc(C=O)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(dibromomethyl)-4-phenylquinoline-2-carbonitrile (2.02 g, 4.81 mmol) in 1,4-dioxane (75 mL) was added a solution of silver nitrate (3.27 g, 19.24 mmol) in 30 mL of water, and the reaction mixture stirred 1 h at reflux. After cooling to rt, the mixture was diluted with EtOAc and filtered. The solid was washed with EtOAc and the organic phases combined. The filtrate was washed twice with water and the combined aqueous layers were back-extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (eluting with acetone-CH2Cl2-toluene, 10:40:50) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 10.39 (s, 1H), 8.80 (s, 1H), 8.21 (s, 2H), 8.07 (s, 1H), 7.66 (m, 5H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29](CCl)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:14]1=[O:22]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(-c2ccc(OC)cc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g. of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 3.8 g. of 4-methoxybenzylchloride and 0.72 g. of NaJ. Eluant for chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.Br[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11]>C1COCC1>[CH:3]1([O:7][CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCC1
Reactant: CC(Br)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OC1CCC1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 732 mg of sodium hydride in 15 ml THF, 2.0 g of cyclobutanol in 0.5 ml THF were added dropwise and stirred for 30 minutes at 25° C. The reaction mixture was then cooled to 0° C. and 2.11 g of (+/−) 2-bromopropanamide in 0.5 ml tetrahydrofuran were added dropwise and then stirred for 18 hours at 25° C. The reaction mixture was poured onto ice-water and extracted once with 75 ml dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo after filtration. The crude product thus obtained was purified by column chromatography on silica gel with hexane/0-50% ethyl acetate. Yield: 0.79 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:9][C:10]1[C:11]([C:19]2[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=2)=[N:12][O:13][C:14]=1[C:15]([F:18])([F:17])[F:16]>C1COCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:24]([C:22]1[S:23][C:19]([C:11]2[C:10]([CH3:9])=[C:14]([C:15]([F:17])([F:18])[F:16])[O:13][N:12]=2)=[CH:20][CH:21]=1)=[O:25]
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Reactant: Nc1cnccc1Cl
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)Nc3cnccc3Cl)s2)noc1C(F)(F)F
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of 3-amino-4-chloropyridine (129 mg, 1.0 mmol) in THF (2 mL) was treated with solid 5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (148 mg, 0.5 mmol, as prepared in Example 2 Method B) and allowed to stir for 1 hr. The reaction was then evaporated and the residue chromatographed on silica gel with EtOAc/hexanes (70%) as eluant to afford product as a colorless solid (31 mg, 16%). 1H NMR (CDCl3) 2.39 (d, J=1.5, 3 H), 7.39 (d, J=5.3, 1 H), 7.56 (d, J=7.56, 4.1, 1 H), 7.72 (d, J=4.1, 1 H), 8.22 (s, 1 H), 8.33 (d, J=4.7, 1 H), 9.61 (s, 1 H). 13C NMR 8.0, 114.8, 118.7 (q, J=271), 129.0, 129, 7, 132.9, 134.6, 140.5, 143.8, 146.1, 157.7, 159.0, 19F NMR −63.1. LC/MS 6.34 min, [M+1]+ 388.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12.[H-].[Na+].Cl.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44]>CN(C=O)C>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][N:10]1[CH:11]=[CH:12][C:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[C:3]3[C:15]([C:16](=[O:36])[C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:29]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:28]=[N:27][N:26]=5)[CH2:21][CH2:20]4)=[O:18])=[CH:14][NH:13][C:4]=23)=[N:9]1
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3cc[nH]n3)ncc(F)c12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.6 %

Procedure:
1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (40 mg, 0.08 mmol) in DMF (1 mL) was treated with sodium hydride (60% in oil, 33.0 mg, 0.8 mmol) and stirred at room temperature for 5 min. 2-chloro-N,N-dimethylethanamine hydrochloride (115.2 mg, 0.8 mmol) was added and the mixture was stirred at rt for 1 h. Reaction was quenched with H2O and concentrated under reduced pressure. The residue was dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a white solid (15 mg, 34%). 1H NMR (500 MHz, MeOD) δ ppm 2.96 (s, 6 H) 3.37 (s, 2 H) 3.63 (s, 2 H) 3.82 (s, 2 H) 3.89 (s, 2 H) 4.76 (s, 2 H) 7.11 (s, 1 H) 7.59 (s, 1 H) 7.64 (s, 2 H) 7.68 (s, 2 H) 7.92 (s, 1 H) 8.25 (s, 1 H) 8.36 (s, 1 H). LCMS: m/e 558 (M+H)+, ret time 1.37 min (method 3).
Reaction SMILES: C([O:8][C:9](=[O:69])[C@@H:10]([NH:23][C:24](=[O:68])[CH2:25][O:26][C:27](=[O:67])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@H:37]2[C@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=3[F:49])[C@:40]([C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][C:53]=3[F:59])([C:50]#[N:51])[C@H:39]([CH2:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH:38]2)=[O:36])=[C:30]([O:65][CH3:66])[CH:29]=1)[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])C1C=CC=CC=1>[Pd].C(O)(C)C>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([C@@:40]2([C:50]#[N:51])[C@H:39]([CH2:60][C:61]([CH3:62])([CH3:64])[CH3:63])[NH:38][C@@H:37]([C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:27]([O:26][CH2:25][C:24]([NH:23][C@@H:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:69])=[O:8])=[O:68])=[O:67])=[CH:29][C:30]=3[O:65][CH3:66])=[O:36])[C@@H:41]2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=2[F:49])=[C:53]([F:59])[CH:54]=1
Reactant: COc1cc(C(=O)OCC(=O)N[C@@H](CCC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Pd]
Solvent: CC(C)O
Product: COc1cc(C(=O)OCC(=O)N[C@@H](CCC(=O)O)C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL three-necked flask, (S)-dibenzyl 2-(2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)acetamido)pentanedioate (Example 70, 61 mg, 62.0 μmol) was combined with isopropanol (5 mL) at room temperature. Then palladium on carbon (33.0 mg, 31.0 μmol) was added. The flask was flushed with nitrogen, and then replaced with hydrogen. It was stirred at room temperature under hydrogen balloon. After 30 min, the reaction mix was filtered through a Celite cake to remove the catalyst. The Celite cake was washed thoroughly with isopropanol. The filtrate and washing solutions were combined and concentrated to give a crude product, which was purified with reverse phase high-performance liquid chromatography. The pure fractions were concentrated and lyophilized to give (S)-2-[2-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-acetylamino]-pentanedioic acid as a white product (20 mg, 33% yield). LCMS (ES+) m/z calcd. for C38H39Cl2F2N4O9 [(M+H)+]: 803. found: 803.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:33])([CH3:32])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=O)=[C:18]([O:34][CH3:35])[CH:17]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:32])([CH3:33])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]3)=[C:18]([O:34][CH3:35])[CH:17]=1
Reactant: NC(=O)c1ccc2c(N)cccc2n1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 160 mg (0.87 mmol) of 5-aminoquinoline-2-carboxylic acid amide is reacted with 341 mg (1.05 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 0.96 ml of concentrated acetic acid and 20 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 340 mg (79% of theory) of the product is obtained.