Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[N:21])[CH:14]=3)[N:11]=[C:10]([C:22](O)=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[N:21])[CH:14]=3)[N:11]=[C:10]([C:22]([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: N#Cc1cc(-n2nc(C(=O)O)cc2-c2cccc(Cl)c2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: N#Cc1cc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cccc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place starting from the compound of Example 109A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 45 mg (77% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[OH:12].CCOC(C)=O>C(OC)(C)(C)C.P([O-])([O-])([O-])=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[OH:12]
Reactant: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: COc1cccc([C@H](O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Silica gel (EM Sciences, 230-400 mesh, 215 g) was added to a solution of (R)-enriched α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5a) (72 g, 0.16 mol, 82% ee) in t-BuOMe (320 mL). The resulting slurry was concentrated (35° C./20 torr) to give a light yellow powder. A mixture of the powder, partially purified Candida cylindracea lipase (17.1 g, equivalent to 522 g of crude enzyme from Sigma) in phosphate buffer (0.1M, pH 7, 5.2 L) was stirred at 45° C. for 4 days. EtOAc (4 L) was added and the mixture was stirred at room temperature for 1 hour. Solid material was removed by filtration, and the two phases in the filtrate were separated. Both the solid and aqueous layer were extracted with EtOAc (2 L). The combined organic solutions were concentrated (35° C./20 torr) to a residue which was purified by flash chromatography (SiO2, 10 cm×15 cm, eluted with 1:1 EtOAc; hexane (8 L) and 1:19 EtOAc: MeOH (8 L)). The desired fractions (TLC, Rf 0.16, acetone) were combined and concentrated (35° C./20 torr) to a residue which was dissolved in methylene chloride (800 mL). The solution was washed with 0.5N NaOH (2×600 mL), brine (600 mL) and dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30° C./20 torr) to give a solid which was recrystallized from cyclohexane (2 L) to give (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a white solid (31 g, 52% yield, 99.9% ee); m.p. 113-114° C., [α]D20+14.0° (c 0.49, CHCl3).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([CH3:18])=[C:12]3[N:11]=[C:10]2[CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.[H-].[Na+].BrCC1C=CC(/[CH:32]=[C:33](/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)\[C:34]([O:36][CH3:37])=[O:35])=CC=1>CN(C=O)C>[C:34](/[C:33](/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[CH:32]\[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([CH3:18])=[C:12]3[N:11]=[C:10]2[CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1)([O:36][CH3:37])=[O:35]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(O)cc1
Reactant: COC(=O)/C(=C\c1ccc(CBr)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(/C=C(\C(=O)OC)c2ccccc2)cc1
Yield: 37.8 %

Procedure:
To a solution of 30 mg (0.171 mmol) of 2-propyl-7-methylimidazo[4,5-b]pyridine (Example 2, Step D) dissolved in 1 mL of dry DMF was added 11 mg of a 60% oil dispersion of NaH (1.5 eq) and the reaction mixture was stirred under an N2 atmosphere. After stirring at room temperature for 30 minutes the product from Step C (27.4 mg, 0.082 mmol) dissolved in 0.5 mL DMF was added via syringe. The reaction mixture was quenched with saturated NH4Cl solution, and the solvent was removed under in vacuo. The residue was dissolved in EtOAc and washed with H2O and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 50% ethyl acetate/hexane to provide 13.2 mg (38%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=1)=[O:14]>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]=1[Br:22])[CH3:2]
Reactant: O=C(c1ccc(O)c(Br)c1)c1cccs1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(C(=O)c2cccs2)cc1Br
Yield: 95 %

Procedure:
This ester was prepared with 95% yield by reaction of ethylbromoacetate with (3-bromo-4-hydroxyphenyl) (2-thienyl) ketone. The product was an oil.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([C:10](=[O:14])[CH:11]=[CH:12][CH3:13])=[C:3]1[CH3:15].C(O)(=[O:18])C>O>[CH3:15][C:3]1[C:2](=[O:18])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]=1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13]
Reactant: CC(=O)O
Reactant: CC=CC(=O)C1=C(C)C(Br)CCC1(C)C
Solvent: O
Product: CC=CC(=O)C1=C(C)C(=O)CCC1(C)C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
125 g of crude 3-bromo-2,6,6-trimethyl-1-(but-2-enoyl)-cyclohex-1-ene [prepared under letter a] were added dropwise to a mixture of 100 g (1 Mole) CrO3, 100 ml acetic acid and 100 ml of water, kept at 20°-25°. After addition of the reactants the reaction mixture was heated under stirring at 40° for 30 min., and finally diluted with 1 l of water. After neutralization of the reactin mixture by means of a 10 % aqueous solution of NaOH, the obtained mixture was submitted to a steam distillation. 3 l of the thus obtained distillate were then extracted with ether (3 × 500 ml), the organic layer was washed with water, dryed over Na2SO4 and finally concentrated under reduced pressure. There were thus obtained 68.2 g (73 %) of a semi-cristalline product, b.p. 71°-116°/o.01 Torr, which was finally cristallized in hexane to afford 51.3 g (55 %) of pure 2,6,6-trimethyl-1-(but-2-enoyl)-cyclohex-1-en-3-one, m.p. 68°-69°.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@@H:24]([CH2:58][OH:59])[C@@H:25]([OH:57])[C@@H:26]([OH:56])[C@H:27]([OH:55])[C:28]([NH:30][C@H:31]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:32][C:33]([O:35]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:34])=[O:29])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@@H:24]([CH2:58][OH:59])[C@@H:25]([OH:57])[C@@H:26]([OH:56])[C@H:27]([OH:55])[C:28]([NH:30][C@H:31]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)CN)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1

Procedure:
Diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-((N-benzyloxycarbonylglycyl)-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (273 ml) was dissolved in methanol (30 ml) and stirred at room temperature with 10% palladium on activated carbon (50 mg) under hydrogen atmosphere for 1.5 hours. After dilution with methanol, the mixture was filtrated and the filtrate was concentrated under reduced pressure to give a residue, which was recrystallized from methanol-diethylether to afford the title compound (154 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-dichlorobenzoic acid (63 μL, 0.45 mmol) and N,N-dimethyl formamide (DMF) (50 μl) was dissolved in dichloromethane (10 mL). Oxalyl chloride (0.57 mL, 6.7 mmol) was added and the solution stirred at room temperature for 2 hours. The reaction was monitored to completion by LC-MS. The reaction was concentrated in vacuo to afford crude 2,4-dichlorobenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([CH:19]=O)[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>CO.ClCCl>[CH2:15]([N:14]1[C:10]2[C:9]3[CH:8]=[C:7]([CH2:19][NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: COc1cccc(CN)c1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(C=O)cc3c21
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(CNCc2ccc3nc(N)c4ncn(CC(C)C)c4c3c2)c1
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
4-Amino-1-isobutyl-1H-imidazo[4,5-c]quinoline-8-carbaldehyde (237 mg, 0.66 mmol) and 3-methoxybenzylamine (100 mg, 1.3 mmol) were combined in methanol (25 mL) and dichloromethane (1 mL). The solution was purged with nitrogen gas and a 1M solution of sodium cyanoborohydride in THF (2 mL) was added. The reaction was stirred for 30 minutes. Additional sodium cyanoborohydride in THF (1M, 1 mL) was added and the reaction was stirred for an additional 15 minutes. Aqueous sodium carbonate (1%, 0.25 mL) was added and the reaction was stirred for 7 days. The solvent was removed under reduced pressure and approximately equal portions of chloroform and water were added. The fractions were separated and the organic fraction was sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-20% CMA). Recrystallization from acetonitrile provided 25 mg of 1-isobutyl-8-{[(3-methoxybenzyl)amino]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 125-126° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=[O:3])[CH3:2].[C:25]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[O:28][C:25](=[O:27])[CH3:26])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccccc1OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)=O)cc1NC(=O)c1ccccc1OC(C)=O
Yield: 66.9 %

Procedure:
In 80 ml of tetrahydrofuran were dissolved 2 g of methyl 2-(2'-acetoxybenzamido)-4-aminobenzoate and 11.8 g of 2-acetoxybenzoylchloride, and to the solution was added dropwise a solution of 0.6 g of triethylamine in 5 ml of tetrahydrofuran while stirring under cooling with ice. Ten minutes after completion of the addition, the mixture was returned to room temperature, followed by stirring at that temperature for one hour. The reaction mixture was then poured into diluted hydrochloric acid-ice to precipitate crystals. The crystals were recovered by filtration and recrystallized from methanol to obtain 2.0 g of methyl 2,4-bis(2'-acetoxybenzamido)-benzoate having a melting point between 143° - 145°C. This product was confirmed to be identical to that obtained in Example 6.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]#[CH:18]>C(#N)C.C1(C)C=CC=CC=1>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 4-hydroxyl-benzyl alcohol 13 (2.5 g, 20 mmol) in acetonitrile (50 mL), K2CO3 (3.96 g, 200 mol %) was added at room temperature (see Scheme 4). After stirring for 1 h, the mixture was treated dropwise with an 80 wt % solution of propargyl bromide in toluene (3.27 g, 110 mol %) and the reaction mixture was heated to 50° C. for 48 h, cooled, filtered and concentrated under vacuum. The residue was purified by flash chromatography using an eluent of 100% to 30% hexane in AcOEt. Evaporation of the collected fractions gave propargyl ether 14 as a yellow liquid (3.12 g, 95.5%): 1H NMR (CDCl3) δ (ppm): 7.28 (d, 2H, Ph-H), 6.96 (d, 2H, Ph-H), 4.69 (d, 2H, PhCH2), 4.57 (s, 2H, CCH2O), 2.54 (t, 1H, OH), 2.39 (s, 1H, CH); 13C NMR (CD3OD) δ (ppm): 157.4, 134.53, 128.97, 115.34, 78.97, 76.04, 65.10, 56.24. Anal. Calcd for C10H10O2: C, 74.07; H, 6.17. Found: C, 73.64; H, 6.03.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])=[O:4].[O-:45][C:46]#[N:47].[K+].C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[O:45]=[C:46]1[NH:47][CH2:2][C:3](=[O:4])[N:5]1[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33]
Reactant: N#C[O-]
Reactant: O=C(CCl)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CNC(=O)N1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 81.2 %

Procedure:
A solution of (2S,4S)-2-(chloroacetylamino)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (1.0 g), potassium cyanate (1.3 g) and tetra-n-butylammonium iodide (0.2 g) in acetonitrile (50 ml) was stirred at 60°-80° C. for 8 hours To a reaction mixture was added ethyl acetate (150 ml) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (50 g) eluting with a mixture of chloroform and acetone (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-(2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (0.82 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C([O-])(O)=O.[Na+].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:12](=[O:14])[CH3:13])=[N:2]1
Reactant: Nc1cc[nH]n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cc[nH]n1
Temperature: 25 °C
Yield: 49 %

Procedure:
1H-pyrazol-3-amine (ALDRICH, 11.32 g, 0.136 mol) was dissolved in 100 mL of distilled water. NaHCO3 (34 g, 0.408 mol) was slowly added. Acetic anhydride was then added dropwise and the resulting suspension was heated at reflux overnight. Then, the mixture was allowed to cool down to room temperature and the solid obtained was filtered off and characterized as the title compound (8.4 g, 0.067 mol, 49% yield). After concentration of the filtrate, a second precipitate was obtained (2.7 g, 0.021 mol, 16% yield), also characterized as the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.23 (br s, 1H), 10.30 (br s, 1H), 7.55 (br s, 1H), 6.45 (br s, 1H), 1.97 (s, 3H). [ES+MS] m/z 126 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30]([OH:32])=[O:31])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]([CH3:62])[CH2:59][CH2:60]O>CN(C=O)C>[CH3:57][N:58]([CH3:62])[CH2:59][CH2:60][O:31][C:30]([C:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[C:11]=1[CH3:29])=[O:32]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCCN(C)C)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of Example 9 (32 mg, 0.073 mmol) in DMF (1 mL), was added diiosopropylethylamine (125 μL, 0.73 mmol) followed by HATU (30 mg, 0.080 mmol). After 1 hour, N,N-dimethylethanolamine (73 μL, 0.73 mmol) was added, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by reverse phase HPLC using a gradient 20-70% acetonitrile in water with 0.1% ammonia to yield the title compound as a white solid (4 mg).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][N:13]=1>N1C=CC=CC=1.CCOC(C)=O>[C:18]1([C:15]2[N:16]=[CH:17][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cnc(-c2ccccc2)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
Phenyl chloroformate (0.64 mL, 5.1 mmol) was added to a vigorously stirred solution of 2-amino-5-phenylpyrazine 1-1 (794 mg, 4.64 mmol) in pyridine (10 mL) at room temperature. After being stirred at room temperature overnight, the mixture was diluted with EtOAc to give a suspension, in which the desired compound precipitated out. The suspension was successively washed with 1 N KHSO4, brine and dist. water. The precipitate was collected by filtration and dried to give phenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (847 mg, 63%). The filtrate was concentrated under reduced pressure to produce precipitate, which was collected and dried to give the second crop (340 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](O)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:34][S:31]([CH:28]3[CH2:30][CH2:29]3)(=[O:33])=[O:32])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N2CCOCC2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Yield: 26.9 %

Procedure:
A mixture of 3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (70 mg, 0.19 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol), cyclopropane sulfonamide (69 mg, 0.57 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (24 mg, 27%) as a light yellow solid: LC/MS m/e calcd for C25H31N3O4S (M+H)+: 470.6, observed: 470.3.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([C:27]#[CH:28])[C:14]=2[CH3:29])=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[C:19]([C:17]1[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([C:27]#[CH:28])[C:14]([CH3:29])=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=2)[CH:18]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: C#Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1c(C)c(C#Cc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
A solution of [4-(5-tert-butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 145, 0.023 g, 0.057 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 1M lithium hydroxide (0.5 mL, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.020 g, 91%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:18](=[O:21])[NH:19][CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C@@H:9]([NH:7][CH3:6])[C:18]([NH:19][CH3:20])=[O:21]
Reactant: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1F)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamic acid tert-butylester (2.4 g; 7.73 mmol) was dissolved in methylene chloride. Trifluoroacetic acid (10 mL) was added and the reaction mixture was stirred for 30 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 1.1 g of (2R)-3-(2-fluorophenyl)-N-methyl-2-(methylamino)-propionamide.