Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:40][C:41]([F:61])([F:60])[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:55][C@H:54]3[C@H:56]([NH2:59])[CH2:57][CH2:58][C@H:53]3[CH2:52]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:61][C:41]([F:40])([F:60])[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:55][C@H:54]3[C@H:56]([NH:59][C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH2:57][CH2:58][C@H:53]3[CH2:52]2)(=[O:49])=[O:50])[CH:45]=[CH:46][CH:47]=1
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (53.1 mg, 0.247 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (94 mg, 0.247 mmol) were combined in dichloromethane (2 mL). After 10 minutes, (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (75 mg, 0.224 mmol) from Step A of Example 254 was added. After stirring for 10 more minutes, N-ethyl-N-isopropylpropan-2-amine (0.098 mL, 0.561 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution, extracted with 2 mL of dichloromethane, washed with 0.1 N HCl, and concentrated in vacuo. The crude material was purified using a 12 g silica gel cartridge with a gradient of 1-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give the title compound: 1H NMR (501 MHz, pyridine-d5, temperature 90° C.) δ ppm 8.29-8.30 (bs, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.66-7.72 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 4.29-4.32 (m, 1H), 4.06-4.10 (m, 1H), 3.68-3.71 (m, 1H), 3.46-3.51 (m, 1H), 3.34-3.42 (m, 1H), 3.26 (dd, J=9.9, 7.4 Hz, 1H), 3.06-3.17 (m, 2H), 2.55-2.57 (m, 2H), 2.09 (d, J=3.0 Hz, 1H), 1.88-1.98 (m, 3H), 1.80-1.88 (m, 1H), 1.59-1.68 (m, 1H), 1.55 (dd, J=13.2, 8.7 Hz, 1H), 1.50 (s, 9H), 1.25-1.37 (m, 1H); MS (ESI+) m/z 532 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C@@:5]([CH3:12])([C:7](OCC)=[O:8])[CH2:4][O:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>CCOCC>[CH:7]([C@@:5]1([CH3:12])[CH2:4][O:3][C:2]([CH3:13])([CH3:1])[O:6]1)=[O:8]
Reactant: CCOC(=O)[C@@]1(C)COC(C)(C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC1(C)OC[C@](C)(C=O)O1
Reaction time: 0.5 h

Procedure:
To a solution of 5 g of ethyl (R)-2,2,4-trimethyl-1,3-dioxolan-4-carboxylate in 30 ml of anhydrous ether, cooled down to -78° , were added dropwise while stirring for about 30 minutes, 4.55 g of diisobutylaluminium hydride in 25 ml of anhydrous ether. The temperature was held at -78° during the entire addition. The stirring was continued at -70° for a further 5 hours in order to complete the reaction. Excess reagent was then decomposed by cautious addition of a mixture of 2 ml of methanol and 2 ml of water, the cooling bath was removed and the reaction mixture was slowly brought to room temperature. While vigorously stirring under ice-cooling, 5 ml of 1-M sodium bicarbonate were added thereto. The addition of a total of 3 g of solid sodium bicarbonate in small portions led to the precipitation of aluminium hydroxide. After further vigorous stirring at 0° for 30 minutes, the precipitate was filtered off and washed three times with 30 ml of ether. The combined ether phases were dried over magnesium sulfate and the solvent was distilled off under normal pressure at about 65° bath temperature. The residue was distilled at about 80° bath temperature and 12 mmHg and there were thus obtained 3.2 g of (R)-4-formyl-2,2,4-trimethyl-1,3-dioxolan.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:14][Mg+].[Br-]>CCOCC.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)COc1cccnc1Cl
Reactant: C[Mg+]
Agent: Cl[Ni]Cl
Agent: [Br-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1ncccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
2-Chloro-3-(2,2,2-trifluoro-ethoxy)-pyridine (1.21 g, 5.73 mmol) (Hoglen, D. K. PCT Int. Appl. (2000), WO 2000005212) and 1,3-bis(diphenylphosphino)propane nickel (II) chloride (217 mg, 0.40 mmol) were taken up in Et2O (40 mL) at room temperature. MeMgBr (3.0M in Et2O, 2.25 ml, 5.73 mmol) was added dropwise via syringe over 3 minutes to give a tan slurry. The mixture was refluxed for 16 h, cooled to room temperature, quenched with water (60 mL) and extracted with CH2Cl2 (8×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-methyl-3-(2,2,2-trifluoro-ethoxy)-pyridine as an orange oil. Purification via column chromatography on silica gel (CH2Cl2) afforded 2-methyl-3-(2,2,2-trifluoro-ethoxy)-pyridine as a yellow solid (0.46 g, 42%). 1H NMR (CDCl3) δ 2.52 (s, 3H), 4.36 (q, 2H, J=7.5 Hz), 7.06-7.14 (m, 2H), 8.19 (d, 1H, J=3.0 Hz). 19F NMR (CDCl3) δ 2.03 (s).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[CH:13]([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])([CH2:15][CH3:16])[CH3:14]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([N:17]([CH:18]([CH2:20][CH3:21])[CH3:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:8]
Reactant: CCC(C)NC(C)CC
Reactant: Cc1ccc(C(=O)O)cc1Cl
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)N(C(=O)c1ccc(C)c(Cl)c1)C(C)CC
Temperature: 25 °C

Procedure:
To these 17.9 g of the chloride of 3-chloro,4-methylbenzoic acid, dissolved in 60 ml of anhydrous benzene, were added 12.9 g of di-sec.butylamine dissolved in 15 ml of anhydrous C6H 6 and 12.3 g of triethylamine. The whole was then boiled to reflux temperature for 1 hour and was then left to cool down to room temperature. The reaction mass was then concentrated to dryness under reduced pressure. The residue was washed with acidulated H2O, with H2O and extracted with ethyl ether. The etheral extract was dried on anhydrous Na 2 SO4, filtered, and the solvent was then removed by reduced pressure. The oily residue was fractionally distilled at a pressure of 0.05 mm Hg. The fraction which passed over at 143°-144°C was collected. Thereby were obtained 26.5 g of 3-chloro,4-methyl-N,N-di-sec.butyl-benzamide.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28]>CN(C=O)C.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>[CH3:30][Si:29]([C:27]#[C:28][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl 3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.65 g, 4.40 mmol) and Cu(I)I (168 mg, 0.880 mmol) in triethylamine (3.07 mL, 22.0 mmol) and DMF (40 mL) for 20 min. Then, ethynyltrimethylsilane (2.16 g, 22.0 mmol) and Pd(PPh3)4 (254 mg, 0.220 mmol) were added, the reaction was flushed with nitrogen, sealed and stirred at rt for 24 h. The reaction was concentrated to a brown oil, and purified by BIOTAGE® Horizon (160 g SiO2, 20-40% EtOAc/hexanes) to yield (1R,3S,5R)-tert-butyl 3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (980 mg) as a yellow solid. LC-MS retention time 3.230 min; m/z 346.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) d ppm 7.18 (s, 1 H), 4.77 (dd, J=9.2, 5.1 Hz, 1 H), 3.20 (br. s., 1 H), 3.14-3.39 (m, 1 H), 2.33 (dd, J=13.2, 9.4 Hz, 1 H), 1.69-1.78 (m, 1 H), 1.34-1.56 (m, 1 H), 1.49 (s, 9 H), 0.85 (dt, J=8.5, 5.7 Hz, 1 H), 0.41-0.47 (m, 1 H), 0.22-0.24 (m, 9 H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:14]=[CH:15][NH:16][C:17](=O)[C:18]=4[N:19]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2>C(#N)C.CN(C)C=O>[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][N:22]1[C:17]1[C:18]2[N:19]=[C:10]([C:8]3[CH:9]=[C:4]4[CH:3]=[CH:2][NH:1][C:5]4=[N:6][CH:7]=3)[CH:11]=[CH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=c1[nH]cnc2ccc(-c3cnc4[nH]ccc4c3)nc12
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: c1ccc2c(c1)CCN(c1ncnc3ccc(-c4cnc5[nH]ccc5c4)nc13)C2
Temperature: 60 °C
Yield: 65 %

Procedure:
0.20 g of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one and 139 μl of 1,2,3,4-tetrahydroisoquinoline are suspended in 10 ml of acetonitrile and 1 ml of dimethylformamide in a flask. 0.65 g of (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate, 255 μl of 1,8-diaza-bicyclo[5.4.0]undec-7-ene are subsequently added, and the mixture is heated at 60° C. under nitrogen until the reaction has proceeded to completion (HPLC check, about 5 hours). A precipitate precipitates out of the reaction solution. This is filtered off, rinsed with water and dried, giving 0.20 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine (“A6”) as white solid (yield 65%, content 94%); MS-FAB (M+H+)=379.1; Rf (polar method): 1.86 min;
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCOCCO
Yield: 93.2 %

Procedure:
A suspension of 30.0 g (202.5 mmol) of phthalic anhydride, 20 mL (21.0 g, 199.4 mmol) of 2-(2-aminoethoxy)-ethanol in 400 mL of benzene was added 1.0×10-2 g (5.3×10-5 mmol) of TsOH.H2O. The reaction flask was connected to a Dean-Stark condenser and then heated to reflux for 14 h. The solvent was removed at reduced pressure and the residue was purified by SiO2 column chromatography (hexanes/AcOEt 1:1 then CHCl3 /MeOH 20:1) gave 43.7 g (93.1%) of 13 as a light yellow syrup. This syrup slowly crystallized on standing at room temperature overnight as needle-like crystals. mp 66°-66.5° C. Rf (hexanes/AcOEt 1:1) 0.17. 1H NMR (CDCl3) d 2.41 (t, 1H, J=6.2 Hz, OH), 3.57-3.93 (m, 8H), 7.69-7.87 (m, 4H). 13C NMR (CDCl3) d 37.52, 61.62, 68.24, 72.24, 123.36, 131.97, 134.00, 168.38 (C=O). Anal Calcd for C12H13NO4 : C, 61.28; H, 5.53; N, 5.96. Found: C, 61.34; H, 5.62; N, 5.94.
Reaction SMILES: [OH:1][CH:2]([CH:7]([OH:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>S([O-])([O-])(=O)=O.[Cu+2].CC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[O:16][C:17]([CH3:22])([CH3:18])[O:1][CH:2]2[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)C(O)C(O)c1ccc(OC)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C1OC(C)(C)OC1c1ccc(OC)cc1
Reaction time: 16 h

Procedure:
Methyl 2,3-dihydroxy-3-(4-methoxyphenyl)propanoate (3.5 g, 15.5 mmol), copper sulphate anhydrous (4.3 g, 27 mmol, 1.8 equiv.) and acetone (40 ml, excess) were stirred in the presence of a catalytic amount of para-toluene sulphonic acid at 35° C. After 16 hours, the copper sulphate was removed by filtration, and the filtrate was removed and evaporated to dryness on a rotary evaporator. The product was purified by flash column chromatography using DCM as eluant. Evaporation of the appropriate fractions left methyl 5-(4-methoxyphenyl)-2,2-dimethyl -1,3-dioxolane 4-carboxylate as a clear, colourless oil (4.0 g, 96%). [a]D=+37.4° (THF, conc.=0.01712, 20° C). 1H-NMR was in accordance with expected signals.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:8]2[CH2:9][CH2:10][N:5]3[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[CH:6]3[CH2:7]2)=[O:22])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)N2CCNCC21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)N2CCN(C(=O)Nc3ccc(F)cc3)CC21
Temperature: 50 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Hexahydro-1,1-dimethyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.10 g, 0.59 mmol) was dissolved in tetrahydrofuran (10 mL). 4-Fluorophenyl isocyanate (0.12 g, 0.88 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:9). After purification, the crystals, which were precipitated while concentrating under reduced pressure, were collected by filtration to obtain the title compound (136 mg, yield 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl.Cl[CH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH3:32]>CC(N(C)C)=O>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][CH2:25][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: CN1CCCC1CCCl
Reactant: Cc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(CCc2ccccc2OCCC2CCCN2C)c1
Yield: 9.8 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3-methylphenyl)ethyl]phenol (prepared as described in Preparation 25), 1.05 g of potassium t-butoxide and 0.870 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 150 mg (yield 11%) of the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li]C.[Br-:10].[Mg+2:11].[Br-]>C1COCC1>[Br:10][Mg:11][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: [Mg+2]
Reactant: Cc1ccccn1
Reactant: [Br-]
Agent: [Li]C
Solvent: C1CCOC1
Product: Br[Mg]Cc1ccccn1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of picoline (31.9 mL, 1.5 eq) in THF (300 mL) was added MeLi (202 mL, 1.6 M, 1.5 eq) drop-wise at −40° C. under nitrogen. The reaction mixture was allowed to warm to −20° C. and stirred for 10 min. and then cooled to −40° C. and magnesium bromide (59.4 g, 1.5 eq) was added in three portions. The reaction mixture was allowed to warm to rt, stirred for 30 min to provide bromo(pyridin-2-ylmethyl)magnesium.
Reaction SMILES: [F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32])=[O:28].C(O)(=O)C.O>C1COCC1>[F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])=[O:28]
Reactant: CCCCC(F)(F)C(=O)CC[C@@H]1[C@H](C/C=C\CCCCCC(=O)OCC(=O)c2ccccc2)C(=O)C[C@H]1OC1CCCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The compound (16-a)(0.514 g) was dissolved in the solvent mixture (acetic acid:water:THF=4:2:1)(30 ml), and the solution was maintained overnight at room temperature. The titled compound (16-b) was obtained by purifying the crude product on silica gel column [yield:0.272 g(61%)].
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CC(C)=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a suspension of methyl valinate hydrochloride (10.0 g, 59.7 mmol) and sodium carbonate (15.8 g, 149 mmol) in acetone (200 ml)-water (100 mL) was added 4-bromobenzenesulfonyl chloride (12.7 g, 49.7 mmol) at 0° C., and the mixture was stirred at room temperature for 12 hr after addition. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with 0.1N hydrochloric acid, water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to give the title compound as a white powder (14.7 g, 84%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 18 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2,2-di methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.51–7.41 (s, 1H), 7.34–7.10 (m, 13H), 6.99–6.80 (m, 2H), 4.81 (s, 1H), 3.40–3.26 (m, 2H), 2.96–2.78 (m, 2H), 2.50–2.25 (m, 3H), 1.98–1.82 (m, 2H), 1.79–1.68 (m, 2H), 1.68–1.45 (m, 4H), 1.23 (s, 9H); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[O:12])[CH2:6]1.[O:23]=[C:24]1[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[O:25]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[O:12])[CH2:6]1)[C:29]([C:26]1[O:25][C:24](=[O:23])[NH:28][CH:27]=1)=[O:30]
Reactant: CNCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)C(=O)c1c[nH]c(=O)o1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-(methylamino)ethyl)morpholine-4-carboxylate (step 2)(169 mg, 0.487 mmol), 2-oxo-2,3-dihydrooxazole-5-carboxylic acid ((Example 21, step 1)) (161 mg, 0.487 mmol), T3P® (50% in DMF) (426 μl, 0.730 mmol) and Huenig's base (425 μl, 2.433 mmol) in DMF (1622 μl) was stirred at room temperature for 20 hours. The resulting mixture was diluted with EtOAc and washed with water. The organic portion was dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was dry loaded with silica onto an ISCO 4 g column eluting with 0-100% EtOAc (1% acetic acid) in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:22][C@H:21]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][C@H:15](C(OC(C)(C)C)=O)[C:14](=[O:30])[N:13]1[C@@:9](N)([CH2:10][C@@H:11]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=4)[N:35]=[C:34]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:33]=3)[CH2:12]1)[C:8](=[O:51])[NH:7]2)=[O:5])C.[Li+].[OH-:53]>C1COCC1.O.CO>[C:6]([O:53][C:14]([NH:13][C@@H:15]1[C:14](=[O:30])[N:13]2[C@@H:9]([CH2:10][C@@H:11]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=4)[N:35]=[C:34]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:33]=3)[CH2:12]2)[C:8](=[O:51])[NH:7][C@@:6]2([C:4]([OH:3])=[O:5])[C@@H:21]([CH2:22]2)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1)=[O:30])([CH3:22])([CH3:21])[CH3:4]
Reactant: [OH-]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCC[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@@]1(N)C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C/CCC[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@@]1(N)C(=O)N2
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C/CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5C=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1

Procedure:
Following the experimental and purification procedure of Step 1i, (1S,4R,6S,12S,16R)-7-trans-12-tert-butoxycarbonyl-amino-16-(7-methoxy-2-phenylquinolin-4-yloxy)-2,13-dioxo-3,14-diazatricyclo-[12.3.0.04,6]heptadec-7-ene-4-carboxylic acid ethyl ester (185 mg, 0.265 mmol) was reacted with 64 mg (1.6 mmol) of LiOH in 15.5 mL of 9:5:1.5 of THF/H2O/MeOH to afford (1S,4R,6S,12S,16R)-7-trans-12-tert-butoxycar-bonyiamino-16-(7-methoxy-2-phenylquinolin-4-yloxy)-2,13-dioxo-3,14-diazatricyclo[12.3.0.04,6]heptadec-7-ene-4-carboxylic acid (180 mg, 100%): 1H NMR (300 MHz, CD3OD) δ 1.24 (s, 9H), 1.33-1.43 (m, 1H), 1.61-1.97 (m, 6H), 2.10 (brs, 1H), 2.28-2.36 (m, 1H), 2.70 (m, 2H), 3.94 (s, 3H), 4.17 (d, J=10.6 Hz, 1H), 4.28 (d, J=4.8 Hz, 1H), 4.65-4.70 (m, 1H), 5.34 (dd, J=15.7, 5.9 Hz, 2H), 5.53-5.62 (m, 2H), 7.14 (d, J=9 Hz, 1H), 7.32 (s, 1H), 7.39 (s, 1H), 7.56 (m, 3H), 8.01-8.02 (m, 2H), 8.22 (d, J=9.2 Hz, 1H). LC-MS (Method E-retention time: 1.49), MS m/z 671 (M++1). HRMS m/z (M+H)+ calcd for C37H43N4O8: 671.3081, found 671.3080. Step 3j: Preparation of Compound 3, Example 3 (1S,4R,6S,12S,16R)-7-trans-[4-Cyclopropanesulfonyl-aminocarbonyl-16-(7-methoxy-2-phenylquinolin-4-yloxy)-2,13-dioxo-3,14-diazatricyclo[12.3.0.04,6]heptadec-7-en-12-yl]carbamic acid tert-butyl ester