Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[CH3:18]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:24]3[CH:25]=[CH:26][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (56.0 mg, 0.30 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (3-5% EtOAc-hexanes) afforded the title compound.
Reaction SMILES: O.O.O.O.O.O.[Cl-].[Cr+3:8].[Cl-].[Cl-].[NH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14].[P:18]([O:30][CH2:31][C@H:32]1[O:36][C@@H:35]([N:37]2[C:46]3[N:45]=[CH:44][N:43]=[C:41]([NH2:42])[C:40]=3[N:39]=[CH:38]2)[C@H:34]([OH:47])[C@@H:33]1[OH:48])([O:21][P:22]([O:25][P:26]([OH:29])([OH:28])=[O:27])([OH:24])=[O:23])(=[O:20])[OH:19]>O>[NH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14].[Cr:8].[P:18]([O:30][CH2:31][C@H:32]1[O:36][C@@H:35]([N:37]2[C:46]3[N:45]=[CH:44][N:43]=[C:41]([NH2:42])[C:40]=3[N:39]=[CH:38]2)[C@H:34]([OH:47])[C@@H:33]1[OH:48])([O:21][P:22]([O:25][P:26]([OH:28])([OH:29])=[O:27])([OH:24])=[O:23])(=[O:19])[OH:20]
Reactant: [Cr+3]
Agent: N[C@@H](CS)C(=O)O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [Cl-]
Solvent: O
Product: [Cr]
Reaction time: 1.5 h

Procedure:
Equimolar amounts of chromium chloride hexahydrate, cysteine, and ATP (10 mM each) were mixed in 50 ml of water at a pH of around 3. The mixture was then incubated at room temperature for 1-2 hours to form the chromium-cysteine-ATP complex. This complex was purified by loading 50 ml of the 10 mM chromium-cysteine-ATP mixture onto a SE53 ion-exchange column having a bed volume of approximately 30 ml. The loaded column was washed with 100 ml of water in order to wash off unbound materials. The bound chromium complex was then eluted with 0.25 M ammonium hydroxide. The eluted fractions (4 ml/fraction) were monitored with a UV spectrophotometer for absorption at wavelengths A260 and A280. An example of the eluting profile is shown in FIG. 1.
Reaction SMILES: [Cl-].[Cr+3:2].[Cl-].[Cl-].[NH2:5][C@@H:6]([CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][SH:17])=[O:13])[C:7]([OH:9])=[O:8]>O>[Cr:2].[NH2:5][C@@H:6]([CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][SH:17])=[O:13])[C:7]([OH:9])=[O:8]
Reactant: [Cr+3]
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: O
Product: [Cr]
Temperature: 40 °C
Reaction time: 3 h

Procedure:
One gram (3.7 mmole) of chromium chloride (CrCl3) was dissolved in 40 ml of deionized water to get a green solution. 4.6 g (15 mmole) of glutathione (GSH) dissolved in 40 ml of deionized water were added, the pH of the reaction mixture adjusted to 6, and the reaction mixture was stirred for 3 hours at 40° C. until the solution turned violet. The absorbance peaks for Cr-GSH are 410 and 550 nm.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[N:6]=1)[CH2:2][CH3:3].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:8]1[C:7]([OH:12])=[N:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=1[OH:11])([O-:15])=[O:14]
Reactant: CCCSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
To a clean and dry reaction assembly containing acetic acid (1000 ml) was added fuming nitric acid (340 ml) over a period of 15 to 20 minutes, while maintaining the temperature between 25-30° C. 2-Propylthio-pyrimidine-4,6-diol (400 g) was added to the mixture over a period of 60 minutes at 25-30° C., followed by rinsing of flask with acetic acid (100 ml). The resulting mass was stirred for 1 hour at 25-30° C. After completion of the reaction, water (2400 ml) was added to the mass for 20 minutes at 25-30° C. The resulting slurry was stirred for 1 hour at 25-30° C. The product was isolated by filtration and washed successively with water (4×800 ml). The wet product was dried under reduced pressure at 50-55° C. to produce the 5-nitro-2-propylthiopyrimidine-4,6-diol as a off-white to yellow powder (375 g, HPLC purity: 99.06% by area).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].[Na+].[Cl-].[OH:15][P:16](=[O:43])([O:26][CH2:27][C@H:28]1[O:42][C@@H:32]([N:33]2[CH:39]=[C:37]([CH3:38])[C:36](=[O:40])[NH:35][C:34]2=[O:41])[CH2:31][C@@H:29]1[OH:30])[O:17]P(=O)(OP(=O)(O)O)O.[As](C)(C)(=O)[O-].[Na+].[Cl-].[Cl-].[Ca+2].SC[C@H]([C@@H](CS)O)O>>[CH3:38][C:37]1[C:36](=[O:40])[NH:35][C:34](=[O:41])[N:33]([C@@H:32]2[O:42][C@H:28]([CH2:27][O:26][P:16]([OH:17])([OH:43])=[O:15])[C@@H:29]([OH:30])[CH2:31]2)[CH:39]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: C[As](C)(=O)[O-]
Agent: Cl
Agent: NC(CO)(CO)CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 6 h

Procedure:
To 300 μl of a solution comprising 10 mM Tris-HCl (pH 7.5), 6 mM MgCl2 and 10 mM NaCl, there was added 400 μg of pCDV1 [Okayama & Berg: Mol. Cell. Biol., 3, 280 (1983)] and, after further addition of 500 units of KpnI, the reaction was carried out at 37° C. for 6 hours, whereby the plasmid was cleaved at the KpnI site. The DNA was recovered by phenol-chloroform extraction and ethanol precipitation. About 200 μg of the KpnI-cleaved DNA was added to 200 μl of a solution prepared by adding dTTP in a concentration of 0.25 mM to a buffer (hereinafter abbreviated as TdT buffer) comprising 40 mM sodium cacodylate, 30 mM Tris-HCl (pH 6.8), 1 mM CaCl2 and 0.1 mM dithiothreitol (hereinafter abbreviated as DTT) and, after further addition of 81 units of terminal deoxynucleotidyl transferase (hereinafter abbreviated as TdT) (P-L Biochemicals), the reaction was carried out at 37° C. for 11 minutes, whereby a poly(dT}chain comprising about 67 dT residues was added to each KpnI cleavage site 3' end of pCDV1. About 100 μg of the poly(dT) chain-added pCDV1 DNA was recovered from the above reaction mixture by phenol-chloroform extraction and ethanol precipitation. The DNA was added to 150 μl of a buffer comprising 10 mM Tris-HCl (pH 7.5), 6 mM MgCl2 and 100 mM NaCl, 360 units of EcoRI was further added, and the reaction was carried out at 37° C. for 2 hours. The reaction mixture was treated by the LGT method, and a DNA fragment of about 3.1 kb was recovered. Thus was obtained about 60 μg of the poly(dT) chain-tailed pCDV1. The DNA was dissolved in 500 μl of a solution comprising 10 mM Tris-HCl (pH 8.0) and 1 mM EDTA, the solution was incubated at 65° C. for 5 minutes and then cooled with ice, and 50 μl of 5M NaCl was added. The mixture was subjected to oligo(dA)-cellulose column (Collaborative Research) chromatography. Molecules having a sufficient poly(dT) chain length were adsorbed on the column and they were eluted with a solution comprising 10 mM Tris-HCl (pH 8.0) and 1 mM EDTA. Thus was obtained 27 μg of the poly(dT) chain-tailed pCDV1 (hereinafter abbreviated as vector primer).
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@@H:2]([OH:6])[C:3]([OH:5])=[O:4].CO[C:12](OC)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:13][C:12]1([CH3:14])[O:6][C@H:2]([CH2:1][C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C[C@@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of D-(+)-malic acid (10 g, 75 mmol) in CH2Cl2 (100 mL) was added 2,2-dimethoxypropane (23 g, 225 mmol) and p-toluenesulfonic acid (0.129 g, 0.75 mmol). The reaction mixture was stirred at rt for 4 h, filtered through silica gel (50% EtOAc/hexane) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[Br:14].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5]([Br:14])=[CH:6][CH:7]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(NC(C)=O)ccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 5-acetylamino-2-bromo-benzoic acid methyl ester (ii, 5.44 g, 20.0 mmol) in H2SO4 (50 mL) at 0° C. was added HNO3 (50 mL). The reaction mixture was stirred at 0° C. for 20 min and poured into ice water (200 mL). The mixture was then extracted with EtOAc (3×200 mL). The combined extracts were washed with saturated aqueous NaHCO3 (3×200 mL), H2O (3×200 mL), brine (1×200 mL), and dried with Na2SO4. Flash column chromatography gave the desired product iii as a yellow solid (3.60 g, 57%). 1H NMR (acetone-d6): δ 9.47 (br s, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.89 (d, J=9.0, 1H), 3.84 (s, 3H), 2.10 (s, 3H). Anal. Calcd for C10H9BrN2O5: C, 37.88; H, 2.86; N, 8.83. Found: C, 38.02; H, 2.74; N, 8.74.
Reaction SMILES: O.[OH-].[Na+].[C:4]1([CH2:10][C:11](=[O:13])[CH3:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([CH2:10][CH:11]([OH:13])[CH3:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O)Cc1ccccc1
Temperature: 80 °C

Procedure:
In a 4 liter three-necked flask fitted with a mechanical stirrer and a reflux condenser, were placed 1500 ml of water, 150 g of sodium hydroxide (pellets), 190 ml of ethanol and 180 g of phenylacetone. The mixture was stirred and heated to 80° C., and 150 g of Raney alloy was added very cautiously by small amounts over about 1 hour. During the addition, heating was discontinued and the temperature was maintained at 85°-87° C.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([CH2:9][CH:10]([OH:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
Sodium borohydride (10.0 g) was added portionwise to an ice cold stirred solution of 1-phenylpropan-2-one (30.0 g) in methanol (500 ml). The mixture was stirred for 4 hours, evaporated and partitioned between water (100 ml) and chloroform (200 ml). The organic phase was dried (MgSO4) and evaporated to give the product as a colourless oil (26.4 g).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7]O.CS([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>CC1CCCCC1>[CH2:16]([O:15][CH:5]([N:4]([CH3:10])[CH3:3])[CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CC1CCCCC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(C)C(OCCCCCCCC/C=C\C/C=C\CCCCC)N(C)C
Reaction time: 13 h

Procedure:
In a nitrogen atmosphere, methylcyclohexane (30 mL) and potassium hydroxide (3.1 g, 54.4 mmol) were added to a four-necked flask, and 3-(dimethylamino)-1,2-propanediol (0.72 g, 6.04 mmol: DAP) was dropped under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) was added, and agitation was performed at 40° C. for 13 hours. The reaction was terminated because remaining linoleyl methane sulfonate became 2.1% (degree of conversion: 68.0%, integrated value of isomer: 0.024).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.C([O-])(=O)C.[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH2:34][CH2:35][C:36]2[NH:45][C:39]3=[N:40][CH:41]=[C:42](I)[CH:43]=[C:38]3[N:37]=2)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:42]3[CH:43]=[C:38]4[N:37]=[C:36]([CH2:35][CH2:34][C:30]5[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=[CH:32][N:31]=5)[NH:45][C:39]4=[N:40][CH:41]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)Nc5ccc(N(C)C)cc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 15.5 %

Procedure:
A mixture of 0.400 g of N-(4-dimethylamino-phenyl)-4-bromo-benzenesulfonamide, 0.315 g of bis-(pinacolato)-diboron, 0.019 g of 1,1′-bis-diphenylphosphino)-ferrocene, 0.025 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.332 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.278 g of 2[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.085 g of tetrakis(tbiphenylphosphine)-palladium(0) and a solution of 0.202 g of potassium carbonate and 0.062 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.06 g of the title compound as a solid of m.p. 221-222° C. The mass spectrum shows the molecular peak MH+ at 529.2 Da.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
10% Palladium on carbon (1.2 g) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 12.7 mmol) dissolved in methanol (250 mL). The flask was repeated evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. Purged with nitrogen gas. Filtered the crude reaction mixture through a short diatomaceous earth (Celite®) plug. Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. Dried residue on high vacuum overnight to afford 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (2.44 g, 94% yield) as a reddish solid. LC-MS (M+H)+205.2. 1H NMR (500 MHz, CDCl3) δ ppm 8.35 (s, 1H) 7.36 (d, J=8.55 Hz, 1H) 6.29-6.34 (m, 2H) 3.80 (s, 3H) 2.46 (s, 3H).
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[CH2:10]([NH2:13])[CH:11]=[CH2:12].C(N(CC)C(C)C)(C)C>CO>[F:8][C:5]([F:6])([F:7])[C:4]([NH:13][CH2:10][CH:11]=[CH2:12])=[O:9]
Reactant: C=CCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyltrifluoroacetate (14.2 grams, 100 mmol) was added to a solution of allylamine (4.05 grams, 6 ml, 80 mmol) and N,N-diisopropylethyl amine (10.32 grams 7.3 ml, 80 mmol) in methanol (30 ml). The reaction mixture was stirred at room temperature for 15 hours. The solvent was thereafter removed under reduced pressure and the product (see, Compound 1 in Scheme 1 below) was extracted with ethyl acetate.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCOCC1>[N:5]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)=[C:1]=[O:2]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(=O)oc2cc(N=C=O)ccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
A 200-mL three-neck flask fitted with a dry ice condenser and magnetic stirrer was charged with a solution of 20% phosgene in toluene solution (2.0 mL) and dioxane (80 mL). To this mixture was added 7-amino-4-methyl-2H-chromen-2-one (2.00 g, 11.4 mmol). The mixture was stirred at 100° C. for 12 h. The initial yellow colour disappeared and a white solid precipitated. An additional 20% phosgene in toluene solution (7.0 mL) was added and the mixture heated for an additional 5 h, at which time the solution cleared. Excess phosgene and traces of HCl was removed by bubbling nitrogen gas through the solution. The cloudy solution was filtered to remove unreacted 7-amino-4-methyl-2H-chromen-2-one and concentrated to give 76 (0.5 g, 25%) as a white solid. H1 NMR (500 MHz, CDCl3): δ=7.50 (1H, d, J=7.40 Hz, ArH), 7.46 (2H, s, ArH), 6.20 (1H, s, ArH), 2.35 (3H, s, CH3): ir (CH2CL2) 2314 (N═C═O), 1726 and 1615 cm−1.
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[CH:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:17]#[C:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:13][C:12]3([CH3:14])[CH3:15])=[CH:26][CH:27]=1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1
Yield: 23.4 %

Procedure:
Following general procedure F and using 2-cyclopropyl-4,4-dimethyl-6-ethynyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13 g, 0.571 mmol), 4-iodo phenyl acetic acid methyl ester (Reagent B, 0.16 g, 0.58 mmol), triethyl amine (0.5 mL), anhydrous tetrahydrofuran (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, 0.05 g of the title compound was obtained as an oil. It was further purified by preparative normal phase HPLC on a partisil-10 silica column using 10% ethyl acetate in hexane as the mobile phase (0.01 g, 6%).
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O.CC(C)=O>[CH2:14]([O:13][C:11]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred and cooled (0° C.) suspension of (+/−)-3-aminobutanoic acid (5 g; 48.5 mmol) in H2O (30 mL) was added NaOH pellets (3.88 g; 97 mmol) portionwise. The resultant mixture was stirred for 15 min to obtain a clear solution. Benzyl chloroformate (7.1 mL; 50 mmol) as a solution in acetone (30 mL) was added dropwise over 15 min. The reaction was allowed to warm to room temperature and stirred for 3.5 h. The reaction was washed twice with EtOAc (20 mL). The aqueous layer was separated and acidified to pH 2 with 6 N HCl. A precipitate formed and was collected by filtration, washed with H2O and dried in a vacuum oven to afford 3-{[(benzyloxy)carbonyl]amino}-butanoic acid as a white solid. LCMS=238.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.34-7.30 (m, 5H), 5.18 (br s, 1H), 5.10 (s, 2H), 4.15-4.10 (m, 1H), 2.59 (s, 2H), 1.27 (d, J=6.9 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)(C)(C)C.[ClH:18].CO>CO>[ClH:18].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1
Reactant: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)N1CCC(N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(1-acetylpiperidin-4-yl)carbamate (330 g, 1.36 mol) in MeOH (1000 mL) was added HCl/MeOH (4M, 300 mL) over 30 min to maintain the temperature at 0° C. After addition, the mixture was stirred at 0° C. for another 2 h and then concentrated to give the crude product. Two batches were run in parallel and produced a combined crude product weight of 310 g. This crude was used in next step without further purification. 1H NMR (400 MHz, D2O) δ 4.35 (dd, J=2.0, 12.0 Hz, 1H), 3.98-3.85 (m, 1H), 3.44-3.30 (m, 1H), 3.18-3.05 (m, 1H), 2.75-2.58 (m, 1H), 2.06-1.92 (m, 5H), 1.61-1.31 (m, 2H); LCMS (m/z): 143.1 (M+1).
Reaction SMILES: CS(C)=O.[C:5]([NH:12][C@H:13]([CH2:18][OH:19])[CH2:14][CH:15]([CH3:17])[CH3:16])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CCN(CC)CC>C(Cl)Cl>[C:5]([NH:12][C@H:13]([CH:18]=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of sulfur trioxide pyridine complex (7.8 g, 49.1 mmol, 3.0 equiv) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) was added to a solution of BOC-L-Leucinol (3.56 g, 16.4 mmol. 1 equiv) and Et3N (8 mL) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) at 0° C. The reaction mixture was stirred at 23° C. for 30 min, then poured into ice water (300 mL), and extracted with Et2O (2×200 mL). The combined organic layers were washed with 0.5 M HCl (150 mL), half saturated NaHCO3 (150 mL) and H2O (2×150 mL), then dried over Na2SO4, and concentrated to afford crude BOC-L-Leucinal as pale yellow oil (3.48 g, 99%). This material was used without further purification. 1H NMR (CDCl3) δ 0.92-0.94 (m, 6H), 1.44 (s, 9H), 1.59-1.64 (m, 1H), 1.67-1.85 (m, 2H), (4.21 (m, 1H), 5.12 (s, br, 1H), 9.57 (s, 1H).