Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[Br:19]C1C=CC(C(C)(C)C)=C(O)C=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[Br:19][C:7]1[CH:2]=[CH:3][C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Br)cc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Using the same general procedure as for the preparation of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 8.18 g (35.7 mmol) of 5-bromo-2-t-butylphenol (Compound D), 0.90 g, 3.6 mmol) of pyridinium p-toluenesulfonate and 4.50 g (4.9 ml, 53.6 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane stirred at room temperature for 21 hours produced a dark yellow solution. At this time an additional 1.80 g (7.2 mmol) of pyridinium p-toluenesulfonate was added to the solution and it was allowed to stir at room temperature for 19 hours. After aqueous workup, a clear, yellow oil was isolated. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a clear, slightly yellow oil. PMR (CDCl3): d 1.38 (9H, s), 1.6-2.1 (6H, m), 3.65-3.75 (1H, m), 3.8-3.95 (1H, m), 5.45 (1H, t, J=2.5 Hz), 7.03 (1H, dd, J=8.4, 2.0 Hz), 7.13 (1H, d, J=8.4 Hz), 7.33 (1H, d, J=2.0 Hz).
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH2:27])=[O:7])[CH:2]([CH3:4])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[CH3:38][C:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH2:46][CH:47]=O)[O:41][N:40]=1.[BH4-].[Na+]>>[CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:47][CH2:46][CH2:45][CH2:44][C:42]1[O:41][N:40]=[C:39]([CH3:38])[CH:43]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(CCCC=O)on1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCN)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCNCCCCc2cc(C)no2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisobutylamide (prepared essentially as described in Example 5.1, 83 mg in 2.5 mL dry CDCl3) at 0° C. was added 240 mg magnesium sulfate followed by 30.6 mg 4-(3-methylisoxazol-5-yl)-butyraldehyde and the mixture stirred at low temperature. After 15 minutes, a cold solution of sodium borohydride (30.2 mg in 1.5 mL dry methanol) was added and the mixture stirred for an additional 15 minutes. At this time the reaction was quenched by the addition of water, extracted with ethyl acetate then methylene chloride and the combined organics dried over sodium sulfate. Purification of the concentrate by preparative TLC on silica gel (methylene chloride:methanol, 9:1) gave the title compound (28 mg). m/e=557 (M+H)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=[O:17])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH2:3]1>CO.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([N:4]2[CH2:3][CH:2]([OH:1])[CH2:5]2)=[O:17])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N1CC(O)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CC(=O)N2CC(O)C2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
1-(3-hydroxyazetidin-1-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.117 mmol) was taken in methanol (20 ml) and at 0° C., Pd—C (10%, 0.5 g) was added. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.42 gm).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[O:20]=[C:21]1[NH:25][CH:24]([C:26](Cl)=[O:27])[CH2:23][CH2:22]1>O>[CH2:1]([NH:13][C:26]([CH:24]1[CH2:23][CH2:22][C:21](=[O:20])[NH:25]1)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CCC(C(=O)Cl)N1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCNC(=O)C1CCC(=O)N1

Procedure:
While cooling and stirring a mixture consisting of 9.2 gm (0.05 mol) of n-dodecylamine and 50 ml of pyridine, 17.3 gm (0.05 mol) of 5-oxo-2-pyrrolidine carboxylic acid chloride were added thereto in small portions, and the resulting mixture was stirred for one hour at room temperature. Thereafter, the reaction mixture was admixed with water, acidified and extracted with chloroform. The organic phase was separated, washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate, yielding 9.0 gm (62% of theory) of the compound of the formula ##EQU5## which had a melting point of 114°-116°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]([CH2:20][CH2:21]/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.O.C(=O)(O)[O-].[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:9]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:20][CH2:21][C@@H:22]([C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:40]=1[F:41])[CH2:23][N+:24]([O-:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC/C=C/[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: OB(O)c1cccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate from Step B (34.0 g, 73.2 mmol), 2,3-difluorophenylboronic acid (28.9 g, 183 mmol) and water (4.62 mL, 256 mmol) in dioxane (240 mL) was degassed with argon for 15 min. To this solution was added sodium bicarbonate (3.08 g, 36.6 mmol), (S)-BINAP (1.28 g, 2.05 mmol) and acetylacetanotobis(ethylene)rhodium(I) (0.472 g, 1.83 mmol). The mixture was stirred at ambient temperature for 2 min then heated to 35° C. After 4 h, (S)-BINAP (255 mg, 0.41 mmol) and acetylacetanotobis(ethylene)rhodium(I) (94 mg, 0.36 mmol) were added. After an additional 2 h, the reaction was partitioned between CH2Cl2 and aqueous NaHCO3. The aqueous layer was extracted with another portion of CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 40:60, to give the title compound. MS: m/z=379 (M-C10H15O4).
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[O:23])[C:12]2=[O:32])=[CH:7][CH2:6]1)[CH3:3].N1CC[CH2:35][CH2:34]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:6]=[CH:7][C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH:13]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[O:23])[C:12]3=[O:32])=[CH:9][CH2:10]2)[CH2:1][CH2:35][CH2:34][CH2:3]1
Reactant: C1CCNC1
Reactant: CN(C)N=C1C=CC(N2C(=O)C(NC(=O)Nc3ccc(Cl)cc3)Cc3ccccc32)=CC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC1Cc2ccccc2N(C2=CCC(=NN3CCCC3)C=C2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.063 mmol) from Example 134, a pre-mixed pyrrolidine (0.037 mL, 0.44 mmol) and HOAc (0.040 mL, 0.70 mmol) were added. The mixture was heated to reflux for 1 h, then was stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (15 mg). MS 488.3 and 490.3 (M+H, Cl pattern).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[S:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][S:11][CH:12]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: OCCc1ccsc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCc2ccsc2)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-4-hydroxybenzonitrile (15.0 g) in THF (100 mL) was added 2-(3-thienyl)ethanol (7.94 mL) and triphenyl phosphine (19.84 g). The reaction was cooled to 0° C. and diethylazodicarboxylate (11.92 mL) was added dropwise. The reaction was stirred at room temperature for 16 h. The solvent was then reduced in vacuo and the residue redissolved in diethyl ether (100 mL). The mixture was stirred at 0° C. for 10 min and then filtered. The filtrate was washed with aqueous sodium carbonate solution (80 mL), 1 M aqueous hydrochloric acid (80 mL) and brine (80 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-bromo-4-(2-thiophen-3-yl-ethoxy)-benzonitrile.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: CCCCOC(=O)c1nc(-c2cccnc2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 3-(tributylstannyl)pyridine: MS (m/z) 344.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1.[CH2:23]([O:30][C:31]([NH:33][C@H:34]([C:38](O)=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:23]([O:30][C:31]([NH:33][C@H:34]([C:38]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:10])=[CH:21][CH:22]=1)=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)c2ccc(OCCO)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2ccc(OCCOC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methoxybenzyl 4-(2-hydroxyethoxy)benzoate (6.6 g, 21.8 mmole), 4-dimethylaminopyridine (0.61 g, 5 mmole) and N-benzyloxycarbonyl-L-valine (6.3 g, 25 mmole) in dichloromethane (80 ml) was added dicyclohexyl-carbodiimide (5.2 g, 25 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated and ethyl acetate (200 ml) was added. The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 10.6 g=90%
Reaction SMILES: C1C2C(C[O:15][C:16]([N:18]([CH2:31][C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH2:19][CH2:20][NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([O:25][CH3:26])=[O:24])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC1C=CC([N+]([O-])=O)=CC=1>CN(C)C=O.ClC(Cl)C>[CH3:30][C:27]([CH3:29])([CH3:28])[C@H:22]([N:21]1[CH2:20][CH2:19][N:18]([CH2:31][C:32]2[N:36]([CH3:37])[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[N:33]=2)[C:16]1=[O:15])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@@H](NCCN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
A solution of the product of Example 148D (0.19 g) in N,N-dimethylformamide (3.5 mL) was treated with diethylamine (0.35 mL), stirred at 25° C. for 1.5 hours and concentrated. A solution of the residue in dichloroethane (7 mL) was treated with bis-(p-nitrophenyl) carbonate (0.128 g, 1.2 equivalents), stirred at 60° C. for 16 hours and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate:dichloromethane (3:2) to give 80 mg (64%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[H-].[Na+].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
(S)-Pyroglutamic acid methyl ester (0.200 g, 1.40 mmol) was dissolved in dry THF (5 ml) and NaH (0.061 g, 1.5 mmol) was added. After gas evolution ceased, 4-nitrobenzyl bromide (0.332 g, 1.54 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution (40 mL) and extracted with EtOAc (2×50 ml). The organic layers were washed with water, brine, dried (MgSO4), filtered, and concentrated to give the title compound as a solid. 1H NMR (CDCl3) δ 8.19 (d, 2H, J=8.6 Hz), 7.40 (d, 2H, J=8.6 Hz), 5.29 (d, 1H, J=15 Hz), 4.19 (d, 1H, J=15 Hz), 4.02 (dd, 1H, J=3,9 Hz), 3.79 (s, 3H), 2.54-2.67 (m, 1H), 2.42-2.51 (m, 1H), 2.27-2.39 (m, 1H), 2.11-2.21 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1(=O)[O:35][C:33](=[O:34])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:33](=[O:34])[C:32]3[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:30]2=[O:35])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (177.9 mg) and triethylamine (98 μL) in THF (2.94 mL) was added phthalic anhydride (105 mg). The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic anhydride (3 mL), and the mixture was stirred at 80° C. for 5 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (252.7 mg).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1>O.ClCCl.O.[Ru](Cl)(Cl)Cl>[F:7][CH2:8][CH2:9][O:10][CH:11]1[C:15](=[O:2])[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)C1CC(OCCF)CN1C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CC(OCCF)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 17 %

Procedure:
A solution of 4.3 g (20.0 mmol) of sodium periodate and 1.7 g (0.6 mmol) of ruthenium(III) chloride hydrate in 50 ml of water was added to 1.45 g (5 mmol) of 1-tert-butyl 2-methyl 4-(2-fluoroethoxy)pyrrolidine-1,2-dicarboxylate in 80 ml of dichloromethane. The mixture was left at room temperature for three days with vigorous stirring. Subsequently, the phases were separated, the aqueous phase was extracted twice with ethyl acetate (25 ml) and the combined organic phases were stirred with 10 ml of isopropanol for 30 min. The mixture was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 0.26 g (17%) of 1-tert-butyl 2-methyl 4-(2-fluoroethoxy)-5-oxopyrrolidine-1,2-dicarboxylate (26) was obtained as.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([CH:9]([C:11](=[O:42])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[C:31][Si](C(C)C)(C(C)C)C(C)C)[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:43])[N:7]([CH:9]([C:11](=[O:42])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[CH:31])[N:14]=1)[CH3:10])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nn(C)c2c(-c3cc(C#C[Si](C(C)C)(C(C)C)C(C)C)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)ncnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1cc(-c2ncnc3c(C)nn(C)c23)cc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl-N-{1-[(4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate D1 (0.52 g, 0.86 mmol), THF (10 ml) and tetrabutylammonium fluoride (1 mol/l solution in THF, 0.95 ml, 0.95 mmol) is stirred at RT for 1 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of sodium hydrogencarbonate and brine. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:10])=[S:9])=[CH:4][CH:3]=1.CO[CH:13](OC)[CH2:14]Br.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:13]=[CH:14][N:10]=2)=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: NC(=S)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-c2nccs2)cc1
Yield: 34.9 %

Procedure:
A stirred mixture of 12.1 grams (0.0703 mole) of 4-chlorophenylthiocarboxamide, 12.1 grams (0.0714 mole) of bromoacetaldehyde dimethyl acetal, and 2 ml of concentrated hydrochloric acid in 280 ml of ethanol was heated at reflux for approximately 18 hours. An additional 1 ml of concentrated hydrochloric acid was added, and the mixture was heated at reflux for two days. The reaction mixture was cooled, and the solvent was removed by evaporation under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1), to yield 4.8 grams of 2-(4-chlorophenyl)thiazole as a solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH:9]1([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:1]([CH2:3][C:4]([NH:16][CH2:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:6])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: NCC1CCCCC1
Product: N#CCC(=O)NCC1CCCCC1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
2-Cyano-N-(cyclohexylmethyl)acetamide was prepared by the method of V. Papesh, J. Org. Chem. 1951, 16, 1879-1889. Ethyl cyanoacetate (Aldrich, 18.41 mL, 173 mmol) was added to neat cyclohexanemethylamine (Aldrich, 19.585 g, 173 mmol), and the resulting solution was stirred for 2 h under nitrogen. At this time, the reaction mixture solidified. After standing for 18 h the white crystalline solid was broken up, filtered, washed with water (150 mL), and dried (0.1 Torr, 40° C.) to provide 2-cyano-N-(cyclohexylmethyl)acetamide (29.030 g, 93%), m.p. 83°-84° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:68]1[CH:69]=[N:70][CH:71]=[C:72]([C:74]([F:77])([F:76])[CH3:75])[CH:73]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:76][C:74]([C:72]1[CH:73]=[C:68]([N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:69]=[N:70][CH:71]=1)([F:77])[CH3:75]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(F)(F)c1cncc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(F)(F)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
Add benzophenone imine (215 mg, 1.19 mmol), cesium carbonate (640 mg, 1.96 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 98 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 90 mg, 0.098 mmol] to the solution of 3-bromo-5-(1,1-difluoroethyl)pyridine (200 mg, 0.9 mmol) in dioxane (10 mL), stir the resulting mixture under nitrogen atmosphere at 100° C. for 16 hrs. Cool the reaction mixture to room temperature, filter off the solid, concentrate the filtrate under reduced pressure, purify by flash chromatography (silica gel, EtOAc:PE=2:1) to yield the title compound (296 mg, 92%). MS: (M+1): 323.
Reaction SMILES: N#N.[NH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.O=[C:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CC#N>[C:16]([O:15][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH:9]([N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:21])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: C1CCNC1
Reactant: CC(=O)CCCNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#N
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(CCCNC(=O)OC(C)(C)C)N1CCCC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of pyrrolidine (79 mg, 1.11 mmol) in dry CH3CN (6 mL) was added tert-butyl (4-oxopentyl)carbamate (291 mg, 1.44 mmol) followed by Na(OAc)3BH (680 mg, 2.88 mmol) at rt. The reaction mixture was stirred at rt until completion of the reaction. Sat. aq. NaHCO3 was then added and the mixture extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC(CH2Cl2-MeOH—NH3) to give pure N-tert-butoxycarbonyl-4-(pyrrolidin-1-yl)pentan-1-amine as a colorless oil. LC-MS-conditions 05c: tR=0.53 min; [M+H]+=257.41. The title compound was obtained after Boc deprotection using 4N HCl in dioxane (10.0 eq.) in CH2Cl2 at rt as a colorless oil.