Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>COCCOC.C(N(CC)CC)C.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:8][C:6]1[CH:7]=[C:2]([C:14]#[C:13][CH2:12][OH:15])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C#CCO
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1cc(C#CCO)ccc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 82.9 %

Procedure:
A suspension of bromoarene 2 (447 mg g; 2.06 mmol); tetrakis(triphenylphosphine) palladium(0) (145 mg, 0.12 mmol) and copper(I)iodide (143 mg, 0.75 mmol) in degassed ethyleneglycol dimethylether (2.5 mL) and triethylamine (1.5 mL), was stirred at room temperature under nitrogen in the dark for 10 min and then treated with neat prop-2-yn-1-ol (0.7 mL, 12 mmol) (or any other alkyne of choice, 5 eq.), and the mixture stirred under the same conditions for 48 h, diluted with dichloromethane (50 mL), filtered through a celite pad and concentrated. Purification by flash chromatography (eluent 50 to 75% AcOEt in hexane) afforded compound 72 (328 mg, 83% yield).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](C2CC(=O)N(O)C2=O)=[O:12])[C:4](=[O:21])[CH:3]=[CH:2]1.[NH2:23][C@H:24]([C:28]([NH:30][C@H:31]([C:33]([OH:35])=[O:34])[CH3:32])=[O:29])[CH:25]([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.Cl>>[O:22]=[C:1]1[CH:2]=[CH:3][C:4](=[O:21])[N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:23][C@@H:24]([CH:25]([CH3:27])[CH3:26])[C:28]([NH:30][C@@H:31]([CH3:32])[C:33]([OH:35])=[O:34])=[O:29])=[O:12]
Reactant: O=C(CCCCCN1C(=O)C=CC1=O)C1CC(=O)N(O)C1=O
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](C)C(=O)O
Yield: 113.9 %

Procedure:
Maleimidocaproyl N-hydroxysuccinimide (1.619 g, 5.25 mmol, 1.05 eq.) and H-Val-Ala-OH (0.941 g, 5 mmol, 1 eq.) were placed in a 25 mL recovery flask with a stir bar and the flask was flushed with nitrogen. DMF (4.7 mL) was added and the resulting white slurry was stirred. DIPEA (0.87 mL, 5 mmol, 1 eq) was added and the mixture was allowed to stir at room temperature overnight. The mixture was cooled in an ice/water bath and 2M HCl (3 mL, 6 mmol) was added dropwise. The viscous mixture was transferred to a separatory funnel and the reaction vessel rinsed with sat. NaCl (7 mL), EtOAc (10 mL), sat NaCl (10 mL) and EtOAc (5 mL). After separation of the aqueous phase, it was extracted with additional EtOAc (2×15 mL). The combined organic extracts were washed with sat NaCl (4×15 mL), until the washings were pH ˜3.5. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 5 as a white solid (2.172 g, 114% crude yield). Crude 5 was suspended in warm CH2Cl2 (35 mL) and filtered to remove a fine white solid. The solids were rinsed with additional CH2Cl2 (3 mL). Toluene (5 mL) was added and the mixture was cooled in an ice/water bath, which resulted in a thick slurry. The solids were collected by filtration, washed with a cold mixture of CH2Cl2 (12 mL) and toluene (2 mL) and dried by pulling air through the sample overnight to give 5 as a white solid (1.327 g, 70% yield). TLC: Rf=0.26, 10% MeOH in CH2Cl2. 1H NMR (CDCl3) (ppm) 0.95 (d, J=17 Hz, 3H), 0.98 (d, J=17 Hz, 3H), 1.30 (m, 2H), 1.40 (d, J=17 Hz, 3H), 1.61 (m, 4H), 2.06 (m, 1H), 2.25 (dt, J=4, 19 Hz, 2H), 3.35 (s, 1H), 3.49 (t, J=17 Hz, 2H), 4.20 (d, J=18 Hz, 1H), 4.38 (m, 1H), 6.80 (s, 2H). Analytical HPLC (0.1% formic acid): tR 9.05 min. LC-MS: tR 11.17 min, m/z (ES+) found 381.9 (M+H)+, m/z (ES−) found 379.9 (M−H)−.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH:14]=[N:13]2)[CH2:9]1)=[O:7])(C)(C)C.F[C:40](F)(F)[C:41](O)=[O:42].CCN(C(C)C)C(C)C.C(O)(=O)C(C)O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:42][CH:41]([CH3:40])[C:6]([N:8]1[CH2:9][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH:14]=[N:13]2)[CH2:11]1)=[O:7]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)ccc1-2
Reactant: O=C(O)C(F)(F)F
Agent: CC(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)C(=O)N1CC(n2cc(-c3ccc4c(c3)OCCc3sc(-c5ncnn5C(C)C)nc3-4)cn2)C1
Reaction time: 2 h
Yield: 16 %

Procedure:
3-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester (2.2 mmol) was dissolved in 5 mL of methylene chloride and treated with 2 mL of trifluoroacetic acid. After 2 h, aqueous workup and concentration of the organics gave the crude deprotected azetidine as a colorless solid that was used in the next step without purification. Crude 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (190 mg) was dissolved in 3 mL of THF and treated sequentially with DIPEA (0.23 mL, 1.3 mmol), lactic acid (0.10 L, 1.3 mmol) and HATU (333 mg, 0.88 mmol). After 2 h at room temperature, aqueous workup and extraction with ethylacetate gave a crude solid that was purified by reverse phase HPLC to give 345 as a colorless solid (35 mg, 16%). LCMS: 506.2. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=2.3 Hz, 1H), 8.33 (d, J=8.3 Hz, 1H), 8.11 (s, 2H), 7.48 (dd, J=8.3, 1.7 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H), 5.84 (m, 1H), 5.28 (m, 1H), 5.23-5.17 (m, 1H), 4.80-4.69 (m, 1H), 4.60-4.50 (m, 1H), 4.39 (t, J=5.0 Hz, 2H), 4.34 (m, 1H), 4.22-4.12 (m, 2H), 3.45 (t, J=5.0 Hz, 2H), 1.56 (d, J=6.6 Hz, 6H), 1.23 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[Cl:20].C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>[Cl:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:3]1[N:4]=[CH:5][C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:7][C:2]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(Nc1cnc(-c2ccncc2Cl)c(Cl)n1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1cnc(-c2ccncc2Cl)c(-c2ccccn2)n1)C1CC1
Reaction time: 20 h
Yield: 48.1 %

Procedure:
An oven dried resealable Schlenk tube was charged with N-[6-chloro-5-(3-chloropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide (0.2 g, 0.65 mmol), 2-(tributylstannyl)pyridine (0.38 g, 1.04 mmol) and xylene (4 mL). The Schienk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 150° C. oil bath. After 20 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Silica gel flash chromatography (98:2 dichloromethane/methanol) furnished the title compound of Example 22 as a light brown solid (110 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][CH:19]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:20][C:21](Cl)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:21][CH2:20][CH:19]([CH3:18])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CCCC(C)CC(=O)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)CCCC(C)CCc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 4-bromo-biphenyl (7.00 g, 0.030 mol), aluminium chloride (4.40 g, 0.033 mol) and 3,7-dimethyloctanoyl chloride (step 2) (6.90 g, 0.036 mol), in dry DCM was prepared at room temperature. The stirring reaction mixture was left to react at room temperature until g.l.c. and t.l.c. analyses revealed a complete reaction, the reaction mixture was then treated with triethylsilane (9.30 g, 0.080 mol) and left stirring overnight. The reaction product was extracted into DCM (2×100 ml) and the combined organic layers were washed with brine, water and dried (MgSO4). The product was adsorbed onto silica gel and purified by column chromatography [DCM] and recrystallised from ethanol to yield a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[C:4]([NH2:18])[C:3]=1[NH2:19].[CH3:20][C:21](=O)[C:22](=O)[CH3:23]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)=[C:4]2[C:3]=1[N:19]=[C:21]([CH3:20])[C:22]([CH3:23])=[N:18]2
Reactant: CC(=O)C(C)=O
Reactant: COc1cc(OC)cc(-c2ccc(Br)c(N)c2N)c1
Solvent: CCO
Product: COc1cc(OC)cc(-c2ccc(Br)c3nc(C)c(C)nc23)c1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A mixture of 4-bromo-3′,5′-dimethoxy-biphenyl-2,3-diamine (Step 85.7) (3 g, 9.3 mmol) and 2,3-butanedione (1 mL, 11.1 mmol, 1.2 equiv) in EtOH (60 mL) was stirred at reflux for 2 h, allowed to cool to rt and stirred for 16 h. Additional 2,3-butanedione (0.4 ml) was added. The reaction mixture was stirred at reflux for 2 h, allowed to cool and concentrated to half of the initial volume. The resulting yellow precipitate was collected vacuum filtration providing 2.9 g of the title compound: ES-MS: 373.1/375.0 [M+H]+; tR=5.60 min (System 1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][O:8][CH2:9][CH2:10][N+]23CCC(C(O)(C4C=CC=CC=4)C4C=CC=CC=4)(CC2)CC3)=[CH:5][CH:6]=1.[Br-:33].C(O)CC.C(O)CCC.CN(C=O)C>CN1C(=O)CCC1.CS(C)=O.CC(N(C)C)=O>[Br:33][CH2:10][CH2:9][O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccccc3)(CC1)CC2
Reactant: [Br-]
Solvent: CCCO
Solvent: CN(C)C=O
Solvent: CCCCO
Product: BrCCOCc1ccccc1

Procedure:
In one aspect, the alcohol used in the preparation of umeclidinium bromide may be, for example, any isomer of propanol or butanol, such as n-propanol. Alternatively, the reaction may be performed in the presence of a dipolar aprotic solvent, which has a boiling point greater than 90° C., including but not limited to, DMF, DMA, DMSO or NMP.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14][CH3:15])[CH3:12].CS(OS(C)(=O)=O)(=O)=O.N1CCCC1.Cl>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:13]2[CH2:14][CH2:15][CH2:12][CH2:11]2)[CH3:9])[N:7]=1
Reactant: CCN(CC)CC
Reactant: CC(O)c1cccc(Br)n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(c1cccc(Br)n1)N1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanol (Example 3, Step 1) (0.5 g, 2.48 mmol) in tetrahydrofuran (4 mL) at 0° C. was charged with triethyl amine (1.04 mL, 7.42 mmol), and then a solution of methanesulfonic anhydride (0.56 g, 3.22 mmol) in tetrahydrofuran (6 mL) added over 30 minutes. The reaction mixture was stirred at 0° C. for 2 hrs and then pyrrolidine (0.21 mL, 2.48 mmol) was added and the mixture was warmed to room temperature. After sixteen days the reaction mixture was poured into aqueous hydrogen chloride (1 M, 10 mL) and dichloromethane (10 mL) The layers were separated and the organic layer was extracted with aqueous hydrogen chloride (1 M, 10 mL). The combined aqueous layers were neutralized with aqueous sodium hydroxide (2 M) until pH=10 and then extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:17][CH2:16][CH2:15][CH2:14][Cl:13])[C:6]=2[CH:10]=1
Reactant: Clc1ccc2nn[nH]c2c1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCCn1nnc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
6-chloro-benzotriazole (15.3 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted with dichlormethane to produce 19.2 g of 6-chloro-1-(4-chlorobutyl)-1H-benzotriazole, with a yield of 79.0%.
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:1]([CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][O:11][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(CCCCCCCC)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 107.8 %

Procedure:
2-Octyl-1-dodecanol (20 ml, 56.14 mmol) and anhydrous triethylamine (16 ml, 112.28 mmol) were dissolved in dry dichloromethane (60 ml). The solution was cooled to 0° C. and methanesulfonyl chloride (5.2 ml, 67.36 mmol) in dry dichloromethane (40 ml) added dropwise. After completion of the addition, the mixture was stirred at 0° C. for 3 hours and then refrigerated (2-8° C.) overnight. The reaction mixture was poured on ice (500 grams), allowed to warm to room temperature, and extracted with ether (3×150 ml). The organic phase was washed consecutively with water (150 ml), 2% H2SO4 (150 ml), water (150 ml), saturated sodium bicarbonate (150 ml) and again with water (150 ml). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure, yielding 22.8 grams of methanesulfonic acid 2-octyl-dodecyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([S:12]C(OC(C)(C)C)=O)[CH2:9][CH:8]1[CH2:20][NH2:21])=[O:6])[CH:2]=[CH2:3].Cl>C(O)(=O)C.O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6]>[NH2:21][CH2:20][CH:8]1[CH2:9][CH:10]([S:12][S:12][CH:10]2[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:8]([CH2:20][NH2:21])[CH2:9]2)[CH2:11][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: C=CCOC(=O)N1CC(SC(=O)OC(C)(C)C)CC1CN
Agent: [Fe+6]
Agent: Cl
Agent: [C-]#N
Solvent: CC(=O)O
Solvent: O
Product: C=CCOC(=O)N1CC(SSC2CC(CN)N(C(=O)OCC=C)C2)CC1CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-allyloxycarbonyl-2-aminomethyl-4-t-butoxycarbonylthiopyrrolidine (10 mmol) in acetic acid (25 ml), was saturated with hydrogen chloride and heated on a steam bath for 5 minutes. The solution was filtered and the filtrate evaporated. The residue was taken up in 2.5N aqueous solution of sodium hydroxide (25 ml) and ethanol (10 ml). A solution of potassium hexacyanoferrate (11 mmols) in water (20 ml) was added portion wise until a yellow colour persisted. The reaction was stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with water, a saturated aqueous solution of sodium chloride and dried (MgSO4). The solvent was removed by evaporation to give diallyl 4,4'-dithiodi[2-(aminomethyl)pyrrolidin-1-carboxylate] as a brown oil. NMR (DMSO-d6): 1.88(m,1H); 2.34(m,2H); 2.87(m, partially obscured); 3.20(m,1H); 3.55(m,1H); 3.76(m, 1H); 3.90(m,1H); 4.5 (m,1H); 5.2(m,2H); 5.94(m,1H): M/S CI (M+H)+= 431.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Br:16][C:17]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:18]=1[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.ClC1C=CC=CN=1>C(Cl)Cl.[OH-].[Na+]>[Br:16][C:17]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:18]=1[C:19]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]=1
Reactant: Cc1cccc(C(=O)NCCc2ccccc2)c1Br
Agent: Clc1ccccn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C2=NCCc3ccccc32)c1Br
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Triflic anhydride (0.18 mL, 1.037 mmol) was added via syringe over 1 min to a stirred mixture of 2-bromo-3-methyl-N-phenethylbenzamide (0.30 g, 0.943 mmol) and 2-chloropyridine (0.11 mL, 1.131 mmol) in DCM (4.7 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 min, then placed in an ice-water bath and warmed to 0° C. After stirring another 5 min, the solution was allowed to warm to RT and then placed in a pre-heated block and stirred at 45° for 2 h. The reaction mixture was allowed to cool to RT, then it was diluted with 1N NaOH (3 mL) and extracted with DCM (15 mL). The organic extract was washed with saturated aqueous NaCl (2×15 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude material was absorbed onto a plug of silica gel and purified by column chromatography eluting with a gradient of 1-10% MeOH/DCM to provide 1-(2-bromo-3-methylphenyl)-3,4-dihydroisoquinoline as off-white glass.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[OH-].[K+]>C(O)(C)C>[O:7]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:9].[O:7]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc(OCCN2CCOCC2)cc1

Procedure:
N-(2-Phenoxyethyl) morpholine was prepared by a modified method of Grail. et al (Journal of American Chemical Society, 1952, 74, 1313-1315). For example, 9.2 g of phenol and 18.6 g of N-(2-chloroethyl)morpholine HCl salt were dissolved in 120 ml of isopropanol and 12 g of potassium hydroxide was added with cooling. The reaction mixture was refluxed for 12 hours. Solid (KCl) was filtered off. The filtrate was distilled off. The residual material was treated with 150 ml of 1N NaOH, then, extracted with dichloromethane (200 ml). Dichloromethane layer was again washed with a solution of 0.1N sodium carbonate in 10% NaCl solution. Dichloromethane layer was dried over anhydrous magnesium chloride, and evaporated under reduced pressure. Residual syrup was dissolved in 100 ml of 1.5N HCl solution, and washed with 100 ml of chloroform. Aqueous layer was treated with 100 ml of toluene and water was removed by Dean-Stark apparatus by distillation. Residual toluene layer was cooled to give crystalline solid, which was collected by filtration. 12 g of N-[(2-phenoxy)ethyl]morpholine HCl salt (50% yield )was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:7][C:6]([N:16]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:54])([C:47]([O:49]C(C)(C)C)=[O:48])[C:40]([O:42]C(C)(C)C)=[O:41])=[CH:35][CH:34]=3)[C:17]2=[O:55])=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[C:1]([C:3]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[CH:7][C:6]([N:16]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:54])([C:47]([OH:49])=[O:48])[C:40]([OH:42])=[O:41])=[CH:35][CH:34]=3)[C:17]2=[O:55])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(Nc2cc(F)ccc2CN2C(=O)N(c3ccc(C#N)c(-c4ccc(F)cc4)c3)C(=O)C2(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C(=O)O)(C(=O)O)c1ccc(Nc2cc(F)ccc2CN2C(=O)N(c3ccc(C#N)c(-c4ccc(F)cc4)c3)C(=O)C2(C)C)cc1

Procedure:
The compound of Example 259 was, as described for the preparation of Example 233, obtained via the corresponding tert-butyl ester. The di-tert-butyl ester 259.3 was obtained via the sequence of 236.1 (di-tert-butyl 2-methyl-2-(4-nitrophenyl)-malonate; 1H NMR: 8.22, d, 2H, 7.64, d, 2H, 1.71, s, 3H, 1.41, s, 18H)→236.2 (di-tert-butyl 2-(4-aminophenyl)-2-methylmalonate hydrochloride; molecular weight (free base) 321.19 (C18H27NO4); retention time Rt=1.61 min. [C]; MS (ESI): 322.21 (MH+))→259.3 (di-tert-butyl 2-(4-{2-[3-(6-cyano-4′-fluorobiphenyl-3-yl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]-5-fluorophenylamino}phenyl)-2-methylmalonate (by reaction with 253.3)). The reaction of the crude product with 4N hydrochloric acid in dioxane afforded compound 259; molecular weight 638.19 (C35H28F2N4O6); retention time Rt=2.59 min. [D]; MS (ESI): 639.30 (MH+).
Reaction SMILES: [CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3C1.[CH3:13]C12CC3CC(CC(C)(C3)C1)C2>>[CH2:4]([C:5]12[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:1]1)[CH2:13]2)[CH3:3]
Reactant: C1CC2CCCC3CCC(C1)C23
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Product: CCC12CC3CC(CC(C3)C1)C2

Procedure:
The same experiment as described in 2th line from the bottom in Table 5 of Example 5 was carried out except that perhydroacenaphthene prepared by hydrogenation of acenaphthene was used in place of TMN. Conversion rate of perhydroacenaphthene was 75.4%, and 1,3-dimethyladamantane and 1-ethyladamantane were obtained at 33.0% and 47.1% of selectivity and at 24.9% and 35.0% of yield respectively. Moreover, when amounts of catalyst was increased from 2 g to 4 g, conversion rate of perhydroacenaphthene was 85.6%, and 1,3-dimethyladamantane and 1-ethyladamantane were obtained at 45.2% and 6.6% of selectivity and at 38.7% and 5.7% of yield respectively.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:15]2[CH:14]=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=2[F:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
N-Ethylpiperazine (0.96 mL, 7.6 mmol, 1.2 equiv) is added to a mixture of 3,4-difluoronitrobenzene (0.7 mL, 6.32 mmol) and potassium carbonate (1.74 g, 12.6 mmol, 2 equiv) in DMF (10 mL). The reaction mixture is stirred at 90° C. for 17 h, allowed to cool to RT, diluted with H2O and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 97:3) to provide the title compound as a yellow solid: ES-MS: 254.1 [MH]+; tR=2.65 min (system 1); Rf=0.30 (DCM/MeOH+1% NH3aq, 93:7).