Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.[CH3:52][NH:53][O:54][CH3:55]>ClCCl.O>[CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([N:53]([O:54][CH3:55])[CH3:52])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCC[C@@H](C(=O)N(C)OC)N(Cc1ccccc1)Cc1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
(S)-2-(dibenzylamino)pentanoic acid (1.57 Kg; 5.286 mol) was dissolved in dry dichloromethane (9.42 L) under a nitrogen atmosphere and cooled to 0-5° C. The resulting solution was treated with N-hydroxybenzotriazole (HOBt; 928 g; 6.875 mol) followed by 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI, 1.51 Kg; 7.931 mol;) at 0-5° C. The reaction mixture was stirred for 3 hours at ambient temperature, then treated with N-methylmorpholine (NMM; 1.62 Kg; 16.07 mol) followed by N,O-dimethylhydroxylamine hydrochloride (1.29 Kg; 13.22 mol) at 0° C. The reaction mixture was stirred at ambient temperature for 15 hours, then water (2.5 L) added, and the mixture stirred for 10 minutes. The organic layer was separated, washed with 1% aqueous hydrochloric acid, followed by saturated aqueous sodium bicarbonate, then brine solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide (S)-2-(dibenzylamino)-N-methoxy-N-methylpentanamide, a compound of formula (6), as a syrupy oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]#[C:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:28])[C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=4)=[CH:13][O:14]3)=[CH:9][CH:8]=2)[CH2:2]1.FC(F)(F)C(O)=O.[C:36](=O)([O:43]N1C(=O)CCC1=O)[O:37][CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:38]1([O:37][C:36]([N:1]2[CH2:4][CH:3]([C:5]#[C:6][C:7]3[CH:16]=[C:15]4[C:10]([C:11](=[O:28])[C:12]([C:17]5[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=5)=[CH:13][O:14]4)=[CH:9][CH:8]=3)[CH2:2]2)=[O:43])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(OC1CCCC1)ON1C(=O)CCC1=O
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(C#CC4CNC4)ccc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(C#CC4CN(C(=O)OC5CCCC5)C4)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(4-(7-(azetidin-3-ylethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.trifluoroacetic acid salt (55 mgs, 0.140 mmol) in dichloromethane (3 mL) was added cyclopentyl 2,5-dioxopyrrolidin-1-yl carbonate (95 mgs, 0.42 mmol) and diisopropylethylamine (0.2 mL, 1.4 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure, and chromatographed (SiO2, 25% ethyl acetate/dichloromethane) to provide cyclopentyl-3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carboxylate:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[Br-].[CH2:10]([O:12][C:13](=[O:17])[CH2:14][CH2:15][Zn+])[CH3:11]>C1COCC1.[Cl-].[NH4+].O.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>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:15][CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:17])=[N:6][CH:7]=1
Reactant: CCOC(=O)CC[Zn+]
Reactant: Clc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1ncc(Cl)cn1

Procedure:
5-Chloro-2-iodopyrimidine (4 g, 16.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.92 g, 1.66 mmol) were suspended in THF (83 mL). 3-Ethoxy-3-oxopropylzinc bromide (33.3 mL, 16.64 mmol) was added, and the resultant mixture was stirred at room temperature for 18 hours. The mixture was diluted with saturated ammonium chloride and water (1:1) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc:Hexanes) to give ethyl 3-(5-chloropyrimidin-2-yl)propanoate. MS ESI calcd for C9H12ClN2O2[M+H]+ 215. found 215. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 1.11 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.O[N:19]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N.O.NN>C(Cl)Cl>[NH2:19][O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: NN
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](ON)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (4.9 g, 20.0 mmol) in CH2Cl2 (50.0 mL) was added 2-hydroxyisoindolin-1,3-dione (3.26 g, 20.0 mmol) and triphenylphosphine (7.86 g, 30.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (5.90 ml, 30.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. Work-up and purification as described in Example 2A, Step 1 afforded (2S,4R)-1-tert-butyl 2-methyl 4-(1,3-dioxoisoindolin-2-yloxy)pyrrolidine-1,2-dicarboxylate as a viscous oil. The resultant oily compound was dissolved in CH2Cl2 (100 ml) and cooled to 0° C. Hydrazine hydrate (4.0 mL, 40.0 mmol) was added drop wise. The reaction mixture was stirred at ambient temperature over night. Work-up and purification as described in Example 2A, Step 2 afforded (2.8 g, 53%, over two steps) of (2S,4R)-1-tert-butyl 2-methyl 4-(aminooxy)pyrrolidine-1,2-dicarboxylate as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9H) 2.13-2.29 (m, 1H) 2.34-2.48 (m, 1H) 3.48-3.68 (m, 2H) 3.72 (s, 3H) 4.23-4.30 (m, 1H) 4.30-4.49 (m, 1H). MS (ES) [M+H] calculated for C11H21N2O5, 261.14. found 261.22.
Reaction SMILES: CO[C:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].Cl.[CH:18]([NH:21][NH2:22])([CH3:20])[CH3:19].C(N(CC)CC)C>C(O)C>[NH2:6][C:5]1[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: CC(C)NN
Reactant: COC(Cc1cccc(Br)c1)=C(C#N)C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1nc(Cc2cccc(Br)c2)c(C#N)c1N
Yield: 87.3 %

Procedure:
Compound 33 (3.124 g, 11.3 mmol), isopropylhydrazine hydrochloride (1.27 g, 11.5 mmol) (purchased from Ryan Scientific) and triethylamine (6.40 mL, 46.0 mmol) were allowed to react in ethanol (75 mL) at room temperature for 1 hr. After concentrating the reaction mixture, it was purified by silica chromatography using a chloroform/methanol solvent system (methanol gradient increased with time from 0-10%). The relevant fractions were concentrated in vacuo to yield a yellow powder (3.15 g, 87% yield): 1H NMR (400 MHz, DMSO) δ 7.41 (m, 2H), 7.26 (td, J=7.7, 1.2, 1H), 7.21 (dt, J=7.7, 1.3, 1H), 6.50 (s, 2H), 4.38 (hept, J=6.5, 1H), 3.81 (s, 2H), 1.27 (d, J=6.5, 6H); 13C NMR (100 MHz, DMSO) δ 151.01, 150.15, 141.24, 131.05, 130.53, 129.16, 127.45, 121.55, 115.16, 71.77, 47.24, 32.88, 21.35; [M+H]+ calculated for C14H15BrN4 319.0, 321.0 found 318.9: 321.0.
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.I[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH:29]=[C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1)[CH3:31]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:31][C:30]1([C:32]2[CH:41]=[CH:40][C:39]3[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=3[CH:33]=2)[C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH2:29]1
Reactant: COC(=O)c1ccc(I)c(OC=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O=CO
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1ccc2c(c1)OCC2(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 60 °C

Procedure:
A mixture of tributylamine (0.5 ml, 2.1 mmol), palladium diacetate (0.03 g, 0.2 mmol), formic acid (0.06 ml, 1.3 mmol) and methyl 4-iodo-3-[2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]-1-propenyloxy]benzoate (0.65 g, 1.3 mmol) in acetonitrile (10 ml) is heated at 60° C. for 4 h. The reaction medium is concentrated on a rotary evaporator under vacuum at 40° C. 20 ml of water and 20 ml of ethyl ether are added. After separation of the phases by settling, the organic phase is washed twice with 20 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CCOCC>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:22])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)COc1ccc(SCCCC(=O)c2ccc(Cl)cc2)c2c1CCC2

Procedure:
Compound 1D (300 mg, 1.26 mmol), 4-chloro-1-(4-chloro-phenyl)-butan-1-one (327 mg, 1.51 mmol), and cesium carbonate (616 mg, 1.89 mmol) in 10 ml anhydrous acetonitrile were stirred at ambient temperature for 72 hours. The reaction was then run through 0.5 g SiO2 eluting with Et2O. The eluant was collected and concentrated to give the title compound, pure enough for subsequent use. MS m/z 419 (M+1).
Reaction SMILES: C(O)(=O)C.[C:5]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8].[N:20]([O-])=[O:21].[Na+].C([O-])(=O)C.[Na+]>C(OC)(C)(C)C.O.O1CCOCC1>[OH:21][N:20]=[C:6]([C:7]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])[C:5]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: O=N[O-]
Reactant: CC(C)COC(=O)CC(=O)OCC(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)COC(=O)C(=NO)C(=O)OCC(C)C
Reaction time: 2 h

Procedure:
112.2 of acetic acid (96%) were added dropwise over 2 hours to a stirred mixture of 216.0 g (1 mol) of diisobutyl malonate, 250 g of 1,4-dioxane, 25.6 g of deionized water ad 80 g (1.15 mol) of sodium nitrite (technical grade), maintained at from 35° to 40° C. The mixture was allowed to continue reacting for 2 hours at 50° C., then 35.0 g of anhydrous sodium acetate and 200 g of methyl tert-butyl ether were added. After cooling of the mixture, the precipitated coarsely-crystalline sodium acetate trihydrate was filtered off and washed using methyl tert-butyl ether. Removal of the low-boilers by distillation at 60° C. under water-pump vacuum gave 258.7 g (88.6% of theory) of residue comprising primarily diisobutyl hydroxyiminomalonate. The content of unconverted diisobutyl malonate was 0.4 FID aea percent.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[Br:26][C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[N:35]([CH2:43]S(C1C=CC=CC=1)(=O)=O)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>O>[Br:26][C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[N:35]([CH2:43][C:13]1[C:14](=[O:17])[CH2:15][CH2:16][C:12]=1[NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:18])([F:19])[F:3])[CH:6]=1)[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1Br
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 360 mg, 9.00 mmol) is added in portions to a mixture of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (2.16 g, 8.96 mmol) and 2-methyltetrahydrofuran (30 mL). After 30 min tert-butyl (2-bromo-4-cyanophenyl)(phenyl-sulfonyl)methylcarbamate (Step 1, 3.35 g, 7.43 mmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue is treated with tert-butyl methyl ether, and the mixture is stirred for 15 min. The precipitate is filtered, washed with tert-butyl methyl ether, and dried. Yield: 3.18 g. ESI mass spectrum: [(79Br)-M+H]+=550, [(81Br)-M+H]+=552; Retention time HPLC: 0.73 min (X012_S01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:7]=[CH:6]2.C(N(CC)CC)C.Cl.[F:26][C:27]([F:41])([F:40])[C:28]1[CH:29]=[C:30]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)[CH:31]=[CH:32][CH:33]=1.C(OCC)(=O)C>C(Cl)Cl>[F:41][C:27]([F:26])([F:40])[C:28]1[CH:29]=[C:30]([C:34]2[CH2:39][CH2:38][N:37]([C:14](=[O:16])[CH:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[CH3:17])[CH2:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2cc(C(C)C(=O)N3CC=C(c4cccc(C(F)(F)F)c4)CC3)ccc2c1
Yield: 60.7 %

Procedure:
A solution of 6-methoxy-α-methyl-2-naphthylacetic acid (3.5 g, 0.015 mol), triethylamine (4.3 ml, 0.03 mol), 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (3.9 g, 0.015 mol), and benzotriazolyl-N-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6 g, 0.015 mol) in methylene chloride (40 ml) is stirred at room temperature for 4 hours. Ethyl acetate (150 ml) is then added thereto and the mixture is washed in sequence with water, 10% NaHCO3, water, 1N HCl, and water. The reaction mixture is then filtered over silica and concentrated to dryness affording 1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6-methoxy-naphth-2-yl)propane (4 g) as a thick oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:15])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1)=[O:4].[BH4-].[Na+].[OH-].[Na+].Cl>CO>[F:15][C:8]1[CH:7]=[CH:6][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:10][C:9]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1cc(C2CO2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
A solution of 0.5 g (1.7 mmol) of 5-bromoacetyl-2-fluoro-benzenesulfonamide V in 20 mL MeOH was cooled to 0° C. NaBH4 26 mg (0.67 mmol) was added and the reaction was stirred at 0° C. for 15 min. 4 mL of 1N NaOH was added and the reaction was stirred at 0° C. for 4 hrs. The reaction was adjusted to pH 6 by addition of dilute HCl. The volatiles were evaporated and the residue dissolved in EtOAc, washed with H2O, dried over Na2SO4 and evaporated. The product was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH::9/1 to give 180 mg of VI (48%); mp 100-103° C.TLC:CH2Cl2/MeOH::9/1 single-spot material Rƒ 0.65.1H-NMR (300 MHz DMSO-D6) δ: (2.82, m, 1H), (3.14, m, 1H), (4.06, m, 1H), (7.40, t, 1H), (7.56, m, 1H), (7.66, m, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1>C(O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: BrCCCCCCOCCCCC#Cc1cnccn1
Agent: [Pd]
Solvent: CCO
Product: BrCCCCCCOCCCCCCc1cnccn1
Reaction time: 11 h
Yield: 87.7 %

Procedure:
A solution of [6-[(6-bromohexyl)oxy]-1-hexynyl]pyrazine (2.76 g) in ethanol (70 ml) was added to a pre-hydrogenated suspension of 10% palladium on carbon (2.00 g) in ethanol (50 ml) and hydrogenated at room temperature and pressure for 11 h. The mixture was filtered through hyflo and evaporated in vaco to afford the title compound as a colourless oil (2.45 g), t.l.c. (ether) Rf 0.55.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22]1([N:32]=[C:33]=[O:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:33]([NH:32][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:34])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4cccc5ccccc45)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
A heterogeneous mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 1-naphthyl isocyanate (0.26 g, 1.6 mmol), and triethylamine (4.9 g, 4.9 mmol) in 25 mL THF was stirred under nitrogen at ambient temperature for 18 hours. The solvent was removed under vacuum. The residue was triturated with 3% aqueous HCl (100 mL) for 1 hour and then filtered, and the filter was washed with additional 3% HCl. The resulting solid was dried, triturated with 30 mL refluxing acetone for 1 hour and filtered, and the filter was washed with additional hot acetone. The resulting solid was dried and then triturated with 30 mL refluxing acetonitrile, filtered, and dried, to provide 0.40 g of the product in 56% yield: 1H NMR (DMSO-d6) δ 2.00-2.09 (m, 1H), 2.35-2.42 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 4.44 (d, J=17.2 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 4.58 (d, J=17.2 Hz, 1H), 5.16 (dd, J=13.1 Hz, J=5.1 Hz, 1H), 7.11 (t, J=5.8 Hz, 1H), 7.09-7.67 (m, 7H), 7.90 (dd, J=6.6 Hz, J=2.9 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 8.09 (t, J=9.0 Hz, 1H), 8.66 (s, 1H), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.6, 31.2, 40.0, 46.2, 51.6, 117.0, 121.4, 121.6, 122.4, 125.5, 125.8, 125.9, 128.3, 128.4, 130.4, 131.7, 133.7, 134.9, 135.5, 140.0, 155.7, 168.1, 171.0, 172.8; Anal. calcd for C25H22N4O4: C, 67.86; H, 5.01; N, 12.66. Found: C, 67.64; H, 4.99; N, 12.28.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[O:17])[NH:9]2)[CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:56](=[NH:69])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.O>[C:56](=[N:69][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[O:17])[NH:9]2)[CH:7]=1)([C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)C[C@@](C)(c2cc(Br)ccc2F)NC(=O)CO1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)C[C@@](C)(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)NC(=O)CO1
Temperature: 105 °C
Yield: 89 %

Procedure:
Under argon in a sealed tube was added to a solution of (S)-5-(5-bromo-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate A16A) (1.0 g, 3.0 mmol) in toluene (20 ml), sodium tert-butoxide (NaOBut) (865 mg, 9.0 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu X-phos) (127 mg, 10 mol %) and tris(dibenzylideneacetone)dipalladium chloroform complex (Pd2(dba)3.CHCl3) (93 mg, 3 mol %) followed by benzophenone imine (1.07 mL, 6.0 mmol). The tube was sealed under argon and the mixture was stirred at 105° C. for 18 h to 2.5 days. The mixture was cooled to 23° C., poured into water, extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulphate. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the (S)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (1.15 g, 88%) as light yellow foam. MS (ISP): m/z=431.3 [(M+H)+].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH2:20]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:19][CH:18]=[CH2:17]
Reactant: NCCc1ccccc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCNCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 2-phenylethylamine (72 mL, 570 mmol) is added K2CO3 (82 g, 570 mmol) and 4-bromo-1-butene (25 g, 185 mmol). The solution is stirred overnight at room temperature. The solution is evaporated to dryness and H2O/EtOAc (1:1) (600 mL) is added. The mixture is extracted with EtOAc (4×150 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:8) to provide 20 g (62%) of the title compound. M+H+=176.10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)(C)C.[Cu](I)I.O>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:19]2[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]2)=[CH:3][CH:4]=1
Reactant: C[C@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: C[C@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(-n2ncccc2=O)cc1
Temperature: 110 °C

Procedure:
A solution of the product from Example 4A (47 mg, 0.16 mmol; 1-[2-(4-bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine), 3(2H)-pyridazinone (CAS # 504-30-3, 20 mg, 0.2 mmol), copper iodide (1.5 mg, 0.008 mmol), N,N′-trans-dimethyl-cyclohexane-1,2-diamine (2.3 mg, 0.016 mmol) and potassium phosphate (75 mg, 0.35 mmol) in a mixture of toluene and isopropanol (4 ml, 1:1) was heated to 110° C. in a screw capped vial for 16 hours. The mixture was cooled to ambient temperature, treated with H2O and extracted with ethyl acetate (2×25 mL). The organic layer was separated, washed with brine and dried with magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure and the resulting oil was purified on silica gel with 1% to 3% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 1.07 (m, 1H), 1.14 (m, 1H), 1.26 (d, J=6 Hz, 3H), 1.40 (m, 1H), 1.58 (m, 1H), 1.90(m, 3H), 2.13 (m, 1H), 2.58 (m, 1H), 2.70 (q, J=9 Hz, 1H), 2.89 (m, 1H), 3.14 (dd, J=12 Hz, J=6 Hz, 1H), 3.44 (m, 1H), 7.07 (d, J=9 Hz, 1H), 7.24 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H), 7.47 (m, 1H), 8.03 (m, 1H). MS (DCl—NH3) m/z 310 (M+H)+.