Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:15](Br)[Br:16].[OH-].[Na+]>CS(C)=O>[Br:16][CH2:15][C:8]([C:9]#[N:10])([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccc(Cl)cc1
Reaction time: 0.58 h
Yield: 75.2 %

Procedure:
In a 300 ml three neck flask fitted with a mechanical stirrer, thermometer and addition funnel was added 20.8 gm (0.1 mol) of (p-chlorophenyl)hexanenitrile, 34.8 gm (0.2 mol) of methylene bromide and 50 ml of DMSO. To the reaction flask was added 24 ml of 50% (w/w) sodium hydroxide, dropwise over a 35 minute period. Upon completion of the reaction, it was quenched by adding 500 ml of water. The aqueous mixture was extracted three times with ether, then the combined ether extracts were washed three times with water and once with brine. The organic phase was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation yielding 22.6 gm of a yellow oil.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)O1.[Cl:41][C:42]1[N:47]=[C:46](Cl)[CH:45]=[CH:44][N:43]=1>>[Cl:41][C:42]1[N:47]=[C:46]([C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)[CH:45]=[CH:44][N:43]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: O=[N+]([O-])c1ccc(-c2ccnc(Cl)n2)cc1
Yield: 53 %

Procedure:
Method as described for intermediate 5 using 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane and 2,4-dichloropyrimidine. The mixture was purified using flash chromatography (0-100% EtOAc in petroleum ether 40-60) to afford the title compound (1.45 g, 53%)
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[N:25][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([O:19][CH2:18][C@H:14]2[O:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:13]2)[CH:24]=[N:25][CH:26]=1
Reactant: Oc1cncc(Cl)c1
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cncc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 27s was synthesised by essentially the same procedure as compound 18s (Example 16). Compound 51 (Example 10; 80 mg, 0.30 mmol), was reacted with 5-chloro-3-hydroxypyridine (59 mg, 0.46 mmol), PPh3 (120 mg, 0.46 mmol), DIAD (90 μl, 0.46 mmol) and THF (1.5 ml). The reaction mixture was stirred at RT for 48 hrs. After this time, the solvent was removed and the crude mixture purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 94:6, then Hex/EtOAc 1:0 to 0:1) to afford compound 27s (71 mg, 91%). Analyses were performed on the free base. The compound was re-purified (36.7 mg, purity 100%), and converted to the HCl salt for assaying.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:9]3([CH2:8][O:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][C:27]([C:25]#[N:26])=[CH:28][CH:29]=5)=[CH:24][CH:23]=4)[CH2:10][CH2:11][CH2:12]3)=[CH:22][CH:21]=2)=[O:32])=[CH:29][CH:28]=1)#[N:26]
Reactant: NCc1ccc(OCC2(COc3ccc(CN)cc3)CCC2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(=O)NCc2ccc(OCC3(COc4ccc(CNC(=O)c5ccc(C#N)cc5)cc4)CCC3)cc2)cc1
Yield: 78 %

Procedure:
The noted compound was prepared according to procedures above using 4-[1-(4-aminomethyl-phenoxymethyl)-cyclobutylmethoxy]-benzylamine from Example 91 and 4-cyanobenzoyl chloride to yield a yellow foam (1.4 g, 78% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[O:13][C@@H:14]([CH2:17]OS(C)(=O)=O)[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]2[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=2)[CH2:26]1.Br.C([O-])(O)=O.[Na+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[O:13][C@@H:14]([CH2:17][N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]4[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=4)[CH2:26]3)[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Reactant: Oc1cccc([C@H]2CCCNC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4cc(OCc5ccccc5)ccc4O3)C2)c1
Temperature: 150 °C

Procedure:
To a solution of methanesulfonic acid (R)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester (129 mg, 0.368 mmol) and (R*)-3-(piperidin-3-yl)phenol.HBr (100 mg, 0.387 mmol) in acetonitrile was added solid KI (40 mg) and NaHCO3 (98 mg 1.162 mmol). The mixture was heated under microwave irradiation at 150° C. for 1 h. Solid material was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved to DCM and washed twice with water and brine. The organic phase was dried (Na2SO4), and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc/heptane) to give the desired product (66.2 mg).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=2)[N:19]=1.C(N(CC)CC)C>>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:31]1[CH2:32][CH2:33][O:34][C@@H:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3[N:19]=[C:18]([CH3:17])[O:22][N:21]=3)=[CH:24][CH:25]=2)[CH2:30]1
Reactant: Cc1nc(-c2ccc([C@H]3CNCCO3)cc2)no1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc([C@H]3CN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (9.80 g, 44.0 mmol) and (2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)morpholine hydrochloride (13.3 g, 47.2 mmol) was added triethylamine (13.4 g, 132 mmol) at room temperature, and the solution was stirred at room temperature for 4 hours. After the solution was concentrated under reduced pressure, the resulting crude product was washed with water, dried under reduced pressure to afford 3-methyl-2-((2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)morpholino)-6-(pyrimidin-4-yl)pyrimidin-4 (3 H)-one (the compound of the present invention, 18.0 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([OH:16])=[C:4]([N+:17]([O-])=O)[CH:3]=1>[Ni].O.CCOC(C)=O>[NH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(Cl)cc(CCc2ccccn2)c1O
Agent: [Ni]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc(CCc2ccccn2)c1O
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a vigorously stirred suspension of Raney Nickel (3.5 g of a 50% slurry in water, washed with ethanol then EtOAc) in EtOAc (20 ml) is added 4-chloro-2-nitro-6-[2-(pyridin-2-yl)ethyl]phenol (2.09 g, 7.50 mmole) in EtOAc (10 ml). The solution is stirred vigorously overnight under an atmosphere of hydrogen. After this time no starting material is visible by TLC analysis. The solution is decanted from the Raney Nickel. The Raney Nickel was washed several times with EtOAc and the washings combined with the reaction mixture solution. Concentration in vacuo yielded a brown oil which is purified by flash chromatography (SiO2 ; 30% EtOAc in hexane) to yield a pale orange oil (1.88 g, 100%). This was recrystallised from EtOAc/pentane to give the title compound as a pale yellow crystalline solid (1.55 g, 83%), m.p. 91-92° C. dH (250 MHz, CDCl3) 11.5 (bs, 1H), 8.49 (dd, J=5.6, 2.0 Hz, 1H), 7.63 (dt, J=7.7, 1.7 Hz, 1H ), 7.20-7.16 (m, 2H), 6.54 (d, J=2.5 Hz, 2H), 3.84 (bs, 2H ), 3.30-3.25 (m, 2H ), 3.06-3.02 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH:28]1([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[N:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([O:33][C:34]2[N:35]=[C:36]([C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]4[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[O:12][C:11]4=[O:27])[CH3:9])=[CH:6][CH:7]=3)[CH:37]=[CH:38][CH:39]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC1(C)OB(c2cccc(OC3CCCC3)n2)OC1(C)C
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(OC3CCCC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 2-(cyclopentyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=2.23 min, m/z=515, 457; 1H NMR (CD3OD) 0.96 (s, 3H), 1.27 (s, 3H), 1.56 (d, 3H), 1.70 (2H), 1.85 (4H), 2.05 (2H), 2.17 (s, 2H), 2.24 (m, 1H), 2.46 (2H), 3.05 (m, 1H), 5.47 (m, 1H), 5.58 (q, 1H), 6.70 (d, 1H), 7.00 (d, 2H), 7.25-7.40 (6H), 7.70 (t, 1H), 7.77 (d, 2H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C(=O)C>[CH3:27][N:13]([CH2:12][CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5](/[CH:4]=[CH:3]/[CH2:2][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:6][CH2:7]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)N(C)C
Product: CN(CC[C@H]1CC[C@H](/C=C/CN2CCCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 473 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][CH2:13][C@H:12]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1C=CC=C[CH:3]=1.ClC(OCC=C)=O.C(N(CC)CC)C.C(OCC)(=O)C>CO.[C].[Pd]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][CH2:13][C@H:12]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[CH:2]=[CH2:3]
Reactant: COC(=O)[C@@H]1CC[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)CC[C@H]1C(=O)OC
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 2.46 g (8.39 mmol) of (2S,5R)-1-benzyloxycarbonyl-5-hydroxy-2-methoxycarbonylpiperidine in 100 ml of methanol was added 500 mg of 5% palladium-carbon, and the mixture was hydrogenated for 2 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was dissolved in 20 ml of dichloromethane. To this solution was dropwise added 1.3 ml (9.33 mmol) or triethylamine followed by 0.98 ml (9.24 mmol) of allyl chloroformate. After stirring for 2 hours, 1.3 ml (9.33 mmol) of triethylamine and 0.98 ml (9.24 mmol) of allyl chloroformate were additionally added to the mixtures, which was stirred for 1 hours. To the mixture was added 200 ml of ethyl acetate, the organic layer was washed successively with water, 1N potassium bisulfate, water, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography (Wakogel®C-300, elution with ethyl acetate - hexane system) to give 1.14 g (yield: 55 %) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)=[O:36]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](N1CCN(C(=O)c2ccc(F)cc2F)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
To a mixture of compound 2 (674 mg, 2 mmol) and triethylamine (0.55 ml, 4 mmol) in tetrahydrofuran (10 ml) was added dropwise 2,4-difluorobezoyl chloride (440 mg, 2.5 mmol) in 5 ml tetrahydrofuran at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 18 h. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (50 ml). The organic phase was washed with brine, dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/hexane, 9:1) to give the title compound as colorless prisms (448 mg, 47%).
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].ClC1C=C(C=CC=1)CCl.CS(C)=O.[C:21](=O)([O-:23])[O-:22].[Na+].[Na+]>O>[CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].[C:5]([OH:7])(=[O:6])/[CH:2]=[CH:4]/[C:21]([OH:23])=[O:22]
Reactant: O=C([O-])[O-]
Agent: CC(C)(N)C(=O)O
Agent: ClCc1cccc(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 500 mg. (5.0 mmole) of 2-methylalanine and 800 mg. (5.0 mmole) of m-chlorobenzyl chloride in 10 ml. of dimethylsulfoxide is stirred at 60° C. for 6 hours and then allowed to cool to 20°-25° C. over 12 hours. Water, 150 ml., is added followed by a saturated sodium carbonate solution until a basic pH of 8 is obtained. The product is extracted into 50 ml. of ethyl ether which is then washed with four 25 ml. portions of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (15-20 mm.) at 35°-40° C. The residue is converted into the hydrogen fumarate salt with 0.40 g. fumaric acid in 25 ml. 80% ethanol-20% ethyl acetate solution followed by precipitation with hexane. After filtering and drying, the m-chlorobenzyl ester of 2-methylalanine as the hydrogen fumarate salt containing one equivalent of fumaric acid as a co-precipitant, m.p. 144.0°-149.0° C., is obtained. Further recrystallization from the aforementioned ethanol-ethyl acetate-hexane system gives an analytical sample.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[F:14].BrC1C(F)=C(N)C=C([N+]([O-])=O)C=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: O=[N+]([O-])c1cc(Br)c(F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Nc1cc([N+](=O)[O-])cc(Br)c1F
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-2-fluoro-3,5-dinitrobenzene (5.4 g, 20.38 mmol, 1 equiv) in acetic acid (200 mL) at room temperature (using a water bath) was added powdered iron portion-wise (5.70 g, 102 mmol, 5 equiv). The resulting solution was stirred for 3 hours keeping the temperature of the mixture below 30° C. LCMS indicated the formation of three products: 3-bromo-2-fluoro-5-nitrobenzenamine-F3 (86%), 3-bromo-4-fluoro-5-nitrobenzenamine-F2 (5%), and 5-bromo-4-fluorobenzene-1,3-diamine-F1 (9%). [Note: After completion of this experiment, to identify regioisomers, 3-bromo-2-fluoro-5-nitrobenzenamine was diazotized and deaminated (see, E. S. Adams and K. L. Rinehart. The Journal of Antibiotics 1994, 47 (12), 1456-1465) to give 3-bromo-4-fluoro-nitrobenzene. This was compared to an authentic sample obtained from a commercial source]. DCM was added to the mixture, and the resulting mixture was filtered through a pad of Celite, and the pad of Celite was rinsed with MeOH. The filtrate was evaporated to dryness. The residue was quenched with 2M NH3/MeOH followed by concentrating to dryness and repeating once—silica gel was added at this stage so that the crude product was absorbed directly on to silica gel. The crude product was purified by column chromatography on silica gel using DCM to give the desired product 3-bromo-2-fluoro-5-nitrobenzenamine (F1 on TLC; 1.87 g, 39%) as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[N:18]([CH3:28])[N:19]=[N:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:13][CH:14]=1)=[O:8])C>O.C1COCC1.CO>[CH3:28][N:18]1[C:17]([CH2:16][O:15][C:12]2[N:11]=[N:10][C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=2)=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:20]=[N:19]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of lithium hydroxide monohydrate (130 mg, 3.06 mmol) in water (5 mL) was added dropwise to a suspension of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (521 mg, 1.53 mmol) in THF (5 mL) and MeOH (0.5 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (320 mg, 67%) as a white solid. MS: m/e=311.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[C:10]([CH2:11][NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[CH:9][O:8][C:6]=2[N:7]=1.[CH2:24]=O.[C-]#N.[Na+].Cl>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[C:10]([CH2:11][N:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[CH3:24])=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: C=O
Reactant: Nc1nc(N)c2c(CNc3ccc4ccccc4c3)coc2n1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: CN(Cc1coc2nc(N)nc(N)c12)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of compound 424 (0.10 g, 0.32 mmol), 30% (w/w) aqueous solution of formaldehyde (0.1 ml) and NaCN BH3 (0.063 g) in acetonitrile (10 ml) was added dropwise concentrated hydrochloric acid until the suspension dissolved. The solution was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue dissolved in a minimum amount of distilled water and the pH of the solution adjusted to 7 with concentrated NH4OH. The resulting suspension was sonicated, cooled to 5° C. and filtered. The residue was washed with cold water (2×3 ml), stirred in MeOH (5 ml) for 12 h and filtered. The residue was washed with MeOH (2×3 ml) to afford 0.065 g (64%) of compound 429 as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][C:6]1[S:7][C:8]([CH2:11][CH3:12])=[N:9][N:10]=1)C.[OH-].[Na+].Cl>C(O)C>[CH2:11]([C:8]1[S:7][C:6]([CH2:5][C:4]([OH:13])=[O:3])=[N:10][N:9]=1)[CH3:12]
Reactant: CCOC(=O)Cc1nnc(CC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nnc(CC(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of (5-ethyl-[1,3,4]thiadiazol-2-yl)-acetic acid ethyl ester (230 mg, 1.15 mmol) in ethanol (5 mL) is added aqueous 1M NaOH (2 mL, 2.0 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is acidified with aqueous 1M HCl and the ethanol is removed under reduced pressure. The remaining aqueous solution is lyophilized to give (5-ethyl-[1,3,4]thiadiazol-2-yl)-acetic acid.
Reaction SMILES: [S:1](=[O:30])(=[O:29])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH:23][CH2:24]CCC)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].S(=O)(=O)(OC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C=CC4)CCC=2C=1)N>>[S:1](=[O:29])(=[O:30])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:28])[NH:23][CH3:24])=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: C[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(OS(N)(=O)=O)ccc3[C@H]1CC2
Product: CNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C

Procedure:
In similar manners to those described for the synthesis of sulfamate 11a, compound 11g was prepared from compound 8. FAB-MS m/z 405 (M+H)+; 1H NMR (270 MHz, DMSO-d6) δ 0.91 (s, 3H, CH3), 1.03 (t, 3H, J=7.1 Hz, CH2CH3), 3.12 (m, 2H, CH2CH3), 6.36 (s, 1H, 16-CH), 6.97 (d, 1H, J=2.3 Hz, ArH), 7.01 (dd, 1H, J=2.3, 8.6 Hz, ArH), 7.33 (d, 1H, J=8.6 Hz, ArH), 7.75 (t, 1H, J=5.7 Hz, NHCH2), 7.89 (s, 2H, NH2).
Reaction SMILES: [C:1]([C:4](C(O)=O)([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[CH:21]1[C:22](/[CH:37]=[N:38]/[OH:39])=[CH:23][CH:24]=[N+:25]([CH2:27][N+:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[N:35]/[OH:36])=[CH:30][CH:29]=2)[CH:26]=1.[Br-:40].[Br-]>C1(C)C(C)=CC=CC=1>[C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[CH:23]1[C:22](/[CH:37]=[N:38]/[OH:39])=[CH:21][CH:26]=[N+:25]([CH2:27][N+:28]2[CH:29]=[CH:30][C:31](/[CH:34]=[N:35]/[OH:36])=[CH:32][CH:33]=2)[CH:24]=1.[Br-:40].[Br-:40]
Reactant: CCC(CCCCCC1=CCCC1=O)(C(=O)O)C(=O)O
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: CCC(CCCCCC1=CCCC1=O)C(=O)O

Procedure:
In the manner described in Example 21, treatment of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime (Example 28) with xylene at reflux for 18 hours gives a yellow oil.