Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[N:18]([CH3:19])[C:17]2[C:16](=[O:20])[N:15]([CH3:21])[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[N:11]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[C:6](/[CH:8]=[CH:9]/[C:10]1[N:18]([CH3:19])[C:17]2[C:16](=[O:20])[N:15]([CH3:21])[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[N:11]=1)([OH:7])=[O:5]
Reactant: Cn1c(=O)c2c(nc(/C=C/C(=O)OC(C)(C)C)n2C)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(nc(/C=C/C(=O)O)n2C)n(C)c1=O
Reaction time: 1 h
Yield: 87.5 %

Procedure:
8-(trans-2-tert-Butyloxycarbonylvinyl)-1,3,7-trimethylxanthine (76 mg, 238 μmol) was dissolved in 3 ml TFA and stirred for 1 h. After evaporation, the residue was triturated with ether to provide the pure product 8-(trans-2-Carboxyvinyl)-1,3,7-trimethylxanthine (55 mg, 88% yield). mp: 278d °C. 1H NMR DMSO-d6 : d 3.27 (s, 3H, NCH3), 3.44 (s, 3H, NCH3), 4.02 (s, 3H N7CH3), 6.78 (d, 1H, J=15.4 Hz), 7.55 (d, 1H, J=15.4 Hz), 8.4 (br s, 1H, COOH). MS (CI NH3) m/e 265 (MH+). Alternatively, compound 8-(trans-2-Carboxyvinyl)-1,3,7-trimethylxanthine was prepared from 8-(trans-2-tert-Butyloxycarbonylvinyl)-1,3,7-trimethylxanthine in DMF/water (1:1) solution by saponification with sodium hydroxide in 49% yield.
Reaction SMILES: [OH: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.[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>>[F:20][CH:16]([C:15]([F:22])([F:21])[F:14])[C:17]([F:19])([F:18])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: FC(F)=C(F)C(F)(F)F
Product: FC(C(F)(F)F)C(F)(F)Oc1ccc(-c2ccccc2)cc1

Procedure:
Analogously, 250 g of 4-hydroxybiphenyl are reacted with hexafluoropropene to give 4-hexafluoropropoxy-biphenyl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]#[N:26]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH2:24][C:25]#[N:26]
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCOc1cc(C(F)(F)F)ccc1F
Reaction time: 20 h

Procedure:
A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent grade acetone (0.55 L) is treated with solid potassium carbonate (7.7 g) followed by the rapid addition of neat bromoacetonitrile (10 mL). The heterogenous mixture is stirred vigorously for approximately 20 hours whereupon it is poured into water and extracted into diethyl ether. The combined ether extracts are washed with saturated sodium chloride and dried over anhydrous potassium carbonate. Filtration and concentration under reduced pressure gives a pale orange solid which is then chromatographed on silica gel, eluting with dichloromethane, to give the desired product as white solid (28.3 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH2:11][NH:12][C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])=[CH:9][N:8]=[C:7]([S:25][CH3:26])[N:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>C1COCC1>[CH:1]1([N:4]2[C:5]3=[N:6][C:7]([S:25][CH3:26])=[N:8][CH:9]=[C:10]3[CH2:11][N:12]([C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])[C:34]2=[O:35])[CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(NCc2cnc(SC)nc2NC2CC2)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(SC)nc3N(C3CC3)C2=O)c1F
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of 7.66 g (20.0 mmol) of cyclopropyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine in 150 mL of dry THF was cooled to 0° C. To this solution was added 2.00 g (50.1 mmol, 2.5 equivalents) of NaH as a 60% oil suspension. The reaction was stirred for 0.5 hour, the ice bath was removed, and the reaction was stirred for another 0.5 hour. To the reaction was added 9.74 g (60.1 mmol, 3.0 equivalents) of CDI. After 0.5 hour the reaction was warmed to reflux for 24 hous.r The reaction was concentrated in vacuo and the residue was partitioned between dichloromethane and a saturated solution of ammonium chloride. The dichloromethane layer was washed again with ammonium chloride and then once with a saturated solution of NaCl, dried, and concentrated in vacuo. The residue was stirred with diethyl ether and the suspension filtered to give 7.73 g (93%) of the title compound as a solid: mp 173° C.–176° C. MS (APCI) (m+1)/z 409.1 Analysis calculated for C18H18F2N4SO3: C, 52.93; H, 4.44; N, 13.72. Found: C, 52.74; H, 4.34; N, 13.80.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]1[C:30]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32][O:31]2)[CH2:29][CH2:28][N:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26]1.[CH3:44][C:45]1[S:46][CH:47]=[C:48]([C:50](O)=[O:51])[N:49]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:44][C:45]1[S:46][CH:47]=[C:48]([C:50]([N:34]2[CH2:35][CH2:36][C:30]3([CH2:29][CH2:28][N:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26][CH2:25]3)[O:31][CH2:32][CH2:33]2)=[O:51])[N:49]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCCO2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.322 g) was added in one portion to a solution at 0° C. of tert-butyl 7-oxa-3,10-diazaspiro[5.6]dodecane-3-carboxylate (example 89, step e) (0.176 g) and 2-methylthiazole-4-carboxylic acid (0.093 g) and triethylamine (0.36 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 210 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:6]([Cl:17])[CH:5]=[CH:4][CH:3]=1.[N:18]([O-])=O.[Na+]>O.Cl>[ClH:17].[Cl:17][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][NH2:18])[C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=N[O-]
Reactant: CC1(C)CON(Cc2c(N)cccc2Cl)C1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CON(Cc2c(Cl)cccc2NN)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a stirred solution of concentrated hydrochloric acid (50 ml) was added 2-[(6-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (4.9 g, 0.019 mole). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (1.3 g, 0.019 mole) in water (20 ml) was added dropwise, with the tip of the addition funnel below the surface of solution. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes. A solution of stannous chloride dihydrate (9.5 g, 0.042 mole) in concentrated hydrochloric acid (30 ml) was then added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for one hour, after which time an insoluble material was removed by filtration. Ethyl acetate was added to the filtrate and more insoluble material was removed. The ethyl acetate mixture was concentrated under reduced pressure, made basic with aqueous sodium hydroxide, and extracted with methylene chloride. The methylene chloride extract was concentrated under reduced pressure. Concentrated hydrochloric acid was added to the residue and the mixture was concentrated under reduced pressure to yield 1.8 g of 2-[(2-chloro-6-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride as a yellow solid; m.p. 180°-184° C. (dec). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:9]2=[O:28])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>C1COCC1.O>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:16]=3)[C:9]2=[O:28])=[CH:4][CH:3]=1
Reactant: O=C1N(c2ccc(O)cc2)CCCCN1c1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1ccc(N2CCCCN(c3ccc(Oc4ccccc4)cc3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-hydroxyphenyl)-3-(4-phenoxyphenyl)-[1,3]-diazepan-2-one (26 mg) was dissolved in THF (2 mL), and sodium hydride (80% in oil, 3 mg) was added. After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 11 mg) was added. After 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 445.57 (C27H31 N3O3); MS (ESI): 446 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Yield: 23 %

Procedure:
The title compound was prepared according to the procedure described in Example-2 using 5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (step-4 of Intermediate-2, 0.100 g, 0.242 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (0.075 g, 0.363 mmol), K2CO3 (0.100 g, 0.726 mmol), tetrakistriphenyl phosphine palladium (0) (0.055 g, 0.048 mmol) and DMSO (3.0 mL) to afford 0.025 g of desired product. 1H NMR (300 MHz, CDCl3): δ 7.19 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.46 (d, J=6.6 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 8.12 (d, J=8.4 Hz, 2H), 10.01 (br s, 1H).
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[Na+].[F:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]3[N:23]([CH:25]=[CH:26][N:27]=3)[CH:24]=2)[CH:16]=[CH:15][C:10]=1[C:11]([NH:13][CH3:14])=[O:12]>C(O)(=O)C>[Br:1][C:25]1[N:23]2[CH:24]=[C:19]([C:17]3[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[C:9]([F:8])[CH:18]=3)[CH:20]=[N:21][C:22]2=[N:27][CH:26]=1
Reactant: CNC(=O)c1ccc(-c2cnc3nccn3c2)cc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(-c2cnc3ncc(Br)n3c2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Bromine (17.4 mL, 0.338 mmol) was added to a mixture of sodium acetate (40.3 mg, 0.491 mmol) and 2-fluoro-4-imidazo[1,2-a]pyrimidin-6-yl-N-methylbenzamide (83.0 mg, 0.307 mmol) in acetic acid (2.6 mL) and the reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel with ethyl acetate in dichloromethane (0-50%) to afford the desired product (95 mg, 88.6%). LCMS: (M+H)=348.8/350.9.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH2:20][OH:21])[CH:17]([CH3:19])[CH3:18].C(O)(=O)C.C([BH3-])#N>CO>[CH3:18][CH:17]([CH3:19])[C@@H:16]([NH:15][CH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1)[CH2:20][OH:21]
Reactant: CC(C)[C@@H](N)CO
Reactant: O=Cc1cccc(-c2ccccc2)n1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccccc2)n1
Reaction time: 0.08 h
Yield: 58.4 %

Procedure:
To a solution of 6-phenylpicolinaldehyde (Tetrahedron Lett. 2010, 51, 5621-5623; 0.391 g, 2.133 mmol) in methanol (4 mL) at ambient temperature was added D-valinol (0.22 mL, 1.9 mmol) followed by acetic acid (0.4 mL, 8 mmol). After 5 min, MP-cyanoborohydride (2.5 mmol/g, 500 mg) was added and stirring continued overnight. The mixture was filtered and the filtrate partitioned between 1N NaOH and CH2Cl2. The organic phase extracted with 1N aqueous HCl. The organic layer was discarded and the aqueous phase was made basic with 1N NaOH and extracted with EtOAc. The organic extract dried, filtered and concentrated to provide 300 mg (57%) of the title compound. MS (DCI30 ) m/z 271 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.04-7.93 (m, 2H), 7.73 (t, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.53-7.35 (m, 3H), 7.21 (d, J=7.5 Hz, 1H), 4.06 (s, 2H), 3.72 (dd, J=11.0, 4.0 Hz, 1H), 3.52 (dd, J=11.0, 6.9 Hz, 1H), 2.55 (td, J=6.7, 4.0 Hz, 1H), 1.91 (td, J=13.6, 6.8 Hz, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[CH2:10][NH:11][CH:12]1[CH2:14][CH2:13]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:36](O)=[O:37])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:36]([N:11]([CH:12]1[CH2:13][CH2:14]1)[CH2:10][C:9]([NH:8][CH2:7][C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:17]1[CH:21]=[N:20][N:19]=[N:18]1)=[O:15])=[O:37])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(CNC1CC1)NCc1cc(Cl)ccc1-n1cnnn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)NCc1cc(Cl)ccc1-n1cnnn1)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N1-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-N2-cyclopropylglycinamide (50 mg, 0.16 mmol), N-(tert-butoxycarbonyl)-4-methyl-D-leucine (42 mg, 0.17 mmol), EDC (49 mg, 0.26 mmol) and HOAt (16 mg, 0.12 mmol) in DMF (1.4 mL) was stirred for 16 h at room temperature. The title compound was isolated by reverse phase HPLC as a white foam and was carried on directly to deprotection. LCMS (M+H): 534.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[C:14]([C:19]([O:21][CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][N:18]=1>C(#N)C>[CH3:22][O:21][C:19]([C:14]1[C:13]2[N:18]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:17]=[CH:16][N:15]=1)=[O:20]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CC#N
Product: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 103.4 %

Procedure:
A mixture of 2-bromo-1-(4-fluorophenyl)ethanone (30.0 g, 138 mmol) and methyl 3-aminopyrazine-2-carboxylate (21.2 g, 138 mmol) in ACN (300 mL) was heated at about 80° C. The mixture was removed from heat after about 72 h and concentrated under reduced pressure. The crude material was partitioned between saturated aqueous NaHCO3 (450 mL) and DCM (350 mL). The layers were separated and the aqueous layer was washed with additional DCM (2×250 mL). The combined organic layers were washed with water (3×350 mL) and brine (20 ml) then dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude title compound (38.7 g, 45.5%) that was carried on without further purification. LC/MS (Table 1, Method h) Rt=2.26 min; MS m/z: 272.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[CH:7]=1
Reactant: COCCN
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Solvent: O
Product: COCCNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added portionwise, with stirring, to 180 ml of 2-methoxyethylamine, heated to 80° C. After the end of the addition the heating is continued for 2 hours 30 minutes. The reaction mixture is diluted with 180 ml of iced water. The expected product precipitates. It is filtered off, washed with water and dried under vacuum at 60° C. in the presence of phosphorus pentoxide. Recrystallized from 96° ethanol, it melts at 90° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CS(C)=O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5]
Reactant: Cc1cc(O)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cc(OCc2ccccn2)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-difluoro-N-{1-[(4-hydroxy-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide (for a preparation see Example 48)(103 mg, 0.30 mmol) in dimethyl sulfoxide (1 ml) was added cesium carbonate (195 mg, 0.60 mmol) and then 2-(bromomethyl)pyridine hydrobromide (107 mg, 0.423 mmol, Aldrich). The resulting red solution was stirred at ambient temperature under nitrogen overnight. The mixture was filtered using a hydrophobic frit and the filtrate diluted with methanol (1 ml). The filtrate was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as an orange gum (28.3 mg); LCMS: (System 4) MH+=435, tRET=2.27 min.
Reaction SMILES: BrC1C=CC(OC)=C([N+]([O-])=O)C=1.[CH3:13][O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[S:31][C:27]=2[C:26](N2CCOCC2)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[S:31][C:27]=2[C:26]([N:18]2[CH2:19][CH2:20][CH:15]([O:14][CH3:13])[CH2:16][CH2:17]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCOCC3)nc12
Reactant: COC1CCNCC1
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(N2CCC(OC)CC2)c2sc(NC(=O)N3CCOCC3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and 4-methoxy-piperidine as described for morpholine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (Example 136) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=407 (M+H+).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[C:7]([F:10])[C:5]([NH2:6])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([S:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH3:14]>>[CH2:13]([S:15][C:16]1[CH:21]=[C:20]([C:2]2[C:8]([F:9])=[C:7]([F:10])[C:5]([NH2:6])=[C:4]([F:11])[C:3]=2[F:12])[CH:19]=[CH:18][CH:17]=1)[CH3:14]
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Reactant: CCSc1cccc(B(O)O)c1
Product: CCSc1cccc(-c2c(F)c(F)c(N)c(F)c2F)c1
Yield: 76.2 %

Procedure:
The title compound (280 mg) was prepared from 4-bromo-2,3,5,6-tetrafluoroaniline (300 mg, 1.22 mmol) and 3-(ethylthio)phenylboronic acid (291 mg, 1.6 mmol) as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:18][CH2:19][C:20]([F:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:19][C:20]([F:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)(F)CNC1CCCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.7 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (970 mg, 5 mmol) in anhydrous acetone (20 ml) at 0° C., was added dropwise a solution of ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate (1.1 g, 4.76 mmol) in acetone (5 mL) over 10 min. After which, potassium carbonate (1.66 g, 12 mmol) was added and the whole was stirred at rt for 18 h. After evaporation in vacuo, the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with NaHCO3, brine and water, dried over Na2SO4 and concentrated in vacuo to give a red residue (1.9 g) which was used directly for next step. [M+H] calc'd for C16H22ClFN4O4, 389; found 389.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[N:36].O>CN(C=O)C>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[N:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Reactant: N#CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A solution o f 5-[3-(tert-butyl-dimethyl-silanyloxy)4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one (150 mg, 0.41 mmol) in DMF (5 mL) was added to NaH (60% by weight in oil, 16 mg, 0.41 mmol) in DMF (10 mL). After 1.5 h, 7-bromoheptanenitrile (78 mg, 0.41 mmol) in DMF (5 mL) was added and the reaction mixture was stirred at 90° C. for 2.5 h. Water (20 mL) was added and the aqueous solution was washed with EtOAc (4×15 mL). The combined organic solutions were washed with water (2×15 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by medium pressure chromatography (1:1 hexanes:EtOAc) provided 7-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl ]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (161 mg). 1H NMR (CDCl3) δ7.09 (m, 2H), 6.95 (m, 2H), 3.81 (m, 1H), 3.54 (m, 2H), 2.86 (m, 1H), 2.68 (m, 2H), 2.29 (m, 4H), 2.06 (m, 1H), 1.74-1.23 (m, 13H), 0.85 (s, 9H), 0.04 (m, 3H), 0.19 (m, 3H); MS 475.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([N:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:3][CH2:2]1.BrCCCC[C:21]12[CH:31]=[CH:30][CH:29]=[CH:28][CH:22]1[C:23]([NH:25][C:26]2=[O:27])=[O:24]>>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][C:28]2[CH:29]=[CH:30][CH:31]=[C:21]3[C:26]([NH:25][C:23](=[O:24])[C:22]=23)=[O:27])[CH2:2][CH2:3][C:4]2([N:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:5][CH2:6]1
Reactant: C1=NC2(CCNCC2)Oc2ccccc21
Reactant: O=C1NC(=O)C2(CCCCBr)C=CC=CC12
Product: O=C1NC(=O)c2c(CCCCN3CCC4(CC3)N=Cc3ccccc3O4)cccc21

Procedure:
From spiro[2H- 1,3-benzoxazine-2,4'-piperidine] and 2-(4-bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 165°-7° C.