Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[CH3:29][N:30]([CH2:32][CH2:33][CH2:34]Cl)[CH3:31]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:34][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)c1
Product: Cc1cccc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared essentially as described in Example 106 except that the compound of Example 120 was reacted with 3-(N,N-dimethylamino)propyl chloride. mp 74° C., NMR, IR, MS 468.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[S:4][N:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[N:14]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Br:15][C:13]1[N:14]=[C:9]([NH:7][C:5]2[S:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(Br)cn(C)c2=O)sn1
Temperature: 120 °C
Yield: 48.7 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 3-methylisothiazol-5-amine (170 mg, 1.5 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (400 mg, 1.5 mmol), Pd(OAc)2 (84 mg, 0.375 mmol), BINAP (116 mg, 0.188 mmol), K2CO3 (450 mg, 4.5 mmol), and 1,4-dioxane (4 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 120° C. in a sealed tube for 18 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100:1 to 25:1) to afford 331a (220 mg, 50%) as a yellow solid. MS-ESI: [M+H]+ 301.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][C:4]=1[O:12][CH3:13].C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)Cl.C(Cl)(Cl)Cl>[S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)([O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:12][CH3:13])[CH:5]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CCO)cc1OC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of 3,4-dimethoxyphenethanol (4.4 g) in methylene chloride (15 ml) containing triethylamine (2.7 g or 3.7 ml), was added gradually a solution of tosyl chloride (5.07 g) in methylene chloride (15 ml). The mixture was stirred at room temperature overnight. The mixture was diluted with chloroform and washed with water. The organic layer was separated, dried and evaporated to yield a crude product (11.7 g). The product was passed through a column of silica gel (250 g) and the eluates were evaporated to give 3,4-dimethoxyphenethyl tosylate (7.2 g): ir(CHCl3) 1600 and 1500 cm-1 ; and nmr(CDCl3) δ2.4 (s, 3H), 2.85 (m, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 4.15 (t, 2H), 6.6 (m, 2H), 7.23 (m, 3H) and 7.64 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21) and 1-methyl-1H-pyrazol-3-ylamine afforded 3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (78.7 mg, 65%); ES+-HRMS m/e calcd for C23H24N5O3F3 [M+H+] 476.1904 found 476.1902. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (m, 1H), 1.26-1.77 (m, 8H), 1.91 (m, 1H), 2.25 (m, 1H), 3.73 (s, 3H), 5.46 (dd, J=4.6, J=10.5 Hz, 1H), 5.92 (d, J=3.0 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.56-7.60 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 8.17 (d, J=3.0 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])[CH2:42][CH2:41]1)=[O:16]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3cccc(F)c3)noc2N)CC1
Yield: 65.8 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (482 mg, 1.21 mmol, 66%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]O)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:39])(=O)=O.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][Cl:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a slurry of 3.3 g (9.2 mmol) N-(4-fluorobenzyl)-2-(hydroxymethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 200 mL anhydrous DMF at 0° C., was added 3.0 mL (22.7 mmol) 2,4,6-collidine and 0.75 g (6.14 mmol) 4-(dimethylamino) pyridine. To this mixture, 1.8 mL (23.3 mmol) of methanesulfonyl chloride was added in two portions of 0.9 mL. The mixture was allowed to slowly warm to room temperature with stirring over night. After 19 hours, the homogeneous dark brown mixture was poured into 1.0 L of water. The resulting slurry was stirred for 2 hours at room temperature. The solids were then collected by vacuum filtration, washed with additional water, and dried in a vacuum oven at 60° C. over a weekend. This provided 2.91 g of the title compound as a tan solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)[C:10]=12
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Reactant: OB(O)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 95 °C
Yield: 49.3 %

Procedure:
A sealed tube was charged with a solution of 3-bromo-4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (480 mg, 1.0 mmol) in toluene (5 mL), pyridin-4-ylboronic acid (246 mg, 2.0 mmol, Lancaster), 0.5 mL of ethanol, and potassium phosphate (1.0 mL, 2 M solution, 2.0 mmol). Argon was bubbled through the mixture for 15 minutes, and the reaction mixture was treated with tetrakis(triphenylphosphine)Pd(0) (58 mg, 0.05 mmol, Strem). The tube was sealed and the mixture was heated at 95° C. for 18 h with vigorous stirring. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The mixture was washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting with 2% MeOH in dichloromethane) to give the desired product (237 mg, 49%) as a thick brown oil. MS(ESI+) m/z 481.1 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])(CC(C(=O)N[C@H](C(=O)NC)CC(C)C)CC(C)C)=[O:8].[N+:29]([C:32]1[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]([O:37][C:38](=[O:39])[C:33]=12)=O)([O-:31])=[O:30]>>[CH3:5][O:6][PH:7]([CH2:27][N:28]1[C:38](=[O:39])[C:33]2=[C:32]([N+:29]([O-:31])=[O:30])[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]1=[O:37])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: CO[PH](=O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
In a manner analogous to that described in Example 3(A), from 0.23 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.105 g of 3-nitrophthalic anhydride, there was obtained 0.105 g of [4-methyl-2-(methylcarbamoyl)butyl]carbamoyl]pentyl][(3-nitrophthalimido)methyl]phosphinic acid methyl ester in the form of a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([C:14]#N)[CH2:11][CH:10]2[CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C([OH:18])C.[OH-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]3=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCO
Reactant: N#C[C@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1OC[C@H]2C[C@@]12c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
(1R)-1-(3,4-Dichloro-phenyl)-2-hydroxymethyl cyclopropanecarbonitrile (24 g, 9.9 mmol), ethanol (48 mL) and 25N sodium hydroxide solution (24 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (24 mL) was added to the reaction mass followed by concentrated hydrochloric acid drop wise to adjust the pH of the reaction mass to 1-2 and stirred for overnight at room temperature. The aqueous layer was extracted with dichloromethane (100 mL).The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 13 g (55%) of product. 1H NMR δ(300 MHz,CDCl3): 1.41-1.43 (1H,t,J=4.9 Hz), 1.58-1.63 (1H,dd,J=7.8,5.0 Hz), 2.56-2.59 (1H,m), 4.28-4.31 (1H, d, J=9.3 Hz), 4.44-4.48 (1H, dd, J=9.4, 4.6 Hz), 7.26-7.30 (1H,dd,J=8.4,2.1 Hz), 7.40-7.43 (1H,d,J=8.4 Hz) 7.52-7.53 (1H,d,J=2 Hz).
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]1[C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:19]([CH3:33])[O:18][N:17]=1.C(N=C(N(C)C)N(C)C)(C)(C)C>N1C=CC=CC=1.CO>[CH:2]1([CH2:5][C:6]2[CH:7]=[C:8]([CH3:14])[C:9]([NH:13][S:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]4[C:16]([CH3:15])=[N:17][O:18][C:19]=4[CH3:33])=[CH:28][CH:27]=3)(=[O:30])=[O:31])=[C:10]([CH3:12])[CH:11]=2)[CH2:3][CH2:4]1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(CC2CC2)cc(C)c1N
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc(CC2CC2)cc(C)c1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Yield: 3.6 %

Procedure:
To a solution of [4-(cyclopropylmethyl)-2,6-dimethylphenyl]amine hydrochloride (100 mg, 0.472 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (157 mg, 0.520 mmol) in Pyridine (1 mL) was added neat Barton's base (2-(tert-butyl)-1,1,3,3-tetramethylguanidine) (0.095 mL, 0.472 mmol). The reaction vessel was sealed and heated in Emrys Optimiser using initial high absorbance to 100° C. for 30 min. After cooling the reaction was analysed and product presence confirmed. The solvent was evaporated in vacuo using the Vaportec V10 to give the crude product. The sample was loaded in methanol and purified by SPE on aminopropyl (NH2) 5 g using methanol. The appropriate fractions were concentrated and the crude material further purified by SPE on sulfonic acid (SCX) 2 g using methanol. The appropriate fractions were combined and dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The samples were dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required products (7.4 mg, 0.017 mmol, 3.56% yield)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:26])[NH:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:14])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[CH:22]1([NH:21][C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH2:12][O:11][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[O:26])[CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
To a solution of 3.2 g 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 40 ml THF and 5 ml water were added 340 mg NaOH portionwise at 0° C. After 4 h the solution was neutralized with Amberlite IR-120 ion exchange resin, filtered and washed with methanol. The crude product obtained after evaporation of the solvents was used in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[NH:17][C:16]2=[O:30])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[C:31](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[N:17]=[C:16]2[O:30][CH3:31])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
A mixture of 9.2 g of crude isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-5-fluoro-4-pentafluoroethyl -1(2H) -pyrimidinyl]-4-fluorobenzoate, 3.36 g of sodium bicarbonate and 3.78 g of dimethyl sulphate in 50 ml of anhydrous acetone is heated to reflux temperature for 3 hours. After cooling the solid constituents are filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is separated by chromatography on a silica gel column using n-hexane/diethyl ether (2:1). There is obtained isopropyl 2-chloro-4-fluoro-5-[5-fluoro-2-methoxy-6-oxo-4-pentafluoroethyl -1(6H)-pyrimidinyl]-benzoate, m.p. 75°-77° C.
Reaction SMILES: [C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Br-].[Br-].[Br-].C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC>C(O)(=O)C>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=1)=[O:18]
Reactant: [Br-]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[NH3+]
Solvent: CC(=O)O
Product: CN1CCOc2c1cc(C(=O)CBr)cc2C(C)(C)C
Reaction time: 0.75 h
Yield: 28.3 %

Procedure:
A solution of the 1-[8-(tert-butyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (2.61 g, 10.6 mmol) and tetra-n-butylammonium tribromide (6.62 g, 13.7 mmol) in acetic acid was stirred at room temperature for 3.5 hours under a nitrogen atmosphere, and then n-butylammonium tribromide (1.02 g, 2.12 mmol) was added and stirring was continued for 45 minutes. After distilling off the solvent under reduced pressure, ethyl acetate was added to the residue and the mixture was washed with saturated aqueous sodium hydrogencarbonate (twice) and brine in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,80 g) and fractionated with hexane-toluene (1:3) to yield the title compound (977 mg, 28.4% yield) as bright golden yellow crystals.
Reaction SMILES: [CH3:1][C@H:2]([C@@H:5]([CH3:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][NH2:4].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(=O)([O-])O.[K+]>O1CCOCC1.O>[CH3:1][C@H:2]([C@@H:5]([CH3:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])[CH2:3][NH:4][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)=CCC[C@H](C)[C@@H](C)CN
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)=CCC[C@H](C)[C@@H](C)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Separate solutions of 2(R),3(S),7-trimethyl-1-amino-6-octene (0.87 g, 5.2 mmol) in 8 mL of dioxane, and benzyl chloroformate (0.86 mL, ~6 mmol) in 8 mL of dioxane were added dropwise simultaneously to a stirred solution of 1.05 g (10.5 mmol) of potassium hydrogen carbonate in 20 mL of water at 0° C. After the additions, the mixture was stirred 8 hrs at room temperature. Most of the volatile solvents were removed in vacuo. The remaining reaction mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate. Solvent removal gave the crude product which was purified on silica gel using 10% ethyl acetate in hexane as solvent to give 1.4 g of the desired carbamate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25]>O1CCOCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:30]2[CH2:31][CH2:32][N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]2)[CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) in dioxane (2 mL) was added with N-isopropylpiperazine (4 mmol). The resulting mixture was heated at reflux for 10 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL) with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-(1H-indazol-6-yl)-2-(4-isopropyl-piperazin-1-yl)-5-nitro-benzamide as a yellow solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:18][CH:19]=[CH2:20])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: C=CCN
Solvent: CCO
Product: C=CCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), prop-2-en-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 0.4), 141 (9), 95 (8), 75 (8), 71 (6), 70 (bp).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([CH2:13][OH:14])[CH2:8][O:7]2)([O-:3])=[O:2].[I:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.[H-].[Na+]>>[I:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:14][CH2:13][CH:9]2[CH2:8][O:7][C:6]3=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]3[CH2:10]2)=[CH:18][CH:17]=1
Reactant: BrCc1ccc(I)cc1
Reactant: O=[N+]([O-])c1cn2c(n1)OCC(CO)C2
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OCC(COCc1ccc(I)cc1)C2
Yield: 42 %

Procedure:
Alkylation of oxazine alcohol 180 (see Example 2MMM) with 4-iodobenzyl bromide and NaH (1.4 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with 0-1% EtOAc/CH2Cl2 (foreruns) and then with 3% EtOAc/CH2Cl2, gave 6-{[(4-iodobenzyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (183) (42%) as a white solid: mp (CH2Cl2/hexane) 161-163° C.; 1H NMR (CDCl3) δ 7.70 (dt, J=8.3, 2.0 Hz, 2H), 7.40 (s, 1H), 7.03 (br d, J=8.3 Hz, 2H), 4.50 (ddd, J=11.4, 3.3, 0.8 Hz, 1H), 4.46 (s, 2H), 4.34 (dd, J=11.4, 7.8 Hz, 1H), 4.13 (ddd, J=12.3, 5.6, 0.8 Hz, 1H), 4.00 (dd, J=12.3, 7.6 Hz, 1H), 3.59 (dd, J=9.6, 5.8 Hz, 1H), 3.53 (dd, J=9.6, 6.5 Hz, 1H), 2.65 (m, 1H); HRFABMS calcd for C14H15IN3O4 m/z [M+H]+ 416.0107. found 416.0108.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH2:16][CH2:17][C:18]([OH:20])=O.C[Si](C=[N+]=[N-])(C)C.C[Al](C)C.[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35].Cl>C1(C)C=CC=CC=1.CO.ClCCl.O>[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH:35][C:18](=[O:20])[CH2:17][CH2:16][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[N:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)CCc1c(Br)cc(Br)nc1-c1ccccc1Cl
Agent: C[Al](C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(CCc1c(Br)cc(Br)nc1-c1ccccc1Cl)Nc1ccccc1Cl
Reaction time: 0.5 h
Yield: 69 %

Procedure:
3-[4,6-Dibromo-2-(2-chlorophenyl)-3-pyridyl]propionic acid (1.09 g, 2.603 mmol) was dissolved in toluene (25 ml)-methanol (5 ml), and a 2M solution of trimethylsilyl-diazomethane in hexanes added (5 ml), and the solution allowed to stand for about 0.5 hours. The solution was evaporated in vacuo, and the resulting oil re-dissolved in dichloromethane (25 ml). This solution was added slowly at 22° to a trimethylaluminium-2-chloroaniline complex [prepared by adding 2M trimethylaluminium in toluene (2.6 ml) to a solution of 2-chloroaniline (0.55 ml, 5.188 mmol) in dichloromethane (30 ml)] and the solution stirred at 22° for 20 h under nitrogen. Water (15 ml) was added (very slowly at first), followed by sufficient 2M hydrochloric acid to dissolve all the precipitated aluminium salts. The organic phase was separated and the aqueous phase further extracted with dichloromethane (60 ml). The combined organic extracts were dried (Na2SO4), evaporated in vacuo, and the oily residue purified by column chromatography over silica (50 g) eluting with cyclohexane ethyl acetate (100:0-70:30) to afford the title compound as a gum (0.95 g, 69%).