Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:31][CH:32](Br)[CH2:33][CH3:34])(=[O:30])[CH2:28][CH3:29].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:32]([O:31][C:27](=[O:30])[CH2:28][CH3:29])[CH2:33][CH3:34])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reactant: CCC(=O)OC(Br)CC
Agent: [I-]
Agent: [Na+]
Product: CCC(=O)OC(CC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-bromopropyl propionate in the presence of sodium iodide to give 1-propionyloxypropyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 100°-108° C. (decompn.).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:14](=[O:17])([O-])[O-].[K+].[K+].CN1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>C(OCC)(=O)C.O>[CH:23]12[CH2:6][CH:5]([CH2:25][CH2:24]1)[CH2:1][CH:22]2[O:26][C:8]1[CH:9]=[C:10]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6]2)[CH:11]=[CH:12][C:13]=1[O:17][CH3:14]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CN1CCCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cn(-c2ccc(OC)c(OC3CC4CCC3C4)c2)c2ccccc12
Temperature: 150 °C

Procedure:
A mixture of (1.0 g, 5.71 mmol, 1.0 eq) 3-carbomethoxy indole, (2.21 g, 7.42 mmol, 1.3 eq) (±)-1-methoxy-2-exo-norbornyloxy-4-bromobenzene (30.7 mg, 0.107 mmol, 0.2 eq) cuprous bromide, and (866 mg, 6.27 mmol, 1.1 eq) potassium carbonate in 15 ml of 1-methyl-2-pyrrolidinone was heated to 150° C. for 24 hours. The reaction mixture was cooled, diluted with 350 ml of ethyl acetate and 350 ml of H2O, and the layers separated. The aqueous layer was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed twice with H2O, once with brine, dried over Na2SO4 and concentrated in vacuo to give a light brown oil. Silica gel chromatography eluting with 20% ethyl acetatehexane gave 1.05 g, 47%, of a white foamy solid. M.P.: 120°-122° C. Elemental Analysis Calc'd for C24H25NO4 : Calc'd: C, 73.64; H, 6.44; N, 3.58. Found: C, 73.70; H, 6.37; N, 3.59.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl.[CH3:54][N:55]([CH3:61])[CH2:56][CH2:57][C:58](O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:8]([O:27][CH2:28][CH2:29][N:30]([C:58](=[O:59])[CH2:57][CH2:56][N:55]([CH3:61])[CH3:54])[CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN(C)CCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt (1.50 g, 2.37 mmol) was diluted with DCM (10 mL) and added to a pre-activated mixture of 3-(dimethylamino)propionic acid HCl salt (383 mg, 2.49 mmol), HATU (1034 mg, 2.72 mmol) and DIEA (831 uL, 4.77 mmol) in DCM (10 mL). The round-bottomed flask was flushed with argon and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated. Purification by silica gel chromatography with a DCM/MeOH gradient yielded (Z)-((3-(dimethylamino)propanoyl)azanediyl)bis(ethane-2,1-diyl) dioleate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([O-:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:12]([CH2:13][C:14]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])=[O:16])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CNc1ccccc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)N(C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
75 g of N-methyl o-nitro aniline and 70 g. of monoethyl malonate (obtained according to M. Freund, Ber. 17, 780, 1884) are dissolved in 550 cc. of benzene, the solution is agitated and 106 g. of phosphorus pentachloride are added, while maintaining the temperature at 20°-23° C.; this is agitated for three hours at room temperature, then heated for 1 hour at 70° C.; a yellow precipitate forms, which dissolves again, giving an orange solution; a water-ice mixture is added, while agitating, to obtain a volume of 1,500 cc., keeping the temperature at 30° C.; the benzene phase is decanted off, washed with water, then with a saturated aqueous solution of sodium bicarbonate and finally with water, dried over sodium sulfate and evaporated under reduced pressure; the residue is purified by recrystallisation in the xylol-petroleum ether mixture (2.5-1). The compound melts at 54°-55° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[N:6][C:7]=1[CH3:8].C([N:12](CC)CC)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([C:20]2[C:19]([C:18]([F:29])([F:28])[F:17])=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([NH2:12])=[O:23])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ncc(N)cc1I
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc(-c2c(C(N)=O)cccc2C(F)(F)F)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5-iodo-6-methylpyridin-3-amine (125 mg, 0.534 mmol) in methylene chloride (1 mL) was added triethylamine (0.087 mL, 0.627 mmol) and cooled at 0° C. Into the reaction was added 3-(trifluoromethyl)benzoyl chloride (0.0812 mL, 0.538 mmol) dropwise and stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with EtOAc and the organic extracts were washed with water saturated Na2CO3, saturated NaCl, dried (MgSO4) and stripped in vacuo. The product was used in the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([C:20]([CH2:27][CH3:28])([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])[CH3:19]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:21](=[O:22])[C:20]([CH2:27][CH3:28])([CH2:18][CH3:19])[C:24](=[O:25])[O:9]2)=[O:7])=[CH:10][CH:11]=1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)NO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(C)cc2)C1=O
Yield: 34.1 %

Procedure:
A mixture consisting of 1.51 g (0.0100 mol) of 4-methylbenzohydroxamic acid, mp 148-150° C. (dec.) (lit. mp 148° C. dec. , Beilstein Handbook of Organic Chemistry, series H, vol 9, p. 491), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 1.977 g (0.0100 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 2 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 mL portions of water, three times with 50 mL portions of 5% hydrochloric acid, and two times with 50 mL portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 0.94 g (34.2%) of crude 2-(4-methylbenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from methanol gave pure 2-(4-methylbenzoly)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 92-93° C.; IR (Nujol) 1805 (s,C=0), 1747 (s, C=0) 1695 cm-1 (s, C=0);H1NMR (400 MHz, CDCl3) δ7.70 (d,2H), 7.29 (d,2H), 2.43 (s,3H), 1.95 (q. 4H), 1.00 (t, 6H); High resolution MS, calc'd for: C15H17NO4 : 275.1157. Found: 275.1163. Anal. Calc'd for: C15H17NO4 : C, 65.44; H, 6.23; N 5 09. Found: C, 65.24; H, 6.45; N, 5.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.Br[CH2:19][CH2:20][CH:21]=[C:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[N:32][C:27]=2[CH2:26][O:25][C:24]2[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]1=2.[I-].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:19][CH2:20][CH:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[N:32][C:27]=4[CH2:26][O:25][C:24]4[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]3=4)[C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccc(Cl)cc2C2(CCNCC2)O1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1C(=O)OC3(CCNCC3)c3cc(Cl)ccc31)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
A solution of 6-chloro-1,2-dihydro-2-oxo-spiro[4H-3,1-benzoxazin-4,4′-piperidine] (Made by the procedure of Bock, et al. GB2,355,465, 0.25 g, 0.7 mmol) in isopropanol (5 mL) was treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.19 g, 0.50 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 5 hr, and evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC to yield 0.029 g (10%) of the title compound, 1H-NMR (CD3OD) δ: 1.50 (3H, s), 2.18 (2H, brs), 2.95–3.2 (6H, m), 5.30 (2H, brs), 6.18 (1H, t), 6.79(1H, m), 6.92 (1H, m), 7.12 (1H, m), 7.38 (2H, m), 7.48 (2H, m), 7.81 (2H, m), 8.31 (1H, m), 8.55 (1H, d).
Reaction SMILES: [OH:1][C@H:2]([C:38]1[CH:47]=[CH:46][C:45]([OH:48])=[C:44]2[C:39]=1[CH:40]=[CH:41][C:42](=[O:49])[NH:43]2)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH2:37][CH2:36][C:24]3([O:29][CH2:28][CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25]3)[CH2:23][CH2:22]2)[CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:29]1[C:24]2([CH2:36][CH2:37][N:21]([CH2:20][C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:38]3[CH:47]=[CH:46][C:45]([OH:48])=[C:44]4[C:39]=3[CH:40]=[CH:41][C:42](=[O:49])[NH:43]4)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:22][CH2:23]2)[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N(CCc1cccc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
A solution of (R)-tert-butyl 2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl(3-((4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethyl)carbamate (example 12, step g) (0.100 g) in methanol (5.0 mL) was treated with a solution of potassium carbonate (0.035 g) in water (5.0 mL) and the resultant mixture stirred at 20° C. for 5 hours. The methanol was evaporated off under a stream of nitrogen and further water (5.0 mL) was added. The solution was acidified by addition of acetic acid and then passed through a 10 g cartridge of C18 silica. The cartridge was washed with water and then flushed with methanol to bring off the product. The solvent was evaporated off under reduced pressure to yield 0.090 g of the acetic acid salt. This solid was dissolved in methanol (2 mL) and passed through 0.700 g of VARIAN Bond Elut NH2 resin and the solvent was evaporated off under reduced pressure to afford the subtitled compound. Yield 0.074 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[H][H]>[C].[Pd].C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:15]([F:16])([F:17])[F:18])[CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed ethyl (2E)-3-[4-hydroxy-2-(trifluoromethyl)phenyl]prop-2-enoate (2.6 g, 9.99 mmol, 1.00 equiv), ethanol (40 mL), Palladium carbon (5 g). To the above hydrogen was introduced in. The resulting solution was stirred for overnight at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.4 g (crude) of ethyl 3-[4-hydroxy-2-(trifluoromethyl)phenyl]propanoate as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.S([CH2:37][N+:38]#[C-:39])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CO.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]4[O:18][CH:39]=[N:38][CH:37]=4)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=O)ccn23)ccc1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(-c4cnco4)ccn23)ccc1F
Yield: 35.9 %

Procedure:
2′-Fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (100 mg), tosylmethyl isocyanide (60 mg) and potassium carbonate (40 mg) were suspended in methanol (10 ml) and heated at reflux for 90 min. The reaction was cooled, diluted with dichloromethane and filtered. The filtrate was evaporated to dryness and the residue partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel eluting with dichloromethane with 1% ammonia on a gradient of methanol (1-5%) gave a solid. Trituration with diethyl ether afforded 2′-fluoro-5′-[7-(oxazol-5-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid (40 mg, 34%): δH (360 MHz, DMSO) 7.53 (1H, d, J 7), 7.65 (1H, s), 7.70 (1H, s), 7.81 (1H, s), 7.87-7.95 (3H, m), 8.06 (1H, d, J 8), 8.11 (1H, s), 8.20 (1H, s), 8.70 (1H, s), 9.19 (1H, d, J 7); m/z (ES+) 382 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[CH2:13]([S:25]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+].O>C(#N)C.C(O)(C)C>[NH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[NH:28][S:25]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:27])=[O:26])=[C:3]([OH:12])[CH:4]=1
Reactant: CCCCCCCCCCCCS(=O)(=O)Nc1ccccc1C(=O)Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCS(=O)(=O)Nc1ccccc1C(=O)Nc1cc(Cl)c(N)cc1O

Procedure:
28.2 g of 2-amino-4-chloro-5-nitrophenol was refluxed in 150 ml of acetonitrile and a solution containing 52.7 g of 2-dodecanesulfonamidobenzoyl chloride obtained in Step (i) above dissolved in 50 ml of acetonitrile was added to the mixture. After refluxing for 4 hours, the reaction mixture was cooled to deposit the crystals. The crystals were collected by filtration, washed with acetonitrile, and dried to yield 56 g thereof. The crystals were refluxed with stirring for 1 hour together with 60 g of reduced iron powder, 2 g of ammonium chloride, 50 g of water, and 500 ml of isopropanol. After removing the iron powder by filtration, the filtrate was poured into 2 liters of water to deposit the crystals. The crystals were collected by filtration and recrystallized from acetonitrile to obtain 36 g of the above described compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1.C(O[C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH2:24][CH:25]1OC1)C>C(O)CC(C)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[N:16]([CH2:21][CH:22]([OH:23])[CH2:28][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[O:23][CH2:24][CH3:25])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1
Reactant: Cn1cc(C2NCCNC2=O)c2ccccc21
Reactant: CCOc1ccccc1OCC1CO1
Solvent: CC(C)CCO
Product: CCOc1ccccc1CC(O)CN1CCNC(=O)C1c1cn(C)c2ccccc12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
11.5 g (0.05 mol) of 3-(1-methylindol-3-yl)-piperazin-2-one, prepared in accordance with Example 34, are dissolved in 100 ml of isoamyl alcohol, 9.7 g (0.05 mol) of 3-(2-ethoxyphenoxy)-1,2-epoxypropane are added and the mixture is stirred for 5 hours at 120° C. The reaction mixture is evaporated in vacuo, the residue is dissolved in ethyl acetate, and the hydrochloride is precipitated by adding hydrochloric acid in ether. The product is filtered off with suction and dried.
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1)([CH3:5])[CH3:4].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23]>C1COCC1>[Cl:16][C:17]1[C:18]([O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH:3]([CH3:5])[CH3:4])[N:7]=[CH:8]3)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[O:23]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)n1ncc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1ncc2cc(Oc3cc(F)c(C(=O)NS(C)(=O)=O)cc3Cl)ccc21
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 8.7 %

Procedure:
Sodium hydride (60% in mineral oil, 0.012 g, 0.306 mmol) was added to a solution of 1-isopropyl-1H-indazol-5-ol (Preparation 39, 0.045 g, 0.225 mmol) in THF (3.0 mL) while cooling the reaction in an ice bath and stirred for 40 minutes. 5-Chloro-2,4-difluoro-N(methylsulfonyl)benzamide (Preparation 28, 0.076 g, 0.28 mmol) was then added and the reaction was heated at 60° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue treated with EtOAc (25.0 mL) and washed with water (30.0 mL), followed by brine (30.0 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by silica gel chromatography eluting with 2% Methanol in DCM to yield the title compound as a white solid (8.3 mg):
Reaction SMILES: [OH:1][CH:2]([CH2:23]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].[BrH:25].O.C([O-])(O)=O.[Na+].[C:32]([OH:35])(=O)[CH3:33]>>[C:32]([O:1][CH:2]([CH2:23][Br:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17])(=[O:35])[CH3:33]
Reactant: Br
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCC(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CBr)CCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(10,11-Dihydroxyundecyl)phthalimide (2.35 g, 7.10 mmol) was stirred for 3 hours with HBr (6.90 mL of a 30% solution in acetic acid, 21.3 mmol). The mixture was then added over 10 minutes to a solution of water (50 mL), ice (25 g) and NaHCO3 (15 g) and stirred for an additional 30 min. The resulting reaction product was extracted with dichloromethane (3×70 mL) and the combined organic phase was dried using magnesium sulfate and evaporated, yielding a residue of N-(10-acetoxy-11-bromoundecyl)phthalimide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20]COS(C)(=O)=O)[N:9]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.O1CCC[CH2:37]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[N:11]=[C:10]([CH2:20][CH2:37][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:9]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCOS(C)(=O)=O)n2)c1
Reactant: C1COCCN1
Reactant: C1CCOC1
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCN3CCOCC3)n2)c1
Temperature: 80 °C

Procedure:
Compound 95, methanesulfonic acid 2-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-ethyl ester (104 mg., 0.25 mmol) was dissolved in tetrahydrofuran (4 mL). To the reaction mixture was added morpholine (43 mg., 0.5 mmol) and the vessel was sealed and heated at 80° C. for sixteen hours. The solvent was removed under reduced pressure and the crude oil was purified by column chromatography to give Compound 94, N-(3-methyl-benzylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yl]-hydrazine (52 mg., 0.13 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:5]([O:19][Si](C(C)(C)C)(C)C)[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.C[O:38][C:39](=O)[C@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:39](=[O:38])[C@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2[C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:19]
Reactant: COC(=O)[C@H]1CCCN1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(N=C2N(c3ccccc3Br)C(=O)[C@H]3CCCN23)c(O)c1
Yield: 77.8 %

Procedure:
The standard procedure was followed using N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide (107 mg, 0.25 mmol), diisopropylethylamine (71 μL, 0.55 mmol), D-proline methyl ester hydro chloride (46 mg, 0.28 mmol) and TBAF (0.30 mL, 0.30 mmol) in THF (2.5 mL) and methanol (0.1 mL) to give 80 mg (78%) of 4-[[(7aR)-2-(2-bromophenyl)-hexahydro-1-oxo-3H-pyrrolo[1,2-c]imidazol-3-ylidene]amino]-3-hydroxybenzonitrile as a tan powder. MS(EI) m/e 411 (100(M+)).