Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8].[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9](=[O:10])[C:7]2=[O:8])[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1C(=O)N(CCCCBr)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(=O)N(CCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of 1-(4-bromobutyl)isatin (5.64 g), 1-benzhydrylpiperazine (7.56 g) and triethylamine (3.0 g) in N,N-dimethylformamide (48 ml) was stirred for 30 minutes at 80° C. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica gel (50 g) using chloroform as an eluent. The fractions containing the object compound were collected and evaporated. The remaining oil (3.25 g) was crystallized from diisopropyl ether, washed with diethyl ether, and then recrystallized from acetonitrile to give crystals of 1-[4-(4-benzhydryl-1-piperazinyl)butyl]isatin (2.69 g), mp. 127° to 129° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][CH3:16])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1>C(Cl)Cl>[CH3:16][O:15][C@H:13]([CH3:14])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[N:19]1[CH2:20][CH2:22][CH2:25][CH2:23]1
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCNC1
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
(2S,3R)-2-(Tert-butoxycarbonylamino)-3-methoxybutanoic acid (643 mg, 2.76 mmol), which is commercially available, and DIPEA (1.440 mL, 8.27 mmol) was mixed in DCM (10 mL). The mixture was cooled to 0° C. TBTU (974 mg, 3.03 mmol) was added and the mixture stirred at rt for 10 min. Pyrrolidine (0.274 mL, 3.31 mmol) was added and the resultant mixture was stirred at rt for 16 h. The mixture was diluted with DCM (10 mL). The organic phase was washed with NaHCO3 (8% in aq. solution) and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1 to 95:5, KP-SIL 340 g column). The solvent was removed under reduced pressure to give the title compound (0.704 g, 95%). 1H NMR (400 MHz, CD3OD) δ 1.15, 1.44, 1.82-2.05, 3.33, 3.35-3.52, 3.54-3.65, 3.66-3.79, 4.36. Total no of protons: 25. LCMS (M+H)+: 287.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:16])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH:21]=O>C1C=CC=CC=1.C([O-])(=O)C.[NH2+]1CCCCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:5]([C:4](=[O:16])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COCC(=O)CC(=O)OCc1ccccc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COCC(=O)C(=Cc1ccc(F)c(F)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
To a solution of benzyl 4-methoxyacetoacetate (84 g, 0.37 mol), 3,4-difluorobenzaldehyde (52.5 g, 0.0.37 mmol), and piperidinium acetate (1.58 g, 2.63 mmol) in benzene (1L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as a white powder (118 g, 91%). The NMR showed this product to be a mixture of cis and trans isomers.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:6]=1C=O.OC1C=CC(C=O)=C[C:18]=1[N+:25]([O-])=O.Cl.NO.N1C=CC=CC=1.[Se](=O)=O>C(Cl)(Cl)Cl.C(O)C>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:9][C:10]([C:18]#[N:25])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1OCCF
Agent: Cl
Agent: NO
Agent: O=[Se]=O
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(OCCF)c([N+](=O)[O-])c1

Procedure:
In a manner similar to Sosnovsky et al. (Synthesis, p 722, (1979)), the reaction of 3.0 grams (0.014 mole) of -(2-fluoroethoxy)-3-nitrobenzaldehyde (prepared by the method of Example 1 from 4-hydroxy-3-nitrobenzaldehyde), 1.1 gram (0.015 mole) of hydroxylamine hydrochloride, and 1.2 ml (0.014 mole) of pyridine (dissolved in 10 ml of chloroform) in 50 ml of chloroform and ethanol (70/30 mixture) followed by treatment with 1.6 gram (0.014 mole) of selenium dioxide yielded 2.3 grams of 4-cyano-2-nitrophenyl 2-fluoroethyl ether as a solid.
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH:15]([NH:17][OH:18])[CH3:16])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.C[Si]([N:27]=[C:28]=[O:29])(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:12][C:11]([C:10]1[CH:9]=[C:8]([CH:15]([N:17]([OH:18])[C:28]([NH2:27])=[O:29])[CH3:16])[CH:7]=[C:6]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:5]=1[OH:4])([CH3:13])[CH3:14]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N(O)C(N)=O
Reaction time: 16 h

Procedure:
To a solution of 0.814 g (0.0025 mole) of 2,6-bis (1,1-dimethylethyl) -4- [1- (hydroxyamino)ethyl]phenol acetate (Example 2) in THF (10 mL) is added 0.868 g (0.0075 mole) of 85% trimethylsilyl isocyanate. The reaction mixture is heated under reflux for 45 minutes and allowed to stand at room temperature for 16 hours. The mixture is poured into saturated NH4Cl, concentrated to remove THF, extracted with EtOAc and dried over Na2SO4. The extracts are evaporated to dryness and the residue is recrystallized from Et2O-n-hexane to give white crystals, 0.46 g (60%), m.p. 162°-163.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(trans-3-hydroxycyclobutyl)carbamate (0.93 g, 4.97 mmol) was dissolved in dry THF (20 mL) under a nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution, sodium hydride (60% dispersion in oil, 0.2 g, 4.97 mmol) was added portion wise (evolution of H2 observed). The mixture was stirred at RT for 30 min then benzyl bromide (0.88 mL, 7.45 mmol) added dropwise and the resulting dark brown suspension stirred at rt for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and partitioned between saturated aqueous NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a off-white solid (0.99 g, 72%). 1H NMR (CDCl3, 400 MHz): δ 7.35-7.31 (5H, m), 4.65 (1H, br, NH), 4.40 (2H, s), 4.24-4.12 (2H, m), 2.50-2.35 (2H, m), 2.18-2.06 (2H, m), 1.43 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:15])[CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:15])=[O:28])=[CH:25][N:24]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: Cc1cccnc1CN(CCCN)C(C)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(CCCNC(=O)c1ccc(O)nc1)C(C)c1ccccn1
Yield: 37.6 %

Procedure:
Using General Procedure G: To a solution of N-(3-Methyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-propane-1,3-diamine (0.33 g, 1.16 mmol) in dry DMF (3 mL) was added 6-hydroxy-nicotinic acid (0.174 g, 1.24 mmol) followed by EDCI (0.257 g, 1.34 mmol), HOBT (0.183 g, 1.35 mmol), and DIPEA (0.40 mL, 2.30 mmol). Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 177 mg (38%) of the free base of the title compound as a colorless oil. Conversion to the HBr salt gave COMPOUND 241 (270 mg, 83%) as a white solid. 1H NMR (D2O) δ 1.55 (d, 3H, J=6.6 Hz), 1.67 (quintet; 2H, J=7.2 Hz), 2.43 (s, 3H), 2.48-2.58 (m, 1H), 2.63-2.74 (m, 1H), 3.12-3.31 (m, 2H), 4.28 (s, 2H), 456 (q, 1H, J=6.6 Hz), 6.61 (d, 1H, J=9.3 Hz), 7.78-7.83 (m, 2H), 7.89-7.94 (m, 2H), 8.11 (d, 1H, J=8.1 Hz), 8.30 (d, 1H, J=8.1 Hz), 8.49-8.58 (m, 2H), 8.74 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 15.07, 16.98, 26.37, 37.59, 50.21, 50.95, 59.83, 115.31, 119.32, 125.82, 126.75, 126.83, 137.21, 137.53, 138.40, 140.83, 142.09, 148.06, 148.24, 152.11, 156.20, 165.43, 166.77; ES-MS m/z 406 (M+H). Anal. Calcd. for C23H27N5O2.3.3HBr.4.2H2O: C, 36.92; H, 5.21; N, 9.36; Br, 35.24. Found: C, 36.85; H, 5.39; N, 9.04; Br, 35.63.
Reaction SMILES: Cl[CH:2]([O:4][P:5]([O-:7])[O-])Cl.C(O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:16](N(CC)CC)C>C(OCC)C>[CH3:16][PH:5](=[O:7])[O:4][CH2:2][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccccc1
Reactant: [O-]P([O-])OC(Cl)Cl
Solvent: CCOCC
Product: C[PH](=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
Dichloromethylphosphite (10.0 g, 77 mmol) in 80 mL of dry diethyl ether was cooled to -20° C. under an atmosphere of nitrogen. A solution of benzyl alcohol (23 g, 213 mmol) and triethylamine (10.2 g, 100 mmol) in 40 mL of diethyl ether was added dropwise over 1 hour while maintaining an internal temperature range of 0° C. to 10° C. Once addition was complete the mixture was warmed to room temperature and stirred overnight. The mixture was filtered and the solid cake washed with 200 mL of diethyl ether. The organics were combined and evaporated under reduced pressure to give 25 g of a clear and colorless liquid. The liquid was purified by flash chromatography and eluted with a 1:1 hexane/ethyl acetate to ethyl acetate gradient. The desired fractions were collected and evaporated to give methyl O-benzylphosphinic acid (1, R=CH3,R1=CH2Ph,6.5 g, 50%) as a clear and colorless oil. Rf 0.1 (1:1, Hexane/EtOAc).
Reaction SMILES: N(C([O:11][CH:12]([CH3:14])C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([OH:37])(=[S:36])C.[CH:38](=[C:40]([CH2:43][CH2:44][CH:45]=[C:46]([CH3:48])[CH3:47])[CH2:41]O)[CH3:39]>O1CCCC1>[C:12]([OH:37])(=[O:11])[CH3:14].[CH:38](=[C:40]([CH2:43][CH2:44][CH:45]=[C:46]([CH3:48])[CH3:47])[CH2:41][SH:36])[CH3:39]
Reactant: CC(O)=S
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CC=C(CO)CCC=C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O
Product: CC=C(CS)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
Diisopropyl azodicarboxylate (2.63g, 0.013 mol) was added dropwise over a 5 min period to a cold (0° C.) mixture of triphenylphosphine (3.40g, 0.013 mol) in tetrahydrofuran (20 mL). The mixture was stirred at 0° C. for 0.5h. A solution of thioacetic acid (0.99g, 0.013 mol) and 2-ethylidene-6-methyl5-hepten-1-ol (1.00g, 0.0065 mol) in tetrahydrofuran (20 mL) was then added dropwise over a 0.5h period to the cold (0° C.) reaction mixture. The mixture was stirred for 1h at 0° C. and then 1h at 25° C. The solvent was removed under reduced pressure. Hexane (40 mL) was added and the mixture was filtered to remove solids. Work-up, chromatography, and kugelrohr distillation (bath temp. 100° C., 0.5 mm) provided 1.15g of 2-ethylidene-6-methyl-5-hepten-1-thiol acetate (GLC purity 94.7%; isomers not separated). NMR (60 MHz, CDCl3) δ 1.62 and 1.68 (6H, 2s), 1.63 (3H, d, J=6 Hz) 2.1 (4H, broad s), 3.57 (2H, broad s), 5.0-5.3 (1H, m), 5.49 (1H, q, J=6Hz); IR (film) vmax 2920, 1685, 1430, 1125 940 cm-1 ; MS m/e 212, 197, 169, 136, 69, 43.
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([Cl:12])=[O:9])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)on1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)on1

Procedure:
A solution of 5-chloroisoxazole-3-carboxylic acid (0.750 g, 4.32 mmol, 1 equiv) and thionyl chloride (9.0 mL, 120 mmol, 28 equiv) in CHCl3 (21 mL) was heated to reflux for 28 h. The volatiles were evaporated to provide a residue which was dissolved in benzene (40 mL), which was subsequently evaporated to give the title intermediate as a yellow oil which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].[CH2:7]([O:9][C:10](=[O:22])[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12])[CH3:8].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:7]([O:9][C:10](=[O:22])[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:2][CH2:3][N:4]([CH3:6])[CH3:5])[CH:14]=1)=[O:12])[CH3:8]
Reactant: CN(C)CCCl
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCN(C)C)c2ccccc12
Yield: 61.7 %

Procedure:
The general procedure 1 was then followed using 1-chloro-2-dimethylaminoethane (6 mmol, 0.65 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6 mmol, 1.3 g) and Cs2CO3 (6.6 mmol, 2.15 g). The purification was achieved by column chromatography (petrolether:ethylacetate:diethylamine 6:3:1) to yield ethyl-2-{1-[2-(dimethylamino)-ethyl]-1H-indol-3-yl}-2-oxoacetate (3.7 mmol, 62%) as pale yellow crystals. Mp=71-72° C. IR {tilde over (ν)} [cm−1]=3139; 3044; 2977; 2946; 2797; 2772; 1727; 1641. EI-MS m/z (rel. int.)=288 (19.15%; M+•). 1H NMR (300 MHz, CDCl3) 8.45 (m; 2H; indole-H); 7.37 (m; 3H; indole-H); 4.41 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.26 (t; 3J=6.9 Hz; 2H; indole-CH2CH2N); 2.76 (t; 3J=6.9 Hz; 2H; indole-CH2CH2N); 2.31 (s; 6H); 1.44 (t; 3H; 3J=7.1 Hz; OCH2CH3).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:25][CH:22]1[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC3CC3)c2)N1C

Procedure:
6.6 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of cyclopropyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. Fair yellow crystals, melting point: 180° C (decomposition).
Reaction SMILES: [CH:1](=[N:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>CC1C=CC=CC=1C>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:18]([C:19]([OH:21])=[O:20])[CH2:17][C:16]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: C(=NCc1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Benzylidene-benzylamine [145.5 gm., 0.75 mole] and succinic anhydride [74.5 gm., 0.745 mole] were refluxed with o-xylene [750 ml.] for 12 hours. The solid, formed upon cooling to room temperature, was filtered, washed with ethanol and air dried. The solid was recrystallized from ethanol to give white needles of the title compound [76.0 gm., 34% yield]. After drying under vacuum and over boiling xylene the solid had a melting point of 169°-171° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[N:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C([Sn](Cl)(CCCC)CCCC)CCC.[N-:32]=[N+:33]=[N-:34].[Na+].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[NH:34][N:33]=[N:32][N:17]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C#N)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCc1nc(=O)c2cc(-c3nnn[nH]3)ccc2[nH]1
Temperature: 25 °C
Yield: 114.7 %

Procedure:
A mixture of 1.1 g of 2-Butyl-6-cyano-4(1H)-quinazolinone 3.2 g of tri-n-butyltin chloride and 640 mg of sodium azide in 30 ml of toluene is heated at reflux for 48 hours. The reaction mixture is cooled to room temperature and dry HCl gas passed through the reaction mixture for 10 minutes. The reaction mixture is diluted with hexane and filtered. The residue is dried, washed with water and dried to give 1.5 g of the desired product as a solid, m.p. 225° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4](C)[C:5]([OH:8])=[CH:6][CH:7]=1.C(N([CH2:18][CH3:19])C(C)C)(C)C.Cl[CH2:21][O:22]C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:18][O:22][CH3:21])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1c(O)ccc(Cl)c1C
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCl
Solvent: C1CCOC1
Product: COCCOc1ccc(Cl)c(C)c1
Temperature: 60 °C
Reaction time: 27.5 h

Procedure:
To a mixture of 4-chloro-3-methylcresol (15.0 g; 0.105 mol), N,N-diisopropylethylamine (23.3 ml; 0.137 mol) and THF (150 ml), was added dropwise chloromethylmethyl ether (9.50 ml; 0.126 mol) at room temperature. The mixture was stirred at 60° C. for 27.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=5:1) to give 2-chloro-5-(methoxyethoxy)toluene as dark reddish-brown oil (17.7 g; 90%).
Reaction SMILES: [CH2:1](OC(=O)C1C=CC(C#CC2C=CC3C(NC4CC4)CCC(C)(C)C=3C=2)=CC=1)C.[Br:30][C:31]1[CH:32]=[C:33]2[C:38](=[C:39]([CH:41]=O)[CH:40]=1)[O:37][C:36]([CH3:44])([CH3:43])[CH2:35][C:34]2([CH3:46])[CH3:45]>CCCCCC>[Br:30][C:31]1[CH:32]=[C:33]2[C:38](=[C:39]([CH:41]=[CH2:1])[CH:40]=1)[O:37][C:36]([CH3:44])([CH3:43])[CH2:35][C:34]2([CH3:46])[CH3:45]
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1
Solvent: CCCCCC
Product: C=Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Yield: 71.6 %

Procedure:
A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and (11.8 mL, 19 mmol) of a 1 .6M solution of n-butyl lithium in hexanes] was added 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Intermediate 30, 0.52 g, 1.75 mmol). After 1 h the reaction mixture was diluted with hexane, washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil (0.37 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:15].C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[NH2:29][C:30]([CH3:35])([CH2:33][CH3:34])[C:31]#[CH:32]>O.O1CCCC1>[CH3:35][C:30]([NH:29][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH:11]=[N:12][O:13][CH3:14])[C:2]([NH2:1])=[C:3]([Cl:15])[CH:4]=1)([CH2:33][CH3:34])[C:31]#[CH:32]
Reactant: C#CC(C)(N)CC
Reactant: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C#CC(C)(CC)NC(=O)c1cc(Cl)c(N)c(C=NOC)c1
Temperature: -30 °C
Yield: 62 %

Procedure:
In a 100 ml, three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 1.27 g (5.5 mmole) of the preceding 4-amino-3-chloro-5-methoxyiminomethylbenzoic acid, (25 ml of tetrahydrofuran and 2.31 ml (16.6 mmole) of triethylamine. The resulting well-stirred mixture was cooled to -30° C. and 0.47 ml (6.1 mmole) of methane sulfonyl chloride were added dropwise keeping the reaction temperature at -30° C. The resulting suspension was stirred at -30° C. during 30 minutes, after which 0.74 g (5.5 mmole) of 3-amino-3-methyl-1-pentyne hydrochloride were added over a 20 minute period. After the addition was completed, the reaction mixture was stirred at -30° C. for an additional 30 minutes. The reaction mixture was poured into water and extracted with methylene chloride (3×25 ml). The combined organic phases were washed sequentially with water (1×20 ml), 5% aqueous hydrochloric acid (2×20 ml), water (1×20 ml), 2% aqueous sodium hydroxide (2×20 ml) and then with water (1×20 ml) and dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator, yielding 1.05 g of the expected N-(3-methylpent-1-yn-3-yl)-4-amino-3-chloro-5-methoxyiminomethylbenzamide, used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(F)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.78 (m, 3 H), 1.13-1.37 (m, 14 H), 1.93 (m, 2 H), 3.41 (m, 2 H), 4.40 (s, 2 H), 5.28-5.45 (m, 1 H), 6.0 (m, 1 H), 6.87-7.07 (m, 3 H), 7.34 (m, 1 H). Rf=0.36 (10% ethyl acetate/n-hexane). mp 117-118° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.C1N=C[N:19]([C:22](N2C=NC=C2)=[O:23])C=1.N>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH2:19])=[O:23]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Under argon atmosphere, to a solution of 2-fluoro-4-iodoaniline 47 (20.0 g) and triethylamine (23.6 ml) in chloroform (200 ml) was added N,N-carbonyldiimidazole (27.4 g) with stirring under ice-cooling. After the completion of the addition, the mixture was stirred under ice-cooling for 15 min and at room temperature for 4 hrs. The reaction mixture was ice-cooled, and 28% aqueous ammonia (100 ml) was added dropwise. The mixture was stirred at room temperature for 1.5 hrs. The precipitated crystals were collected by filtration, washed with water and dried to give (2-fluoro-4-iodophenyl)-urea 78 (23.5 g, yield 98.8%) as pale-pink crystals.