Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]([C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]2[CH2:21][C@@H:20]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17]2)=[O:14])=[CH:4][CH:3]=1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43](B(O)O)[CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:2]([C:43]2[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=2)=[CH:3][CH:4]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:39])[CH3:40])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:17]1)=[O:14]
Reactant: COCCCCn1c(Br)ccc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)ccc1-c1cccnc1
Yield: 106.7 %

Procedure:
A mixture of tert-butyl (3S,5R)-3-[{[5-bromo-1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (188 mg), pyridin-3-ylboronic acid (41 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), sodium carbonate (371 mg), ethanol (2 ml), toluene (2 ml) and water (2 ml) was heated under reflux for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure, and crystals were collected by filtration to give the object product (200 mg).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23].[NH3:24]>C(O)C>[NH2:24][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23]
Reactant: N
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCCl
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCN

Procedure:
Dissolve N-(2-chloroethyl)-2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline hydrochloride (19.3 g, 50 mmol) in 100 ml ethanol, and bubble is NH3 (8.5 g, 0.50 mol). Heat in a steel bomb 16 hours at 100°. Let cool and partition between ether and water. Extract the ether with 1.0 N HCl. Basify the aqueous with Na2CO3, extract with ether, dry and concentrate. Recrystallize from ether-hexane to give the title compound as a solid product, m.p. 158°-161° C.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[C:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)=[O:18])=[O:14])[CH2:9][CH2:10]1)(=[O:4])[CH3:3]
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CC(=O)N1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 32.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-acetylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 236, (S)-2-(2-(4-acetylpiperazin-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (14.4 mg, 32.8%). 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 8.01 (d, 1H), 7.60 (d, 2H), 7.30 (s, 5H), 7.20 (t, 2H), 7.02 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.74 (m, 2H), 3.41 (m, 5H), 3.03 (s, 2H), 2.40 (m, 3H), 1.98 (s, 3H). MS (EI) for C30H33FN4O5: 549.7 (MH+).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:59]=CC(N)=[CH:55][CH:54]=2)[CH2:48][CH2:47]1.N[C:61]1C=CC=C[CH:62]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:55]=[CH:54][C:53]([CH2:52][N:49]6[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]6)=[CH:59][CH:30]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:61][CH2:62]1)[CH2:5][O:12][CH2:9]2
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccccc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(CN5CCN(C)CC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-((4-methylpiperazin-1-yl)methyl)aniline as the aniline component. (30%, MS=582.3 (M+H))
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.[Cu][C:15]#[N:16].CN(C)C=O.Cl>[Fe](Cl)Cl.O>[OH:12][CH2:11][CH:9]1[CH2:8][CH2:7][C:6]2[CH:13]=[C:2]([C:15]#[N:16])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: OCC1CCc2cc(Br)ccc2O1
Reactant: N#C[Cu]
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCC(CO)O2
Yield: 49.3 %

Procedure:
A mixture of 297 parts of 6-bromo-3,4-dihydro-2H-1-benzopyran-2-methanol and 108 parts of copper (I) cyanide in 450 parts of N,N-dimethylformamide was stirred and refluxed for 4 hours. The reaction mixture was poured onto a solution of 600 parts of iron chloride in 180 parts of hydrochloric acid and 1000 parts of water. The whole was stirred for 20 minutes at 60° C. The aqueous phase was extracted with methylbenzene. The extract was filtered over Hyflo. The filtrate was washed successively with 10% hydrochloric acid, water, 10% sodium hydroxide and again with water, filtered again, dried and evaporated, yielding 112 parts (49.3%) of 3,4-dihydro-2-(hydroxymethyl)-2H-1-benzopyran-6-carbonitrile; mp. 85° C. (intermediate 2).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:11].C[O:13]B(OC)OC.C([Li])(C)(C)C>>[F:11][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[CH:8][S:9][C:10]=2[C:2]=1[OH:13]
Reactant: Fc1ccc2ccsc2c1Br
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Product: Oc1c(F)ccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
(Ref: Briner, K; Burkholder, T. P; Conway, R. G; Cunningham, B. E; Finley, D. R; Heinz, L. J; Jesudason, C. D; Kohlman, D. T; Liang, S. X; Xu, Y. C. Preparation and use of serotonergic benzothiophenes. WO 0109126 A1. Chem. Abs. 134:162912). To a solution of 7-bromo-6-fluoro-1-benzothiophene (0.2 g, 0.9 mmol) and trimethylborate (0.2 mL, 1.8 mmol) at −78° C. was added tert-butyllithium dropwise. After 10 mins at −78° C. the reaction was quenched by pouring onto saturated ammonium chloride. This was extracted with ethyl acetate (3×10 mL) and the solvent removed in vacuo from the combined organic extracts. The residue was taken up in ethyl acetate (4 mL) and 10% aqueous hydrochloric acid (4 mL) was added, the mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo. The residue was taken up in THF (10 mL), water (2 mL) and cooled to 0° C. then 10% aqueous sodium hydroxide (2 mL) and 28% hydrogen peroxide (1 mL) were added to this and stirred for 0.5 h at 0° C. The mixture was warmed to room temperature and stirred for 2 hours, before a acetic acid (3 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL), dried (MgSO4) and the solvent removed in vacuo, to give a purple solid. This was purified by flash chromatography with a gradient of 0–20% ethyl acetate in iso-hexane to give the title compound (56 mg, 38%); δH (300 MHz, CDCl3) 7.41 (4H, m, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C1S(=O)(=O)CCC1>[OH:1][C:2]1[C:11]([N+:18]([O-:19])=[O:17])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1c(O)ccc2ccncc12

Procedure:
To a 300 ml round bottom flask is added 14.5 g (0.1 mole) of 7-hydroxyisoquinoline and 100 ml of warmed tetramethylene sulfone. The brown slurry is stirred and to it is added portionwise 18.6 g (0.14 mole) of nitronium tetrafluoroborate with cooling (ice bath). The reaction is stirred for 3 hours. The reaction is then quenched with 100 ml of methanol, evaporated to dryness and triturated twice with ether to precipitate a dark solid (19.0 g, 100%).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2>C(OC(=O)C)(=O)C>[CH2:12]1[C:13]2[C:9](=[CH:8][C:7]([NH:6][C:1](=[O:4])[CH3:2])=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 100 °C

Procedure:
A mixture of 70 ml of acetic anhydride and 15 g of sodium acetate is added dropwise, with stirring, to 50 g of-5-aminoindane. At the end of the exothermic reaction, the solution is heated at 100° C. for one hour. The solution is then poured into 500 g of ice; a precipitate is observed to form, which is collected by filtration and taken up in 400 ml of ethyl acetate. The solution is washed with 2×250 ml of water, 2×200 ml of a 20% sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The title compound is obtained in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH2:7])=[NH:6])([CH3:4])[CH3:3].Cl.[O-]CC.[Na+].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[C:2]([C:5]1[N:7]=[C:16]([OH:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][N:6]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)C(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g, 27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated and the residue was dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried under vacuum to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H+).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][CH2:6][C:7]([NH2:9])=[O:8].C(O)(=O)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:29][CH3:30])=[C:19]([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=1>CO>[NH2:9][C:7](=[O:8])[CH2:6][NH:5]/[C:21](/[C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:29][CH3:30])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Reactant: NCC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)/C=C(\NCC(N)=O)c1cc(Cl)ccc1OC
Temperature: 65 °C
Yield: 105.4 %

Procedure:
A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65° C. for 1 hour before cooling to 50° C. and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 mL) and ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating to reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10° C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65° C.) for 14 hours to afford the title compound (339.4 g).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])(=[O:6])=[O:5].C[N:18](C=O)C>>[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([NH2:18])[CH:11]=[C:10]2[CH3:16])(=[O:6])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2ccc(S(C)(=O)=O)cc12
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(N)c2ccc(S(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (1.06 g, 26.6 mmol, 60% in mineral oil) in DMF (15 mL) at 0° C. is treated with 5-methanesulfonyl-3-methyl-1H-indole (370 mg, 1.77 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (1 g, 8.85 mmol) portion wise and warmed to rt overnight. The mixture is then poured over ice, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5-methanesulfonyl-3-methyl-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[N:3][CH:2]=1.N1C=CC=CC=1.CN(C)C=O.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>O>[NH2:8][C:4]1[C:5]([NH:7][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: Nc1cncnc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1ncncc1NC(=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a stirred mixture of 20.2 parts of 4,5-pyrimidinediamine, 40 parts of pyridine and 144 parts of N,N-dimethylformamide was added dropwise a solution of 24.2 parts of 4-fluorobenzoyl chloride in 36 parts of N,N-dimethylformamide at 10° C. Upon completion, stirring was continued for 30 minutes at room temperature. 600 Parts of water were added. The product was filtered off and dried, yielding 30 parts (70%) of N-(4-amino-5-pyrimidinyl)-4-fluorobenzamide (interm. 11).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCCCCC.C(Cl)Cl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCCCCCCCCCCCCCCCBr
Reactant: CCCCCCOc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To 350 mL of dehydrated methylene chloride, 12.8 g (66 mmol) of 2-hexyloxyphenol, 23.3 g (73 mmol) of 16-bromohexadecane-1-ol, and 20.0 g (99 mmol) of tri-n-butylphosphine were added. The resulting mixture was cooled with ice under argon. After 25.0 g (99 mmol) of 1,1′-(azodicarbonyl)dipiperidine was added bit by bit while stirring the mixture, 150 mL of methylene chloride was added. Under argon, the mixture was stirred at ambient temperature for 30 minutes and was refluxed for 6 hours. After being cooled, the reaction solution was put into 100 mL of hexane and was filtered. The filtered liquid was purified by silica-gel column chromatography. As a result, 26.5 g of a transparent liquid was obtained.
Reaction SMILES: [Na][Na].[P:3]([CH2:7][NH:8][CH2:9][C:10]([OH:12])=[O:11])([OH:6])([OH:5])=[O:4].[CH:13]12[C:25](=[O:26])[O:24][C:22](=[O:23])[CH:14]1[CH:15]1[C:20](=[O:21])[O:19][C:17](=[O:18])[CH:16]12.[OH2:27]>>[C:10]([CH2:9][N:8]([CH2:7][P:3]([OH:6])([OH:5])=[O:4])[C:17]([CH:16]1[CH:15]([C:20]([OH:19])=[O:21])[CH:14]([C:22]([OH:27])=[O:23])[CH:13]1[C:25]([OH:24])=[O:26])=[O:18])([OH:12])=[O:11]
Reactant: O
Reactant: O=C1OC(=O)C2C1C1C(=O)OC(=O)C21
Reactant: O=C(O)CNCP(=O)(O)O
Agent: [Na][Na]
Product: O=C(O)CN(CP(=O)(O)O)C(=O)C1C(C(=O)O)C(C(=O)O)C1C(=O)O

Procedure:
To a 28.6 grams (0.03 mole) portion of the disodium salt of N-phosphonomethylglycine, prepared as described in previous examples, there is added 4.2 grams (0.015 mole) of cyclobutane-1,2,3,4-tetracarboxylic dianhydride. A pH of about 8 is maintained with periodic additions of alkali, and further anhydride, in 4.2 grams and 1.0 gram portions, are added to complete the reaction. The reaction mixture is diluted with water and passed through a column of ion exchange resin in the acid form. The second through fourth 20 ml. cuts are collected and dried to yield N-carboxymethyl-N-phosphonomethyl-2,3,4-tricarboxycyclobutanecarboxamide (in the monohydrate form) as a cream colored brittle foam. Elemental analysis gives 33.38% carbon, 3.94% hydrogen, 3.27% nitrogen and 7.31% phosphorus as against calculated values of 32.93%, 4.02%, 3.49% and 7.72% for C11H14NO12P.H2O. ##STR21##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: Cc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)c(OCCc2cccc(C)c2)c1
Yield: 32.7 %

Procedure:
10.0 g of 3-hydroxy-4-iodo-benzoic acid methyl ester, 7.2 g of 1-(2-bromo-ethyl)-3-methyl-benzene and 10.0 g of potassium carbonate were stirred in 100 ml of anhydrous DMF for 28 h at 80° C. The solvent was evaporated and the residue dissolved in 200 ml of water and 400 ml of EA. The organic layer was separated, washed with 200 ml of water, dried with magnesium sulfate and evaporated. Silica gel chromatography (EA/HEP gradient) of the residue yielded 4.66 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7](=[N:8][OH:9])[O:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1.[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[C:7](=[N:8][O:9][C:17](=[O:18])[NH:16][CH3:15])[O:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1
Reactant: CN=C=O
Reactant: CC1(C)Oc2ccccc2OC1=NO
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1Oc2ccccc2OC1(C)C
Reaction time: 16 h

Procedure:
To a solution of 17.9 g of 3,3-dimethyl-2-oximinobenzodioxane and 5 drops of triethylamine was added 18.0 ml of methyl isocyanate. The reaction mixture was then left at ambient temperature for 16 hours. The reaction mixture was concentrated and filtered to yield 3,3-dimethyl-2-[O-(methylcarbamoyl)oximino]benzodioxane, m.p. 174°-176° C.
Reaction SMILES: C1([CH2:4][O:5][C:6]2[C:11]([C:12]3[N:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)[C:15]4[CH:29]=[C:30](F)[C:31](F)=[CH:32][C:14]=4[N:13]=3)=[CH:10][CH:9]=CN=2)CC1.[Cl:35][C:36]1C=CC(C2NC3C=CC=CC=3N=2)=C(OC)[CH:37]=1.BrCC1CCCCC1>>[Cl:35][C:36]1[CH:9]=[CH:10][C:11]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:15]3[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=3[N:13]=2)=[C:6]([O:5][CH3:4])[CH:37]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Reactant: COc1cc(Cl)ccc1-c1nc2ccccc2[nH]1
Agent: BrCC1CCCCC1
Product: COc1cc(Cl)ccc1-c1nc2ccccc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-Chloro-2-methoxy-phenyl)-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No 2550-36-9). Brown solid (48%). MS (Turbo Spray): m/z=355.3 (M+H).
Reaction SMILES: [C:1]([C@:3]1([OH:24])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[CH:11]=[CH:10]3)#[CH:2].C(Cl)CCl.ClC1C=CC=C(C(OO)=[O:37])C=1.C(O)(C)(C)C>C(OCC)(=O)C>[C:1]([C@:3]1([OH:24])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[C@H:11]1[O:37][C@@H:10]31)#[CH:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
750 mg. of 17α-ethinyl-11β-fluoro-17β-hydroxy-4,6-androstadien-3-one in 50 ml. of ethylene chloride is combined with 1.2 g. of m-chloroperbenzoic acid in 5 ml. of tert.-butanol and 1 ml. of ethylene chloride. The mixture is agitated at room temperature for 21 hours. The solution is then diluted with ethyl acetate and washed successively with sodium bisulfite solution and water. In this way, 420 mg. of 17α-ethinyl-6α,7α-epoxy-11β-fluoro-17β-hydroxy-4-androsten-3-one is isolated. UV: ε239 = 16,300 (methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O>C(O)C.[NH4+].[Cl-].[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N=Nc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1ccc(NNc2ccccc2)cc1
Yield: 100.3 %

Procedure:
Zinc powder (10.0 g; 0.15 mol) was added to a stirred mixture of 4-methoxyazobenzene (4.24 g; 20.0 mmol) in 96% ethanol (75 ml) and saturated NH4Cl solution (2.0 ml) at 0° C. (bath temperature). Two more portions of saturated NH4Cl solution (2.0 ml) were added at 1.5 h intervals. The yellowish solution was poured into cold water (100 ml) and filtered. The residue was extracted with methylene chloride (5×50 ml). The combined aqueous phases were extracted with methylene chloride (3×25 ml). The combined organic solutions were,dried (Na2SO4), filtered and evaporated to give 4.3 g crude 1-(4-methoxyphenyl)-2-phenylhydrazine as a reddish oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:15])=[O:4].[OH:16][CH:17]([CH:19](O)[CH3:20])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:12]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:15])[C:6]=2[NH:5][C:3](=[O:4])[CH2:2][Cl:1])[O:16][CH:17]([CH3:18])[CH:19]([CH3:20])[O:14]1
Reactant: CC(O)C(C)O
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cccc(C2(C)OC(C)C(C)O2)c1NC(=O)CCl

Procedure:
The product from Example 1 (10.6 g), 2,3-dihydroxy-butane (8.5 g) and p-toluene sulfonic acid (1.5 g) in 200 ml benzene were refluxed to 2 hours, removing water with a Dean-Stark trap. The solution wash washed with 10% NaOH, dried (MgSO4) and stripped. The product was chromatographed on a silica gel column, eluting with 30% ether-hexane. Yield: 3.8 g of the title product, mp 55°-57° C.