Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH:12]1[C:19]([O:21]C)=O)=O)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:13]1[CH:12]2[C:19](=[O:21])[NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][S:14]1(=[O:17])=[O:18]
Reactant: COC(=O)C1CS(=O)(=O)CCN1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCN2CCS(=O)(=O)CC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of methyl 4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-3-thiomorpholinecarboxylate 1,1-dioxide (D17; 295 mg, 0.88 mmol) in 3 ml of anhydrous dichloromethane was added 1 ml of trifluoroacetic acid and the resulting solution was stirred at room temperature under nitrogen for 1 h 30 min. The solvent was removed under reduced pressure and the residue loaded on a SCX column, washed with methanol and eluted with methanolic ammonia. The product was purified further by chromatography (silica cartridge, cyclohexane to ethyl acetate, then dichloromethane to dichloromethane:methanol 70:30) to give 165 mg of the target compound.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:22]=[C:6]1[CH2:5][CH2:4][C@@:3]2([CH:2]=[O:1])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])=[CH:7]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O
Reaction time: 0.25 h

Procedure:
To a solution of 30 g of 19-hydroxyandrost-4-ene-3,17-dione in 3 liters of acetone cooled in an ice bath is added 28 ml of Jones reagent over a 1 hour period. The reaction mixture is stirred for an additional 15 minutes, filtered and the solvent removed under reduced pressure at 35° C. The residue is taken up in a large volume of ether and 1.5 liters of water. The ether layer is collected, dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane to give 3,17-dioxoandrost-4-en-19-al, M.P. 126°-129° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CO.B#[Ni]>[C:1]([OH:12])(=[O:11])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC#CCC(=O)O
Agent: B#[Ni]
Solvent: CO
Product: CCCCCCC=CCC(=O)O
Reaction time: 2 h

Procedure:
To 4.5 g (27 mmol) of 3-decynoic acid from Example 30 dissolved in methanol in a Paar bottle is added 2 mg of nickel boride as catalyst. The bottle is flushed with hydrogen, sealed and pressurized with H2 at 2 pounds per square inch. The hydrogenation is allowed to proceed at room temperature for 2 hours. The methanol is stripped in vacuo and the residue is partitioned between ethyl acetate and in HCl. The ethyl acetate layer is separated, dried, (Na2SO4) and is stripped to afford an almost quantitative yield of 3-decenoic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]#[N:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C.O[Li].O>C1COCC1.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]#[N:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1CC#N
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#CCn1c(C(=O)O)cc2cc(Cl)ccc21
Reaction time: 6 h
Yield: 84 %

Procedure:
To a solution of 1.0 eq. of 5-chloro-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (prepared according to Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1989), 28B(12), 1065-8) in a mixture of THF/H2O ((9/1) was added LiOH.H2O (1.0 eq.) and the R/M stirred 6 h at R/T, acidified to pH2 and then partially concentrated until precipitation of the crude product which was filtered off and washed with Et2O and then dried to give the desired product as a light yellow solid (84%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH2:41]([O:48][P:49]([O-:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])(O)=O.[Na+]>C(#N)C.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][P:49](=[O:58])([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a solution of 500 mg (133 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 20 ml acetonitrile were added 0.64 ml (6.7 mmol) CCl4, 16.3 mg (0.13 mmol) DMAP and 0.48 ml (2.9 mmol) N,N-diisopropylethylamine. The reaction mixture was stirred for 15 min at room temperature and 0.43 ml (1.9 mnmol) dibenzylphosphite were added dropwise. After 20 min. 20 ml sat. NaHCO3 solution was added and the aqueous phase was extracted with ethylacetate (3×30 ml) and the combined organic layers were washed with water, dried over MgSO4, filtrated and the solvent was removed under reduced pressure. Purification of the crude product by chromatography over silica gel (ethylacetate/hexane 2/1) yielded 700 mg (11 mmol, 83%) phosphoric acid dibenzyl ester (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[F:18])[N:6]=[CH:5]2.[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH3:30])=[CH:29][CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[C:12]([F:18])[CH:13]=1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)c(F)c1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3c(cnn3-c3ccc(N)cc3F)c2)cc1

Procedure:
Compound 388 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-amino-2-fluorophenyl)indazole and 4-dimethylaminobenzoate. [M+H]+ calcd for C22H20FN5O: 390.17; found: 389.96.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Nc1ccc(-n2cnc(C(F)(F)F)c2)nc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(trifluoromethyl)-1H-imidazole (2000 mg, 14.70 mmol), 2-chloro-5-nitropyridine (2330 mg, 14.70 mmol), and potassium carbonate (4060 mg, 29.4 mmol) in acetonitrile (14.7 mL) was heated at 85° C. overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in ethanol (20 mL) and ethyl acetate (15 mL). 10 wt % Palladium on carbon (500 mg) was added to the solution. The mixture was pressurized to 50 psi hydrogen and was shaken for 5 hours. The reaction was filtered through celite, rinsing with methanol. The filtrate was concentrated to give 6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-amine. 1H NMR (400 MHz, CDCl3, δ): 8.15 (s, 1H), 7.93 (d, J=2.73 Hz, 1H), 7.85 (s, 1H), 7.20-7.15 (m, 1H), 7.14-7.09 (m, 1H), 3.13-2.30 (m, 2H). MS (M+HCO2−): 273.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[S:13][C:14]#[N:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:15][C:14]1[S:13][C:3]2[C:4]([OH:12])=[N:5][C:6]([C:8]([F:10])([F:11])[F:9])=[N:7][C:2]=2[N:1]=1
Reactant: N#CSc1c(N)nc(C(F)(F)F)nc1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc2nc(C(F)(F)F)nc(O)c2s1
Yield: 78.8 %

Procedure:
A solution of the compound (4.25 g) obtained in Step 5 in N,N-dimethylformamide (128 ml) was stirred at 130° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, xylene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in ethyl acetate, collected by filtration and dried to give the title compound (3.35 g).
Reaction SMILES: C1([C:7]2[C:16]3[C:11](=CC=CC=3)[CH:10]=[C:9]3[C:17](O[C:20](=[O:21])[C:8]=23)=[O:18])C=CC=CC=1.[NH2:22][NH2:23]>>[C:17]1(=[O:18])[C:9]2[C:8](=[CH:7][CH:16]=[CH:11][CH:10]=2)[C:20](=[O:21])[N:23]=[N:22]1
Reactant: NN
Reactant: O=C1OC(=O)c2c1cc1ccccc1c2-c1ccccc1
Product: O=C1N=NC(=O)c2ccccc21

Procedure:
Later it was found (F. G. Baddar, M. F. El-Newaihy and M. R. Salem, J. Chem. Soc. 838, 1969) that in the reaction of 1-phenylnaphthalene-2,3-dicarboxylic anhydride (R=H in formula (XXX)) ##STR5## with hydrazine that a mixture of the N-amino compound and the phthalazine-1,4-dione were obtained. The 4'-7-dimethoxy anhydride (R=OMe) however gave the N-amino compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:19])[CH:18]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)[C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: COC(OC)N(C)C
Reactant: CC(C)C(=O)Cc1ccnc(F)c1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)C(=CN(C)C)c1ccnc(F)c1
Temperature: 90 °C

Procedure:
To a solution of 1-(2-fluoro-pyridin-4-yl)-3-methyl-butan-2-one (4.8 g, 26.5 mmol) in anhydrous toluene (20 mL) is added N,N-dimethylformamide dimethylacetal (16.0 mL, 120.6 mmol). The reaction is heated at 90° C. for 4 h. The mixture is concentrated in vacuo to give the crude product, 1-dimethylamino-2-(2-fluoro-pyridin-4-yl)-4-methyl-pent-1-en-3-one. The crude product is used as it is.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:7][CH:6]=1)#[N:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22]Br>CN(C)C=O>[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22][N:11]([C:12]1[CH:17]=[N:16][CH:15]=[N:14][CH:13]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1Br
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(F)c(Br)c2)c2cncnc2)cc1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a suspension of 0.04 g of sodium hydride (60% in a mineral oil) in 2 ml of N,N-dimethylformamide was added 0.2 g of 5-[N-(4-cyanophenyl)amino]pyrimidine at room temperature, followed by stirring at that temperature for 1 hour. To the solution was added 0.27 g of 3-bromo-4-fluorobenzyl bromide while cooling with ice, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and water was added to the residue, followed by extraction with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to collect crude crystals from the chloroform eluate. The crude crystals were recrystallized from a mixed solvent of ethyl acetate and ethyl ether to obtain 0.25 g of 5-[N-(3-bromo-4-fluorobenzyl)-N-(4cyanophenyl)amino]pyrimidine.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:24]([NH:26][C:27]2[C:28]([N:37]3[CH2:42][C@H:41]([CH3:43])[C@@H:40]([OH:44])[C@H:39]([NH:45]C(=O)OC(C)(C)C)[CH2:38]3)=[C:29]3[CH2:35][CH2:34][CH:33]([OH:36])[C:30]3=[N:31][CH:32]=2)=[O:25])=[N:11][C:12]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[C:13]([F:15])[CH:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:24]([NH:26][C:27]2[C:28]([N:37]3[CH2:42][C@H:41]([CH3:43])[C@@H:40]([OH:44])[C@H:39]([NH2:45])[CH2:38]3)=[C:29]3[CH2:35][CH2:34][CH:33]([OH:36])[C:30]3=[N:31][CH:32]=2)=[O:25])=[N:11][C:12]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[C:13]([F:15])[CH:14]=1
Reactant: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)c(F)cc3NC(=O)OC(C)(C)C)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)c(F)cc3N)cnc3c2CCC3O)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (7.0 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had the following properties:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([CH:20]([OH:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:40][CH3:41])([O:38][CH3:39])=[O:37])[NH2:35].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:38][CH3:39])([O:40][CH3:41])=[O:37])[NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([CH:20]([OH:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][C:11]=1[Cl:10]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: O=C(O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
Diisopropylethylamine (0.61 mL, 3.5 mmol) was added to a solution of rac.-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoic acid (Example 96; 270 mg, 0.88 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (397 mg, 1.2 mmol) ), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (350 mg, 0.97 mmol) and 1-hydroxybenzotriazole (131 mg, 0.97 mmol) in N,N-dimethylformamide (7 mL). The solution was stirred at room temperature for 17 h and then it was concentrated under high vacuum to remove N,N-dimethylformamide. Ethyl acetate (25 mL) was added and the solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine. Each of the aqueous layers was back-washed in turn with ethyl acetate (10 mL). The combined organic layers were dried (MgSO4), filtered, evaporated and the resulting residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to flirnish N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (260 mg, 61% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C@H:2]([C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1>CCCCCCC>[OH:15][C:13]([CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=1)[CH3:1])=[O:14]
Reactant: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Solvent: CCCCCCC
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 220 °C
Yield: 361.2 %

Procedure:
Heptane is removed as stream 18, FIG. 1, by distillation in an evaporator at atmospheric pressure from a mixture [stream 15, FIG. 1]containing S(+)-ibuprofen (0.1912 moles, 39.43 g), R(-)-ibuprofen (0.5136 moles, 105.95 g), and heptane (ca. 390 g). During the distillation, water [30 g, stream 17]is injected into the base of the evaporator to help strip out the last traces of heptane and to minimize formation of ibuprofen ethyl ester. The molten evaporation residue [stream 33], which contains ibuprofen with an S/R ratio of 27/73, is first racemized by being heated under nitrogen at 220° C. for four hours and is then distilled at about 220° C., 10 mm HgA in an evaporator to provide a distillate [stream 19] of substantially pure racemized ibuprofen (0.6907 moles, 142.48 g, S/R ratio of 47:53) and an undistilled residue [stream 20, 2.91 g] for incineration as a waste stream. Racemized ibuprofen distillate [stream 19] is recycled to the first crop crystallization of crude S(+)-ibuprofen lysinate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1.C(OCC)(=O)C>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCC2)cc1
Reaction time: 0.5 h

Procedure:
5.0 g of 4-[1- (imidazolyl)methyl]benzonitrile is dissolved in 150 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour at -60° combined with 2 5 g of cyclopentanone, further stirred for 1 hour, and heated to 25°. Then water is added to the mixture, the latter is diluted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 6.9 g of crude 4-[1-hydroxycyclopent-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(#N)C.O1CCOCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(Nc1cc(Cl)ccc1N1CCCNCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.4 %

Procedure:
To a solution of 4-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.100 g, 0.215 mmol) in acetonitrile (5 mL) is added 2.0 mL of hydrogen chloride as a 4.0 M solution in 1,4-dioxane. The mixture is stirred at room temperature for 48 h during which time a solid precipitates from solution. The off-white solid is collected by filtration, washed with methylene chloride and dried on the filter pad to provide 0.070 g of 3-chloro-N-(5-chloro-2-[1,4]diazepan-1-yl-phenyl)-benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:12]([CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:13](=[O:16])[CH:14]=[CH2:15])[N:10]=[CH:11][C:4]=12.[OH:24][CH:25]([C:30]1[CH:31]=[CH:32][C:33]([CH:36]=[O:37])=[N:34][CH:35]=1)[C:26]([OH:29])([CH3:28])[CH3:27].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[OH:24][CH:25]([C:30]1[CH:31]=[CH:32][C:33]([C:36](=[O:37])[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([N:9]2[C:5]3=[N:6][CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[CH:11]=[N:10]2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:34][CH:35]=1)[C:26]([OH:29])([CH3:27])[CH3:28]
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCOCC1)n1ncc2c(OC)ccnc21
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccnc2c1cnn2C(CC1CCOCC1)C(=O)CCC(=O)c1ccc(C(O)C(C)(C)O)cn1
Temperature: 0 °C
Yield: 93 %

Procedure:
A mixture of 4-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (178 mg), 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (132 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (18 mg), triethylamine (30 μL), tetrahydrofuran (5 mL) and ethanol (5 mL) was heated under reflux for 3 hr under argon stream. The reaction solution was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (268 mg, yield 93%) as a pale-yellow oil from the fraction eluted with ethyl acetate. MS: 511 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: CCC(CC)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: CCC(CC)CN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC12CCCC2

Procedure:
1-(Hydroxymethyl)cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-1-(2-ethyl-1-butyl)-3-thia-1-azaspiro[4.4]nonane.