Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCO>[ClH:1].[OH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])[NH:2][CH2:3][CH2:4]2
Reactant: CCOC(=O)C=O
Reactant: NCCc1cccc(O)c1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCCc2cc(O)ccc21
Yield: 90.1 %

Procedure:
A solution of 3-(2-aminoethyl)phenol hydrochloride (4.60 g, 26.49 mmol) and 47% ethyl glyoxylate/toluene solution (polymer form) (6.15 mL, 29.14 mmol) in a mixed solvent of toluene/EtOH (50 mL) was heated under reflux for 18 hr. The reaction mixture was concentrated under reduced pressure. The precipitate was collected by filtration, and washed with ethyl acetate/diethyl ether to give ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride (6.15 g, 23.86 mmol, 90%) as a white powder.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[NH2:16]OS(O)(=O)=O>CN(C)C=O.O>[NH2:16][N:11]1[CH:12]=[CH:13][C:9]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:10]1
Reactant: NOS(=O)(=O)O
Reactant: O=C(c1ccccc1)c1cc[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nn1ccc(C(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-benzoylpyrrole (4.92 g) in 50 ml of dry dimethylformamide was added milled potassium hydroxide (8.06 g). Hydroxylamine-O-sulfonic acid (4.23 g) was added to the suspension in 4 portions over a period of 1 hour with stirring at room temperature. After the addition was completed the reaction mixture was stirred for 30 minutes at room temperature, and subsequently diluted with 50 ml of water and extracted with DCM. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, DCM/ethyl acetate, 5:1), affording starting material (1.44 g) and the desired product as the second fraction. Recrystallization from ethyl ether/hexane gave the product as crystals (1.80 g), which was combined with material obtained from a 36.9 mmol scale reaction and recrystallized from DCM/hexane affording 3.20 g of crystals, m.p. 82°-83° C.
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]4[O:27][CH2:26]C[O:24][C:21]=4[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCN([C:41]2[C:50]3[C:45](=CC(F)=[C:48](F)[CH:49]=3)[N:44]=[CH:43][N:42]=2)CC1)=O)(C)(C)C.[N-]=C=O.[N-:56]=[C:57]=[S:58]>>[CH2:26]1[O:27][C:20]2[CH:19]=[C:18]3[C:23]([C:14]([N:11]4[CH2:10][CH2:9][N:56]([C:57](=[S:58])[NH:42][CH2:41][C:50]5[CH:45]=[N:44][CH:43]=[CH:48][CH:49]=5)[CH2:13][CH2:12]4)=[N:15][CH:16]=[N:17]3)=[CH:22][C:21]=2[O:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc4c(cc23)OCCO4)CC1
Reactant: [N-]=C=S
Agent: [N-]=C=O
Product: S=C(NCc1cccnc1)N1CCN(c2ncnc3cc4c(cc23)OCO4)CC1

Procedure:
In the following Examples 372-375, substantially the same procedure as in Example 329 was repeated, except that 4-(6,7-ethylenedioxy-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester obtained in Reference Example 14 was used in place of 4-(6,7-difluoro-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester, and the corresponding isocyanate (used in Example 372) or isothiocyanate was used in place of 4-phenoxyphenyl isocyanate, to give the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[CH2:11][N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:8]=2[CH:24]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27]>N1C=CC=CC=1.C(O)C.C(Cl)Cl>[CH2:14]([N:13]1[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[N:26][OH:27])[CH3:2])=[CH:24][C:8]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:10][CH2:11][C:12]1=[O:16])[CH3:15]
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCO
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=NO)ccc21
Reaction time: 4 h

Procedure:
A solution of 13.0 g (40.1 mmol) of 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 13.0 g of hydroxylamine hydrochloride in 65 ml of pyridine and 65 ml of ethanol is left to stand at room temperature for 4 hours. The mixture is taken up in methylene chloride, washed with 2 N hydrochloric acid and water, dried and evaporated. Traces of pyridine are removed by azeotropic evaporation with toluene. The residue gives, from methylene chloride/hexane, 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-2H-1,4-benzodiazepin-2-one of melting point 236°-238°.
Reaction SMILES: Cl.CO.[CH2:4]([C@:8]12[CH2:16][CH2:15][C@@H:14]3[C:17]4[CH2:18][CH:19]=[C:20]([O:25]C)[CH2:21][C:22]=4[CH2:23][CH2:24][C@H:13]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[OH:27])[CH:5]([CH3:7])[CH3:6]>O>[CH2:4]([C@:8]12[CH2:16][CH2:15][C@@H:14]3[C@@H:17]4[C:22]([CH2:23][CH2:24][C@H:13]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[OH:27])=[CH:21][C:20](=[O:25])[CH2:19][CH2:18]4)[CH:5]([CH3:7])[CH3:6]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
Add to a mixture of concentrated hydrochloric acid (4.8 cc.), water (3.2 cc.) and methanol (.72 cc. ) 13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17β-ol (2.0 g.). Heat the resulting solution on a steam bath for 30 minutes with stirring. Cool to room temperature, dilute the solution with water (160 cc.) and extract with ether. Wash the ethereal solution with water, sodium bicarbonate, and water, dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure to give a gum. Recrystallize from ethyl acetate to obtain the title compound (0.8 g., 43%, m.p. 124.0°-125.5°; ultraviolet absorption peak at 240 mμ (ε18,200).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>C(O)(=O)C.CO>[CH3:20][C:21]1[N:11]([C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Reactant: CCOC(C)(OCC)OCC
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (131 mg, 0.469 mmol) in acetic acid (1.3 mL) was added triethyl orthoacetate (275 μL, 1.50 mmol). The mixture was stirred at 120° C. for 30 min. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (60 mg, 42%). LCMS calculated for C15H18N3O2S (M+H)+: m/z=304.1. Found: 304.1.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[C:10]1(C)[C:11](S(O)(=O)=O)=CC=C[CH:15]=1>COC(OC)(C)C.C1C=CC=CC=1>[OH:2][C:1]1[C:3]2[O:4][C:10]([CH3:11])([CH3:15])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc(O)c1O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: COC(C)(C)OC
Product: CC1(C)Oc2cccc(O)c2O1

Procedure:
A solution of pyrogallol (63 parts) in 2,2-dimethoxypropane (100 parts) and benzene (100 parts) containing toluenesulphonic acid (0.01 parts) was slowly distilled through a fractionating column during 4 hours, removing liquid (150 parts), boiling point 57°-64° C. A few drops of triethylamine were then added and the mixture thoroughly washed with water, dried and evaporated. Distillation gave 4-hydroxy-2,2-dimethyl-1,3-benzodioxole (36 parts), boiling point 110° C/0.7 mm., which was purified by recrystallisation from carbon tetrachloride. Melting point 88°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([C:13]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc2ccccc2cc1C(=O)O
Reactant: Nc1nnn[nH]1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1cc2ccccc2cc1C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 8.2 g. of 3-methoxy-2-naphthoic acid, 5.2 g. of aminotetrazole, and 80 ml. of pyridine was added dropwise 6.4 ml. of thionyl chloride, maintaining the temperature below 70° C. After stirring for one hour, the mixture was cooled to 25° C. and evaporated to dryness. The residue was washed with dilute hydrochloric acid, then recrystallized from N,N-dimethylformamide, then dissolved in base, filtered, reprecipitated with dilute acid, filtered, washed with methanol, then recrystallized again from N,N-dimethylformamide to provide 3-methoxy-N-(tetrazol-5-yl)naphthalene-2-carboxamide (a type IV compound), m.p. 280°-283° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.ClC1C=C(C2[NH:31][C:32](=[S:42])NC=2C2C=CC(F)=CC=2)C=CN=1>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[NH:31][C:32](=[S:42])[NH:2][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)Oc1cc(C(N)C(=O)c2ccc(F)cc2)ccn1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1
Agent: Cl
Product: CC(C)Oc1cc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)ccn1

Procedure:
24c was prepared from 23c (2.5 g; 7.6 mmol) using the method described in the synthesis of 24a.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:5][OH:6])=[N:39][CH2:38][C:37]([F:41])([F:40])[F:36]
Reactant: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: NCC(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: ONC(=NCC(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 75 °C
Yield: 40 %

Procedure:
To a solution of 2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (i.e. the product of Step 3, 250 mg) in DMF (5 mL) was added N-chloro succinimide (81 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo to ¼ the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2,2,2-trifluoro ethylamine (57 mg) and triethylamine (0.15 mL, 0.11 g) in THF (10 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (122 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][CH2:38][C:39]2(O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:34]([F:46])=[CH:33][N:32]=1.CC([O-])=[O:49].[K+]>CC(N(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][CH2:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]4[OH:49])[C:34]([F:46])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: OC1(CNc2nc(Cl)ncc2F)CCCCC1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CCCCC4O)n3)c3cc(Cl)cnc32)cc1
Temperature: 140 °C

Procedure:
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.15 g, 0.35 mmol), 1-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol, 14a, (0.09 g, 0.35 mmol) and aqueous KOAc solution (1.04 mL of 1M solution, 1.04 mmol) in dimethylacetamide was added palladium triphenylphosphine (0.04 g, 0.03 mmol). The reaction mixture was heated at 140° C. in microwave for 15 min and then cooled to room temperature. The reaction mixture was filtered through celite, concentrated in vacuo, and the resulting crude residue was purified by by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 14b:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:4]2[C:5]([N:7]([C:10]3[C:15]4[O:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:8](=[O:9])[C:3]=12)=[O:6].[OH-:25].[Na+].Cl>CO>[C:5]([C:4]1[C:3]([C:8]([NH:7][C:10]2[C:15]3[O:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:2]([Cl:1])[CH:23]=[CH:22][C:21]=1[Cl:24])([OH:25])=[O:6]
Reactant: Cc1oc2c(N3C(=O)c4c(Cl)ccc(Cl)c4C3=O)cccc2c1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1oc2c(NC(=O)c3c(Cl)ccc(Cl)c3C(=O)O)cccc2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo[b]furan (100 mg) in a mixture of aqueous 1N-sodium hydroxide (2 ml) and methanol (3 ml) was stirred at ambient temperature overnight. The reaction mixture was acidified with 1N-hydrochloric acid. The separated solid was collected, washed with water and dried to give 7-(6-carboxy-2,5-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (60 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:20]([NH2:22])=[O:21])[N:16]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:20]([NH2:22])=[O:21])[N:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: NC(=O)n1ccc(-c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)n1ccc(-c2ccc(Oc3ccc(N)cc3)cc2)n1
Yield: 62.9 %

Procedure:
A solution of 3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole-1-carboxamide (100 mg, 0.308 mmol) in ethanol was flushed with nitrogen for 5 min, then palladium (10% on carbon, 20 mg) was added. The mixture was shaken under 40 psi of hydrogen for 16 hours. The mixture was then filtered through a bed of Celite and the solvent was removed in vacuo. The crude product was purified by column chromatography to give 57 mg (60%) of the title compound as a solid, mp 158-160° C. 1H NMR (CDCl3): δ8.22 (d, J=3.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.10 (bs, 1H), 6.90 (d, J=9.0 Hz, 2H), 6.70 (d, J=9.0 Hz, 2H), 6.66 (d, J=3.0 Hz, 1H), 5.25 (bs, 1H), 3.61 (bs, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:17]([Cl:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3,4-dichlorobenzaldehyde in analogy to Example 18. 1H NMR (400 MHz, CDCl3): 8.82-8.81 (m, 2H), 7.98-7.96 (m, 2H), 7.65-7.57 (m, 3H), 7.16-7.13 (m, 1H), 3.88-3.81 (m, 4H), 3.50 (s, 2H), 2.60-2.53 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 65.8 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 64, 775 mg, 1.57 mmol), iron (525 mg, 9.40 mmol) and NH4Cl (62.8 mg, 1.17 mmol) was heated at reflux in ethanol (21 mL) and water (7 mL) for 2 h. The mixture was then cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and then dissolved into CH2Cl2. This solution was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 2-6% 7N methanolic ammonia in CH2Cl2 gave the title compound (480 mg, 66%) as a brown gum; 1H NMR: 2.26 (3H, s), 2.52 (4H+DMSO, m), 2.89 (4H, t), 3.68 (3H, s), 4.35 (2H, d), 6.73 (1H, s), 6.99 (1H, d), 7.13 (1H, td), 7.28-7.39 (1H, m), 8.38 (1H, d), 8.39-8.46 (2H, m), 8.82 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 465.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12]O.S(=O)(=O)(O)O>O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
A mixture of 100 g of 3,4-dihydroxy benzoic acid, 600 ml methyl alcohol and 10 ml of concentrated sulfuric acid is heated at reflux for 18 hours. The reaction mixture is cooled to room temperature, poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium bicarbonate and sodium chloride, dried and concentrated in vacuo to give 50.6 g of the desired product.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]2[CH2:20][O:19]2)[CH:11]=1)(=O)C1C=CC=CC=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[N:23]=1.C1C=CC(=O)C(O)=C(C2C=NC=NC=2)C=1>CC(O)C.CS(C)=O>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:30][CH2:31][CH:32]([NH:35][CH2:20][CH:18]([OH:19])[CH2:17][O:16][C:12]3[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=3)[CH2:33][CH2:34]2)[N:23]=1
Reactant: O=C(Oc1cccc(OCC2CO2)c1)c1ccccc1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Agent: O=c1ccccc(-c2cncnc2)c1O
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3cccc(O)c3)CC2)n1
Yield: 14 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 24 h), using 200 μmol 3-(oxiran-2-ylmethoxy)phenyl benzoate and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give O-benzoylated intermediate, which was directly treated according to SP10. Title product was obtained by purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 14% yield (LCMS: detected [M+1]=373.2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](OC)[CH:14]=3)[O:11][C:10](=[O:21])[NH:9]2)C=N[CH:7]=1.[Br:22][C:23]1[N:28]=C(C=O)C=CC=1.[F:31]C1C=CC(CP(=O)(OCC)OCC)=CC=1>>[Br:22][C:23]1[N:28]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([F:31])=[CH:17][CH:18]=3)[O:11][C:10](=[O:21])[NH:9]2)[CH:3]=[CH:2][CH:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cncc(Br)c2)c1
Reactant: CCOP(=O)(Cc1ccc(F)cc1)OCC
Product: O=C1N[C@H](c2cccc(Br)n2)[C@@H](c2ccc(F)cc2)O1

Procedure:
Prepared according to the same procedure as optically-enriched (4R,5R)-4-(5-bromopyridin-3-yl)-5-(3-methoxyphenyl)oxazolidin-2-one, starting with 6-bromopicolinaldehyde and diethyl 4-fluorobenzylphosphonate. 1H-NMR (CDCl3, 500 MHz) δ 7.65 (dd, J=7.9, 7.6, 1H), 7.51 (d, J=7.6, 1H), 7.46 (dd, J=8.9, 5.2, 2H), 7.41 (d, J=7.6, 1H), 7.13 (m, 3H), 5.61 (d, J=7.5, 1H), 4.90 (d, J=5.8, 1H). 13C-NMR (CDCl3, 126 MHz) δ 163.1 (d, J=249), 159.4 (d, J=55), 142.6, 139.8, 134.0, 128.3, 127.8, 127.7, 119.6, 116.2, 116.0, 83.1, 64.4.
Reaction SMILES: C(OCC)(=O)C.[NH2:7][C:8]1[C:9]([I:22])=[C:10]([C:14]([I:21])=[C:15]([C:18]([NH2:20])=[O:19])[C:16]=1[I:17])[C:11](O)=[O:12].S(Cl)([Cl:25])=O>CN(C)C(=O)N(C)C.O>[NH2:7][C:8]1[C:9]([I:22])=[C:10]([C:14]([I:21])=[C:15]([C:18]([NH2:20])=[O:19])[C:16]=1[I:17])[C:11]([Cl:25])=[O:12]
Reactant: NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=S(Cl)Cl
Solvent: CN(C)C(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Temperature: 74 °C
Yield: 79.8 %

Procedure:
A 4000 L glass-lined reactor was charged with ethyl acetate (2250 kg), 3-amino-5-(aminocarbonyl)-2,4,6-triiodobenzoic acid (1125 kg) and tetramethylurea (4.75 kg). The reaction mixture was stirred and heated to 74° C. Thionyl chloride (528 kg) was charged over 1 hour. The reaction mixture was maintained at 74° C. for 12 hours. While cooling to 45° C., additional ethyl acetate (180 kg) was charged. Water (73 kg) was charged over 1 hour and the reaction mixture was cooled to 28° C. After stirring for 7 hours, the solid product was isolated by filtration and the solids were washed with ethyl acetate (250 kg). After drying at 40° C. under vacuum, 927 kg of 3-amino-5-(aminocarbonyl)-2,4,6-triiodobenzoyl chloride were isolated which had a chromatographic purity of 92.4 area %.
Reaction SMILES: [CH3:1][NH2:2].[C:3](O)(=O)[CH3:4].[CH2:7]1[CH2:11]O[CH2:9][CH2:8]1>>[CH2:9]([N:2]1[CH2:4][CH2:3][CH:3]([CH3:4])[CH:9]([NH:2][CH3:1])[CH2:1]1)[C:8]1[CH:11]=[CH:7][CH:8]=[CH:11][CH:7]=1
Reactant: CN
Reactant: C1CCOC1
Reactant: CC(=O)O
Product: CNC1CN(Cc2ccccc2)CCC1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.75 %

Procedure:
To a stirred solution of the product from Method E (3.81 grams/0.019 mol) and 38 mL of 2.0 M methylamine in THF was added 2.2 mL of acetic acid and the resulting mixture stirred at room temperature for 1.5 hours. Triacetoxysodiumborohydride (NaB(OAc)3H) (7.94 grams/0.038 mol) was added as a solid and the new mixture stirred at room temperature for 18 hours. The reaction was quenched with 2 N hydrochloric acid and the pH adjusted to 1. The reaction mixture was washed two times with ether, the aqueous layer then adjusted to pH of 12 with 6 N sodium hydroxide (aq) and extracted three times with dichloromethane The combined dichloromethane layers were dried over Na2SO4, filtered and evaporated to dryness in vacuo affording 3.51 grams (87.75%) of the title compound as dark yellow oil. LRMS: 219.1 (M+1).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].[C-:13]#[N:14].[Na+]>CS(C)=O>[C:13]([CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])#[N:14]
Reactant: [C-]#N
Reactant: CCCCOC(=O)C[C@H](O)CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC(=O)C[C@H](O)CC#N
Temperature: 65 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
The resulting compound was cyanogenated in the same manner as in Example 1-(2). That is, 58.5 g (0.3 mol) of n-butyl (S)-(-)-4-chloro-3-hydroxybutyrate was dissolved in 180 ml of dimethyl sulfoxide, and 67.5 ml of an aqueous solution containing 16.7 g (0.34 mol) of sodium cyanide was added thereto, followed by stirring at 65° C. for 2 hours. The reaction mixture was worked up in the same manner as in Example 1-(2) to obtain n-butyl (R)-(-)-4-cyano-3-hydroxybutyrate in a percent yield of 58%.