Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[OH:29]O>C(Cl)Cl.CO>[CH3:1][N@@+:2]1([O-:29])[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Reactant: OO
Solvent: CO
Solvent: ClCCl
Product: C[N@@+]1([O-])C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 50 °C

Procedure:
A solution of the product from Example 1G (5 g, 13.44 mmol) in DCM (80 mL) and MeOH (40 mL) was treated with hydrogen peroxide (5.2 mL, 30% in H2O, 53.8 mmol). The mixture was heated to 50° C. for 48 hours. The mixture was concentrated under reduced pressure to a smaller volume while still in a solution. The solution was loaded onto an ANALOGIX SuperFlash silica gel column (ANALOGIX is a registered trademark of Analogix Inc. of Burlington, Wis.) and eluted with NH4OH/MeOH/DCM (1/10/90) to obtain the faster moving component (comparing with Example 1I) as the title product. 1H NMR (300 MHz, DMSO) δ ppm 8.06 (m, 1H), 7.69 (d, J=9 Hz, 2 H), 7.57 (d, J=9 Hz, 4 H), 7.50 (d, J=6 Hz, 1 H), 7.08 (dd, dd, J=9, 4.0 Hz, 1 H), 6.70 (d, J=9 Hz, 2 H), 4.72 (d, J=6 Hz, 1 H), 3.75-3.82 (m, 1 H), 3.52-3.59 (m, 2 H), 3.36-3.45 (m, 3 H), 3.15-3.21 (m, 1 H), 3.14 (s, 3 H), 2.05-2.12 (m, 1 H), 1.80-1.86 (m, 1 H); MS (DCI,) M+=388.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)[C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:3][CH:2]([CH3:4])[C:1](=[O:5])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)C(=O)CC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
3 g of molecular sieve (4 Å) were activated in a microwave oven at 100 W for 5 min. The molecular sieve obtained in this manner was then initially charged, and 200 ml of anhydrous toluene were added. 4.9 g (30.97 mmol) of ethyl isobutyrylacetate and 4.02 g (37.2 mmol) of benzyl alcohol were then added. The reaction mixture was heated at reflux temperature for 6 h. After cooling, the molecular sieve was filtered off and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). This gave 4.70 g (65% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].C1CCCCC1.[OH2:65].C(OCC)(=[O:68])C>C(O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:68].[OH2:65].[OH2:6]
Reactant: CCOC(C)=O
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Solvent: CCO
Solvent: C1CCCCC1
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 7.5 °C
Reaction time: 0.46 h
Yield: 70 %

Procedure:
Crude docetaxel (1.0 g,) was dissolved in a solution of ethanol:cyclohexane:demineralised water:ethyl acetate (20:2:10:0.8) at 25-30° C. under constant stirring. The clear biphasic reaction was then concentrated to 20 ml and cooled to 5-10° C. The precipitated solid was stirred for 25-30 min. at 5-10° C., then filtered, washed with DM water (1 ml) and dried under vacuum under humid atmosphere (until the moisture content was between 5-7% by Karl Fischer method) to afford Docetaxel trihydrate in 70-90% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:42])[C:37]([OH:41])=[C:38]([OH:40])[CH:39]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[C:36]([OH:42])[C:37]([OH:41])=[C:38]([OH:40])[CH:39]=3)[N:24]=2)[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1cc(O)c(O)c(O)c1
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3cc(O)c(O)c(O)c3)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 4 was coupled with 5-(2-Amino-ethyl)-benzene-1,2,3-triol following procedure F. LC-MS showed the product had the expected M+H+ of 588. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 2H) 8.0 (m, 1H) 7.6 (m, 2H) 7.3 (m, 3H) 4.8 (m, 1H) 4.5 (s, 2H) 3.9 (m, 2H) 3.3 (m, 2H) 3.0 (m, 2H) 2.9 (m, 5H) 1.6 (m, 2H) 1.4 (s, 9H).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5](/[Mg]Br)=[CH:6]\[CH3:7].[Si:10]([O:17][CH2:18][C@@H:19]([N:25]([CH2:33][C:34](N(OC)C)=[O:35])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:20]([CH:22]1[CH2:24][CH2:23]1)=[CH2:21])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1>[Si:10]([O:17][CH2:18][C@@H:19]([N:25]([CH2:33][C:34](=[O:35])[CH:5]=[CH:6][CH3:7])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:20]([CH:22]1[CH2:23][CH2:24]1)=[CH2:21])([C:13]([CH3:15])([CH3:14])[CH3:16])([CH3:12])[CH3:11]
Reactant: C/C=C/[Mg]Br
Reactant: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C=CC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A suspension of cerium (III) chloride (27.8 g, 112.95 mmol) in THF (100 mL) at room temperature was stirred vigorously for 2 hours. The suspension was cooled to −78° C. and (E)-prop-1-enylmagnesium bromide (0.5 M in THF) (226 mL, 112.95 mmol) was added dropwise. The mixture was stirred at −78° C. for 1.5 hours. (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 235, 5 g, 11.30 mmol) in THF (20 mL) was then added dropwise at −78° C. The reaction was stirred at −78° C. for 30 minutes and then warmed to 0° C. for 15 minutes. The reaction was quenched with 10% citric acid, diluted further with water and extracted twice with ether. The organics were washed once with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound as a light yellow oil (4.0 g, 84%).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH3:13])[C:11]=1[NH2:12].[OH-].[Na+].O1CCOCC1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>O>[NH2:12][C:11]1[N:10]([CH3:13])[N:9]=[CH:8][C:7]=1[NH:6][C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]
Reactant: Cn1ncc(N)c1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)Oc2ccccc2)c1N
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 4,5-diamino-1-methylpyrazole sulfate (158 g) in water (1.1 L) was neutralized to pH 6.9 with 4N aqueous sodium hydroxide solution, and dioxane (474 ml) was added to this solution. To the resulting mixture was added dropwise phenyl chloroformate (124 g) maintaining pH of the mixture at 6.9 with 4N aqueous sodium hydroxide solution at a temperature below 10° C. The reaction mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give 5-amino-1-methyl-4-phenoxycarbonylaminopyrazole (155 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([NH2:12])[CH2:9][C:10]#[CH:11].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>O.C1COCC1>[CH2:8]([NH:12][S:22]([CH2:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1)(=[O:24])=[O:23])[CH2:9][C:10]#[CH:11]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: C#CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCCNS(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of potassium carbonate (40.2 g, 296 mmol) in water (50 mL) and THF (50 mL) at 15-20° C. was added but-3-ynylamine hydrogen chloride (10.4 g, 98.5 mmol). Then, (3,4-dichlorophenyl)methanesulfonyl chloride (5, 30.7 g, 118 mmol) was added in portions during of a period of 30 ml. The mixture was stirred for 4 h at rt. THF is evaporated. The mixture is extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na4SO4. The solvent is evaporated to give a white solid (20.5 g, 71%%). 1H NMR (CDCl3): δ7.53 (d, 1H, J=2.0 Hz), 7.47 (d, 1H, J=4.2 Hz), 7.27 (m, 1H), 4.52 (t, 1H, J=6.2 Hz), 4.22 (s, 2H), 3.17 (dd, 2H, J=6.2 Hz, 12.5 Hz), 2.41 (m, 2H), 2.07 (m, 1H)
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P(Cl)(Cl)(Cl)=O.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C1C=CC=CC=1.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][NH:2][C:3](=[N:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CNC(=O)C(C)(C)C
Reactant: Nc1ccccc1CN1CCOCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CNC(=Nc1ccccc1CN1CCOCC1)C(C)(C)C

Procedure:
A mixture of N-methylpivalamide (6.2 g) in benzene (50 ml), 4-(2-aminobenzyl)morpholine (9 g) in benzene (40 ml) and phosphorus oxychloride (5 ml) was heated at 80°-85° C. for 12 hours to yield a solid which was dissolved in methanol (25 ml) and treated with fumaric acid (1.4 g) to give N-methyl-N'-(2-morpholinomethylphenyl)pivalamidine monofumarate (m.p. 167°-168° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:25][C:19]2=[CH:20][N:21]=[C:22]([Cl:24])[CH:23]=[C:18]2[C:17]=1[OH:26])=O)C>>[Cl:24][C:22]1[CH:23]=[C:18]2[C:17](=[O:26])[CH2:16][O:25][C:19]2=[CH:20][N:21]=1
Reactant: CCOC(=O)c1oc2cnc(Cl)cc2c1O
Agent: O=C1COc2cnccc21
Product: O=C1COc2cnc(Cl)cc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 5-chloro-3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: C(O[C:6](=O)[N:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC(C)C)(C)(C)C.C(ON(C)C(=O)OC(C)(C)C)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:13]([O:12][NH:7][CH3:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CN(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNOCc1ccccc1

Procedure:
Using the general method of Compound 54 Part C, tert-butyl N-benzyloxy-N-methylcarbamate (3.0 g, 13 mmol) was reacted with trifluoroacetic acid (10 mL, 130 mmol) to provide 1.58 g of N-benzyloxy-N-methylamine as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.CC([O-])(C)C.[Na+].[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(Cl)(Cl)Cl>O1CCCC1>[Br:26][C:27]1[CH:28]=[N:29][C:30]([O:1][CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[N:31][CH:32]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ncc(Br)cn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
4-Hydroxymethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole (0.538 g, 2.0 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (10 ml) followed by the addition of NaOtBu (0.231 g, 2.4 mmol). After stirring for 15 min at r.t., 5-bromo-2-chloro-pyrimidine (0.426 g, 2.2 mmol) in THF (5 ml) is added slowly over a period of 10 min and stirred for further 30 min at r.t. Chloroform (25 ml) is added; the mixture is washed with 0.5N hydrochloric acid (HCl) and water, dried over MgSO4 and concentrated in vacuo. After flash column chromatography (100% chloroform) 5-bromo-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl-methoxy}-pyrimidine can be isolated as an off-white solid. Yield 0.60 g (71%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:15][CH:14]1[O:16][C:2]2[C:3]([CH3:17])=[N:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:11]=2[NH:12][CH2:13]1
Reactant: Cc1nc2ccccc2c(NCC(C)O)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2c2c1OC(C)CN2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 18.5 g of 3-bromo-N-(2-hydroxypropyl)-2-methyl-4-quinolinamine and 7.0 g of potassium tert-butoxide in 100 ml of DMF was stirred at 80°-90° C. for 1 hour. The mixture was cooled to room temperature, diluted with 300 ml of ice-water and stirred for 1 hour, whereupon a solid separated which was filtered and recrystallized twice from isopropanol and finally from isopropyl acetate. The yield was 8.7 g, mp 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH:26]2[CH2:31][CH2:30][N:29]([C:11]([N:10]3[CH2:9][C:8]4[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=4[O:6][C:5]4[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][C:4]3=4)=[O:12])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C1CCN(C2CCNCC2)CC1
Product: O=C(N1CCC(N2CCCCC2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 86.9 %

Procedure:
The title compound of Example 2 (0.6 g, 2.0 mmol) was combined with 1,4'-bipiperidine (0.38 g, 2.2 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 0.74 g of the title product was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]=O)[CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[N:22][C:21]=1[O:32]C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C2C(=CC=C(CC=O)C=2)C=C1C1C(=O)NN=C([C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)C=1)=O)(C)(C)C.N1CCOCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(=O)=O>ClC(Cl)C.ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH:61]3[CH2:60][CH2:59][CH2:64][CH2:63][NH:62]3)[CH:15]=2)[CH:10]=[C:9]1[C:20]1[C:21](=[O:32])[NH:22][N:23]=[C:24]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:25]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccncc3)n[nH]c2=O)cc2ccc(CC=O)cc21
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CC=O)cc2n1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccncc3)n[nH]c2=O)cc2ccc(CCC3CCCCN3)cc21

Procedure:
54 mg of a mixture of 6-(2-oxoethyl)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 6-(2-oxoethyl)-2-(3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-yl)indole-1-carboxylic acid tert-butyl ester are dissolved in 9 mL dichloroethane. 160 □L morpholine and then 0.46 mL acetic acid are added. 129 mg sodium triacetoxyborohydride are added in several portions over 4 hours. Sat. aq. NaHCO3-solution is added and the reaction mixture is stirred until the CO2-evolution stopped. The reaction mixture is diluted with dichloromethane, the aq. phase washed with dichloromethane, the combined org. phases dried (MgSO4) and concentrated in vacuo. 8 mg (13%) crude product (mixture of 6-(2-piperidylethyl)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 2-(3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-yl)-6-(2-piperidyl-ethyl)-indole-1-carboxylic acid tert-butyl ester is obtained, which is directly used in the next step.
Reaction SMILES: [CH2:1]([NH:6][C:7](=S)[NH:8][NH2:9])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[CH3:20][C:18]1[NH:9][N:8]=[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCCCCNC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: C1CCOC1
Product: CCCCCNc1n[nH]c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
A stirred solution of 25.8 g (0.16 mole) of 4-pentyl-3-thiosemicarbazide in 150 mL of tetrahydrofuran was treated with 26.4 g (0.16 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 2 hr, heated at reflux for 4 hr, and stirred for ~16 hr at ambient temperature. The reaction mixture contained amorphous material and large yellow crystals, which dissolved on heating at reflux for 1 hr. Upon cooling, large yellow crystals separated and were removed by filtration (sulfur). The filtrate was diluted with ice water, made acidic with 6N sulfuric acid and filtered to remove additional sulfur. The filtrate was adjusted to pH 6 with sodium carbonate and a total of 32.2 g of precipitated product was collected in 3 fractions. All the material was chromatographed twice on silica gel without purification, first by eluting with methylene chloride and the second time by eluting with benzene. A third column of 800 g of silica gel was eluted with isopropyl ether to give an orange oil which was not the product, then eluted with 50/50 isopropyl ether/methylene chloride. The product crystallized from the second eluent to give 7.8 g of white crystalline product after washing with isopropyl ether to remove a yellow color, mp 117°-119° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][C@@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[CH:12](O)=O.C(=O)([O-])O.[Na+].[OH-].[Na+]>C=O>[CH3:12][N:1]1[CH2:11][CH2:10][CH2:9][C@@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1
Reactant: O=CO
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)[C@@H]1CCCN(C)C1
Yield: 73 %

Procedure:
(R)-Ethyl nipecotate (5.7 g 365 mmol), (prepared by resolution of ethyl nipecotate by treatment with L(+)-tartaric acid as described in J. Org. Chem. 1991, (56), 1168), was dissolved in 38.5% aqueous formaldehyde solution (45 ml) and formic acid (90 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and added dropwise to cooled saturated aqueous sodium hydrogen carbonate solution. The mixture was adjusted to pH12 by addition of sodium hydroxide and the mixture was extracted with methylene chloride. The organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation to give (R)-ethyl 1-methylpiperidine-3-carboxylate (4.51 g, 73%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]2[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]2)[CH2:10][CH2:9]1
Reactant: CN1CC(CCCl)OC1=O
Reactant: Clc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCO
Product: CN1CC(CCN2CCN(c3ccccc3Cl)CC2)OC1=O
Yield: 75 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 5.5 g (0.028 mol) of 1-(2-chlorophenyl)piperazine (Aldrich), 4.6 g (0.028 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 8.9 g (0.08 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of 1-butanol gave 6.8 g (75%) of off-white solid, mp 79.5°-81.5° C. (2-propanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([Cl:26])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Cl)cc1OC
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
25.90 g (0.07 mol) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoic acid were mixed with 75 ml of toluene, 17.30 g (0.08 mol) of phosphorus pentachloride were added and the mixture was stirred at 40-45° C. for 2.5 h. Then the mixture was concentrated in vacuo to half of its volume and the product that precipitated was filtered off with suction and washed with a small amount of toluene. 25.30 g (93%) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl chloride having a melting point of 175-177° C. were obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:13])(=O)[CH2:8][CH2:9][CH:10]=[CH2:11].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.CN(C=O)C>[C:15]1([NH:14][C:7](=[O:13])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCC(=O)O
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a stirred solution of oxalyl chloride (2.0 M in CH2Cl2, 11.5 mL, 23.1 mmol) in CH2Cl2 (100 mL) and DMF (1 drop) at 0° C. was added 4-pentenoic acid (2.25 mL, 22.0 mmol). This was allowed to warm to ambient temperature. Upon cessation of gas evolution, the mixture was returned to 0° C. and a solution of aniline (2.00 mL, 22.0 mmol) and TEA (6.72 mL, 26.3 mmol) in CH2Cl2 (5 mL) was added dropwise. After warming to ambient temperature, the reaction was allowed to proceed for 3 h. The mixture was concentrated under reduced pressure, and then partitioned between HCl (1 N, 10 mL) and EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×15 mL) and the organic layers combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave a yellowish solid, which was recrystallized with toluene to obtain 42 as white crystals (1.97 g, 11.24 mmol, 51%). TLC Rf 0.68 (50% EtOAc/hexanes); 1H-NMR (300 MHz, CDCl3) δ 7.49 (d, 2H), 7.29 (t, 2H), 7.08 (t, 1H), 5.88 (m, 1H), 5.10 (dd, 2H), 4.42 (br s, 4H).