Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:33]4[C:32]([C:29]([OH:31])=[O:30])=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1B(O)O
Reactant: O=C1N(c2ccccc2)C(c2cccc(Br)c2)CN1S(=O)(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1cccc(C2CN(S(=O)(=O)c3ccccc3)C(=O)N2c2ccccc2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 5, step 2) was reacted with 2-carboxyphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 3′-(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl)-biphenyl-2-carboxylic acid as an off-white solid. MS: 497.1 ([M−H]−)
Reaction SMILES: N.[Na].[CH3:3][O:4][C:5]1[C:6]2[CH:19]=[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][C:7]=2[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[CH3:25]I.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1.O.CCOCC>[CH3:3][O:4][C:5]1[C:6]2[CH:19]=[C:18]([CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][C:7]=2[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1
Reactant: CI
Reactant: COC(=O)Cc1ccc2c(c1)C(OC)=Cc1ccccc1C2
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C)c1ccc2c(c1)C(OC)=Cc1ccccc1C2
Reaction time: 0.5 h

Procedure:
Small pieces of ferric nitrate nonahydrate were added to 75 ml of liquid ammonia, and subsequently 0.733 g of metallic sodium was added little by little. The mixture was stirred for 30 minutes. To the stirred mixture was added dropwise over the course of 10 minutes a solution of 6.25 g of methyl 11-methoxy-5H-dibenzo[a,d]cyclohepten-2-acetate obtained in Example 12 in 12 ml of dry toluene. The mixture was stirred for 25 minutes, and a solution of 1.98 ml of methyl iodide in 2 ml of dry toluene was added dropwise over the course of 2 minutes. The mixture was further stirred for 1 hour, and then 1.83 g of ammonium chloride and 12 ml of toluene were added. Ammonia was released at room temperature. Then, 24 ml of 10% hydrochloric acid was added under ice cooling and stirring, and the mixture was stirred for 15 minutes. Ether (100 ml) and 100 ml of water were added to extract the solution. The organic layer was successively washed with water, a 10% aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was chromatographed on a silica gel column using benzene as an eluent. From the eluate, 5.91 g of methyl 2-(11-methoxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionate was obtained as a colorless oily substance.
Reaction SMILES: [CH2:1]([C:3]1([CH3:12])[NH:7][C:6](=S)[C:5]([CH2:10][CH3:11])([CH3:9])[NH:4]1)[CH3:2].[OH-].[Na+].OO.[OH:17]S([O-])=O.[Na+]>O>[CH2:1]([C:3]1([CH3:12])[NH:7][C:6](=[O:17])[C:5]([CH2:10][CH3:11])([CH3:9])[NH:4]1)[CH3:2]
Reactant: CCC1(C)NC(=S)C(C)(CC)N1
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(C)NC(=O)C(C)(CC)N1
Temperature: 1 °C
Reaction time: 2 h

Procedure:
A 5 liter 4-necked round-bottomed flask equipped with a mechanical stirrer and thermocouple thermometer was charged with 250 ml water and 43.3 g (0.232 mol) of 2,5-diethyl-2,5-dimethylimidazolidin-4-thione. In order to make the thione dissolve, 1.8 g NaOH was added. The solution was cooled to 0-2° C. with a dry ice-acetone bath. The flask was fitted with two additional funels. Simultaneously, a solution of 16.7 g NaOH in 100 ml water (total of 18.5 g or 0.464 mol of NaOH used) was added through one of the funnels and 105 ml (0.928 mol) of 30% H2O2 was added through the other funnel. The reaction mixture was stirred rapidly and required extensive cooling during the addition. The 5 liter flask was used to provide a large surface area for efficient cooling of the exothermic reaction. The heat of reaction was 269.2 Kcal/mol; 124. The addition was completed in 2 hours; the mixture was stirred an additional half hour. At the end of this time, TLC indicated that no thione remained. Then, 27.9 g of NaHSO3, (0.172 mol) was added to quench excess peroxide; this reaction is also somewhat exothermic (temperature increases from 26 to 43° C.). The reaction mixture was transferred to a 2 liter round-bottomed flask and the solvent removed with a rotary evaporator (aspirator pressure) to give a white residue. The residue was extracted with 850 ml of boiling ethanol. Then, 50 ml of toluene was added to the solution and 130 ml of water/ethanol/toluene azeotrope distilled to remove any remaining water. The solution was cooled and filtered to remove a small amount (˜1 g) of Na2SO4 and then the ethanol was removed on the rotary evaporator to give a syrup that crystallized on cooling to room temperature. The yield was 37.5 g (95%) mp 58-64° C. IR (nujol) 1705, 1659 cm-1. 1H NMR (CDCl3+D2O) ppm (combination of equal amounts of 2 sets of cis-trans pairs) 0.95-0.98 (m, 12H, CH3 on 4 ethyls), 1.27, 1.31, 1.34, 1.38 (4 s, total 12H, 4 CH3), 1.50-1.70 (m, 8H, CH2 on 4 ethyls). The singlets at 1.34 and 1.38 collapse to a singlet in D2O but now integrate 6H.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:24][NH2:25]>CC(O)=O>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[NH:24][NH:25][C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: NN
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(=O)[nH][nH]c(=O)c3cc2C1
Temperature: 125 °C

Procedure:
A mixture of 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.17 g, 0.5 mmol) and hydrazine hydrochloride (0.05 g, 0.7 mmol) in glacial HOAc (10 mL) was refluxed at 125° C. for 4 h. The reaction was cooled, concentrated, and converted to an HCl salt. The resulting solid was recrystallized from EtOAc/MeOH to give a white solid. This white solid was further purified via reverse phase chromatography eluting with H2O/MeOH (95:5). The resulting product was converted to an HCl salt and recrystallized from hot MeOH to give 134 as a white solid (m.p.>300° C.).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6](=[O:11])([O:8][CH2:9][CH3:10])[NH2:7]>COC1C=CC(O)=CC=1.ClC=C(Cl)Cl>[CH3:4][CH:3]([NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[CH2:2][CH:1]([NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11]
Reactant: C/C=C/C=O
Reactant: CCOC(N)=O
Agent: COc1ccc(O)cc1
Solvent: ClC=C(Cl)Cl
Product: CCOC(=O)NC(C)CC(NC(=O)OCC)NC(=O)OCC
Reaction time: 0.5 h
Yield: 52 %

Procedure:
35 g of crotonaldehyde are added dropwise at 60°-83° C. to a mixture of 133.5 g of ethyl carbamate, 15 g of acid ion exchanger resin (Duolite C 265), 0.2 g of hydroquinone monomethyl ether and 200 ml of trichloroethylene in the course of 20 minutes, and the mixture is thereafter left at 80° C. for 30 minutes. The catalyst is filtered off, the solvent is distilled off and the residue is crystallized from ethyl acetate/petroleum ether. This gives 83 g (52% yield, based on starting crotonaldehyde) of 3-methyl-1,1,3-tri(ethoxycarbonylamino)propane having a melting point of 103°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=2[O:31][CH3:32])[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:36]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:41]=1>>[CH2:36]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:41]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2cc(Cl)cc(Cl)c2)c1OC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(3,5-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,5-dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.C(C1N=C(C2C=C(OC3CC4C(C(=O)N(C)CCCCC=CC5C(C(NS(C6CC6)(=O)=O)=O)(NC4=O)C5)C3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:53][S:50]([CH:47]6[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NCCCCCC=CC5CC5(C(=O)O)NC(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NCCCCCC=CC5CC5(C(=O)NS(=O)(=O)C5CC5)NC(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 18-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-3,14-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (80) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]° C.tadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (47): m/z=750 (M+H)+. 1H NMR (CDCl3): 0.90-0.96 (m, 1H), 1.1-1.2 (m, 4H), 1.39 (d, J=6.9 Hz, 6H), 1.4-1.55 (m, 5H), 1.80-1.92 (m, 5H), 2.15-2.25 (m, 1H), 2.30-2.40 (m, 1H), 2.45-2.55 (m, 2H), 2.68 (s, 3H), 2.85-2.92 (m, 1H), 3.15-3.30 (m, 2H), 3.45-3.55 (m, 2H), 3.96 (s, 3H), 4.09 (dd, J=11.5 Hz, J=3.8 Hz, 1H), 4.61 (t, J=7.9 Hz, 1H), 4.99 (t, J=9.0 Hz, 1H), 5.51-5.53 (m, 1H), 5.71 (dd, J=18.6 Hz, J=8.2 Hz, 1H), 6.86 (s, 1H), 7.03 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.50 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 9.40 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: O=C(O)c1c(CC(=O)N2CCCCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with piperidine at 22° C. to give the title compound as a white solid. MS: 445.4 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][CH:35]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:13][C:14]([OH:16])=[O:15])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40](=[NH:41])[NH2:42])=[CH:38][CH:39]=1)[CH3:2]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2CC)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(COc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-ethyl-2-[(4-amidinophenyl)-oxymethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:19]2)=[CH:14][CH:13]=1.[C:35](O)([C:37]([F:40])([F:39])[F:38])=[O:36].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[F:38][C:37]([F:40])([F:39])[C:35]([N:25]1[CH2:26][CH2:27][N:22]([CH:18]2[CH2:19][C:20]3[CH:21]=[C:12]([N:3]4[C:4](=[O:11])[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[C:2]4=[O:1])[CH:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)[CH2:23][CH2:24]1)=[O:36]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3ccc(N4C(=O)c5ccccc5C4=O)cc3C2)CC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1c1ccc2c(c1)CC(N1CCN(C(=O)C(F)(F)F)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with tert-butyl 4-[7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate (300 mg, 0.65 mmol) and a stir bar was added TFA (2 mL). The mixture was allowed to stir at RT for 1 hour. LC showed complete removal of the Boc group. TFA was removed under reduced pressure, and the residue was dissolved in DCM (5 mL). To the solution was added pyridine and trifluoroacetic anhydride (0.27 mL, 2.0 mmol). LC showed formation of the desired product within 30 minutes. The product was purified by MPLC.
Reaction SMILES: C(OC([NH:8][S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH:28]=[C:27]([CH3:41])[N:26]=3)[CH:22]=[CH:21][CH:20]=2)[CH:14]=1)(=[O:11])=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:41][C:27]1[N:26]=[C:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:15]3[CH:14]=[C:13]([NH:12][S:9]([NH2:8])(=[O:10])=[O:11])[CH:18]=[CH:17][CH:16]=3)[N:24]=2)[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=2)[CH:28]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(NS(N)(=O)=O)c3)n2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 108.6 %

Procedure:
To N-(tert-butoxycarbonyl)-N′-{3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-phenyl}-sulfamide (example 334) (0.100 g, 0.171 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.090 g, 98%). MS (ISP) 485.4 [(M+H)+].
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([Si:10]([CH3:23])([CH3:22])[O:11][CH:12]1[CH2:15][CH:14]([N:16]2[CH:20]=[C:19](I)[CH:18]=[N:17]2)[CH2:13]1)([CH3:9])([CH3:8])[CH3:7].CO[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1>C1COCC1>[Si:10]([O:11][CH:12]1[CH2:15][CH:14]([N:16]2[CH:20]=[C:19]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)[CH:18]=[N:17]2)[CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:23])[CH3:22]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(n2cc(I)cn2)C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C3CC(O[Si](C)(C)C(C)(C)C)C3)c2)OC1(C)C
Temperature: 0 °C

Procedure:
Over the course of 5 minutes, a 2.00 M solution of isopropylmagnesium chloride in THF (0.13084 mL, 0.26168 mmol) was added dropwise to an ice cooled solution of 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-4-iodo-1H-pyrazole (Compound 100B, 30.00 mg, 0.07930 mmol) in THF (0.33 mL). The reaction mixture was stirred at 0° C. for another hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.057933 mL, 0.33939 mmol) was added at 0° C. and then the mixture was stirred at rt for another hour. The reaction mixture was cooled back down to 0° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to dryness, giving the title compound as a colorless oil. Compound was taken on for the next step without further purification. MS (ES+): m/z 379.04 (100) [MH+]; HPLC: tR=3.85 min (ZQ3, polar—5 min).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH:18]([N+:36]([O-])=O)[CH2:19][CH2:20][C:21]2([O:35][CH2:34][CH2:33][O:32]2)[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:36][CH:18]([CH2:19][CH2:20][C:21]1([O:32][CH2:33][CH2:34][O:35]1)[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:17][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=1
Reactant: COc1ccc(CCC2(CCC(Cc3ccc(OC)c(OC)c3)[N+](=O)[O-])OCCO2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CCC2(CCC(N)Cc3ccc(OC)c(OC)c3)OCCO2)cc1

Procedure:
To a suspension of 6.6 g. (0.174 mole) of LiAlH4 in 200 ml. of dry tetrahydrofuran was added dropwise a solution of 25 g. (0.058 mole) of 1-(3,4-dimethoxyphenyl)-5,5-ethylenedioxy-7-(4-methoxyphenyl)-2-nitroheptane in 100 ml. of dry THF at room temperature at such a rate as to control reflux of reaction solution. After addition of substrate was completed, the reaction mixture was refluxed under N2 for 2 hours, and cooled to ice bath temperature. The excess LiAlH4 was decomposed with saturated Na2SO4 solution. The inorganic salt was filtered off and thoroughly washed with ethyl acetate and chloroform. The filtrate was concentrated in vacuo to give 28 g. of brown, oily product. Without further purification, the amino ketal derivative was used for the next reaction.
Reaction SMILES: [CH:1]1([C:4]2[N:8](CC3C=CC=CC=3F)[N:7]=[C:6]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][CH3:31])=[CH:19][N:18]=3)[C:5]=2[CH3:32])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C1COCC1>CS(C)=O.CC(O)(C)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][CH3:31])=[CH:19][N:18]=3)[C:5]=2[CH3:32])[CH2:3][CH2:2]1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c(C3CC3)c2C)nc1Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
410 mg of 2-[5-cyclopropyl-1-(2-fluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 2-1-10 (0.952 mmol, 1.0 eq.) were dissolved in 1.1 mL of dry dimethyl sulfoxide and 1.4 mL of dry 2-methylpropan-2-ol. 6.56 mL of 1M potassium 2-methylpropan-2-olate in THF (6.56 mmol, 6.9 eq.) were added. The mixture was flushed three times with oxygen and stirred for 5 hours at rt. Then the reaction mixture was partitioned between aqueous saturated ammonium chloride solution and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography provided 200 mg (0.62 mmol, 65.1%) of analytically pure target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH2:9])[CH3:8].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[O:24]=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[N:26]1[CH2:35][CH2:36][CH2:37][CH:38]=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:9][CH2:38][CH2:37][CH2:36][CH2:35][N:26]1[C:27](=[O:34])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]1=[O:24])[CH3:8]
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: C[C@@H](N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1

Procedure:
Using General Procedure B, reaction of (R)-1-pyridin-2-yl-ethylamine (Shin, C-G et al, Bull. Chem. Soc. Jpn. 2002, 75, 1583-1596) in CH2Cl2 and 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde with NaBH(OAc)3 gave 2-[4-(1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione as a yellow oil. 1H NMR (CDCl3) δ 1.37 (d, 3H, J=6.0 Hz), 1.51-1.54 (m, 1H), 1.66-1.71 (m, 2H), 2.02-2.03 (m, 2H), 2.41-2.45 (m, 1H), 2.52-2.57 (m, 1H), 3.66 (t, 2H, J=7.5 Hz), 3.81-3.88 (m, 1H), 7.12-7.14 (m, 1H), 7.28-7.30 (m, 1H), 7.63-7.64 (m, 1H), 7.68-7.71 (m, 2H), 7.81-7.84 (m, 2H), 8.53-8.54 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:32]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared as described in Example 384, substituting 2-(3,4-difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 347) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 248 mg, 42%). mp 149-151° C. 1H NMR (300 MHz, DMSO-d6) δ 0.8 (d, J=6 Hz, 6H), 1.48 (m, 2H), 1.54 (m, 1H), 4.4 (t, 2H), 7.51 (m, 3H), 7.6 (m, 1H), 7.85 (m, 3H), 7.95 (d, J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 450 (M+H)+, 467 (M+NH4)+. Anal. calc. for C21H21F2N3O4S: C, 56.12; H, 4.71; N, 9.35. Found, C, 56.12; H, 4.67; N, 9.15.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][CH:8]([CH2:11][CH3:12])[CH:9]=O>>[CH:1](=[O:6])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:12][CH2:11][CH:8]([CH3:9])[CH3:7]
Reactant: CCCCC=O
Reactant: CCC(C)C=O
Product: CC(C)CCCCC=CC=O

Procedure:
This example describes the process of the invention for the co-aldol condensation of n-pentanal and 2-methylbutanal (2-MBA) to give an isodecenal consisting of the isomers 2-propyl-4-methylhexenal (1+2) and -propylheptenal (1+1) using the cosolvent diethylene glycol (DEG). 400 kg/h of catalyst were passed through the reactor (as described in Example 3) at a tempera ture of 110° at the autogenous pressure of the reactants.