Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][CH2:19][O:18]1)=[O:16])[CH3:13]>C1COCC1>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][C:21]([OH:23])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:20][CH2:19][O:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CC(=O)CCO1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(O)(C#C[Si](C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
A cold (−78° C.), stirred solution of (trimethylsilyl)acetylene (1.80 g, 18.24 mmol) in anhydrous THF (30 mL) was treated with nBuLi (7.3 mL in hexane, 18.24 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.62 g, 15.2 mmol) in anhydrous THF (30 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water (30 mL). After removal of THF, the product was extracted with EtOAc (2×60 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 2.50 g (61%) of yellow oil: 1H NMR (CDCl3) δ 0.17 (s, 9H), 1.30 (t, 3H), 1.76-1.90 (m, 3H), 2.25 (m, 1H), 3.66 (tt, 1H), 4.11-4.21 (m, 2H), 4.24 (q, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[I:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: BrCc1cccc(I)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(I)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (680 mg, 3.5 mM), 3-iodobenzyl bromide (1.2 g, 4.7 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified trituration with methylene chloride-diethyl ether) to afford 0.70 g (55%) of the 9-[(3-iodophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSO-d6) δ7.7-7.6 (m, 3H), 7.2 (m, 2H), 7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1732, 1639, 1441, 1421, 1273, 1117, and 763. MS (ES) m/e 458, 460.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1cc2cc(O)ccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C=O)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of 2-chloro-6-hydroxyquinoline-3-carbaldehyde (2.35 g, 11.3 mmol) in N,N-dimethylformamide (15 mL) was added tert-butyl 2-bromoacetate (2.0 mL, 13.6 mmol) and potassium carbonate (3.13 g, 22.6 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction was diluted with water (100 mL) and allowed to stir for 1 hour. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (3.62 g, 99%) as an off-white solid. +ESI (M+H) 322.1; 1H NMR (400 MHz, CDCl3, δ): 10.54 (s, 1 H), 8.60 (s, 1 H), 7.99 (d, J=9.36 Hz, 1 H), 7.59 (dd, J=9.17, 2.93 Hz, 1 H), 7.11 (d, J=2.73 Hz, 1 H), 4.65 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[S:31]([NH2:41])(=[O:40])([C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)=[O:32].C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([S:31]([NH2:41])(=[O:32])=[O:40])=[CH:34][CH:35]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(S(N)(=O)=O)cc4)nc32)cc1
Temperature: 116 °C
Yield: 56.3 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.34 mmol), sulfanilamide (125 mg, 0.73 mmol) and trimethylsilyl chloride (TMSCl) (0.100 mL, 0.79 mmol) inn-butyl alcohol (4 mL) was heated at 116° C. for 96 h. The mixture was then purified by HPLC to give 4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzenesulfonamide (110 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([CH2:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>CCOCC.O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:18][CH2:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C

Procedure:
p-Toluenesulphonyl chloride (2.12 g, 11.1 mmol) was added to a solution of cyclopentanemethanol (1 ml, 9.25 mmol) in ether (25 ml), and the solution cooled in an ice/salt bath. Freshly powdered potassium hydroxide (4.7 g, 83.3 mmol) was added and the reaction mixture allowed to warm to room temperature, over 2 hours. The reaction was diluted with water, the phases separated, and the aqueous layer extracted with ether. The combined organic solutions were dried (MgSO4), and evaporated under reduced pressure, to give the title compound as a clear oil, 2.18 g.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH:4]=[CH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[Pd]>[OH:1][C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COc1ccc(O)c(C=CC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(O)c(CCC(=O)OC(C)(C)C)c1
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 2-hydroxy-5-methoxycinnamate (27.5 g, 0.11 mol) and 10% Pd/C (2.6 g) in MeOH (350 mL) under H. pressure (45 psi) was shaken for 8 h and filtered. The filtrate was concentrated to to the titled compound (27 g).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[O:3]1.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[Cl:12][CH2:11][CH:10]1[O:13][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH2:9]1
Reactant: CC1(C)OC(=O)C=C(CC(O)CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CC(=O)OC(CCl)C1
Temperature: 25 °C
Reaction time: 9 h
Yield: 78 %

Procedure:
A mixture of 470 mg (2.13 mmol) of (+)-2,2-dimethyl-6-(3-chloro-2-hydroxypropyl)-1,3-dioxin-4-one (99% ee), 441 mg (3.20 mmol) of potassium carbonate and 5 ml of methanol was stirred at room temperature for 9 hours. After completion of the reaction, methanol was distilled off, and the resultant residue was neutralized with 10% HCl, extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography (an eluent of hexane:ethyl acetate=3:1), thereby obtaining 270 mg (yield 79%) of (+)-6-chloromethyltetrahydropyran-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[OH-].[Na+:23]>O>[Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[Na+:23].[Na+:23].[Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 55 °C
Reaction time: 48 h
Yield: 106.2 %

Procedure:
A 22 L, Pyrex glass, five-neck, round bottom flask was equipped with an overhead stirrer, thermocouple temperature read out, and heating mantle. The flask was charged with 2602.3 g of N-(5-chlorosalicyloyl)-8-aminocaprylic acid and 4000 mL water. To this stirred slurry was added a solution of 660 g of sodium hydroxide dissolved in 2000 mL water. The mixture was heated to about 55° C. and most of the solids dissolved. The slightly hazy solution was hot filtered through Whatman #1 filter paper to remove the insoluble particulates. The filtrate was transferred to the pot flask of a large laboratory rotary evaporator. The rotary evaporator was operated with a bath temperature of about 60° C. and a pressure of 60 mmHg. Water was removed from the disodium salt solution until a solid mass was obtained in the rotary evaporator pot flask. The vacuum was released and pot flask removed from the rotary evaporator. The solids were scraped from the pot flask into trays. These trays were then placed in a vacuum oven and the solids dried at about 60° C. and full vacuum for about 48 hours. The dried solids were run through a laboratory mill until all the solids passed through a 35 mesh screen. The milled and sieved disodium N-(5-chlorosalicyloyl)-8-aminooctanate was put into trays and placed back into the drying oven. Drying was continued at about 45° C. and full vacuum to obtain 2957.1 g of the desired product as a dry powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([N:1]=[CH:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)[CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Reactant: Nc1cc(Cl)ccc1O
Product: Oc1ccc(Cl)cc1N=Cc1ccc(-c2ccc(Cl)cc2)o1

Procedure:
Using 2-amino-4-chlorophenol and 5-(4-chlorophenyl)furan-2-carbaldehyde, 3.18 g of 4-chloro-2-{[5-(4-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 95%).
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].C(OCC)(=O)C>C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.34 g of t-butyl α-(6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl)acetate [prepared as described in Example 7(g) above] was N-alkylated with 0.45 g of butyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The resulting product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as the eluent. As a result, the title compound was separated into isomers A and B (resulting from the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14]([O:16]C)=[O:15])=[N:7]2.O1CCCC1.O.[OH-].[Li+]>O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14]([OH:16])=[O:15])=[N:7]2
Reactant: COC(=O)c1ccc2c(Br)ccc(OC)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c2ccc(C(=O)O)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.9 %

Procedure:
Methyl 5-bromo-8-methoxyquinoline-2-carboxylate (154 g), tetrahydrofuran (40 ml), water (40 ml) and lithium hydroxide monohydrate (0.436 g) were combined and stirred at room temperature for 1.5 h. The tetrahydrofuran was removed in vacuo and the resulting aqueous mixture was acidified with hydrochloric acid. The resulting white precipitate was collected by filtration and dried in vacuo to give the title compound (1.33 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH3:16])[CH2:26][CH2:27]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: Cc1ccccc1CCC1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: Cc1ccccc1CCC1CCN(c2ccc(C(=O)NCCC(C)C)nn2)CC1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-[2-(2-methylphenyl)ethyl]piperidine. MS (+ESI) m/z 395 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:8][C:7]2=[O:19])([O-])=O.[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([S:28]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:7]3=[O:19])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: O=c1[nH]n(-c2ccccc2)c2ccc([N+](=O)[O-])cc12
Product: N#Cc1cccc(S(=O)(=O)Nc2ccc3c(c2)c(=O)[nH]n3-c2ccccc2)c1

Procedure:
This compound was obtained in analogy to example 32 (step B and C) using 5-nitro-1-phenyl-1,2-dihydro-indazol-3-one (prepared according to Combinatorial Chemistry and High Throughput Screening 2003, 6(5), 471-480) in step B and 3-cyanobenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI+): 391.1[M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][C:18]=1[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:1][C:2]2[CH:3]=[C:4]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:18]([CH2:30][CH2:31][CH3:32])[CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCBr
Reactant: NS(=O)(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
A solution of 3-hydroxybenzenesulfonamide (0.5 g, 2.89 mmol) and 1-(3-bromopropoxy)-4-phenoxy-2-propylbenzene (1.01 g, 2.89 mmol) with cesium carbonate (1.04 g, 3.18 mmol) in dry DMF (10 mL) was stirred at 50° C. for 5 h. The reaction suspension was cooled to room temperature and concentrated under vacuum to an orange residue. The residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was chromatographed over silica gel with hexanes/ethyl acetate (2:1) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:21])=[C:14]([F:20])[C:15]4[N:16]=[CH:17][O:18][C:19]=4[C:11]=3[NH:10][C:9]2=[O:22])=[C:4]([F:23])[CH:3]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.[H-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:21])=[C:14]([F:20])[C:15]4[N:16]=[CH:17][O:18][C:19]=4[C:11]=3[N:10]([S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])[C:9]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Product: O=c1n(-c2ccc(Br)cc2F)c2c(F)c(F)c3ncoc3c2n1S(=O)(=O)C1CC1
Yield: 48.5 %

Procedure:
Intermediate I-25a was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-16a: 220 mg, 0.57 mmol), cyclopropanesulfonyl chloride (120 mg, 0.86 mmol) and NaH (34 mg, 0.86 mmol) using procedures analogous to those described above for Intermediate I-19a to afford 135 mg of the product (48.5% yield). H1NMR (DMSO-d6, 300 MHz): δ 8.97 (s, 1H), 7.97 (dd, 1H), 7.80 (t, 1H), 7.70 (dd, 1H), 3.54-3.44 (m, 1H), 1.48-1.39 (m, 2H), 1.34-1.26 (m, 2H). HPLC: 94.1%
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:19])[CH3:18]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
A mixture of cyclopropylamine (1.39 g, 24.3 mmol) and triethylamine (3.5 g, 35 mmol) was added drop-wise to a 0° C. solution of ethyl chloro(oxo)acetate (3.5 g, 26 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at 0° C. for 10 minutes and filtered; the filtrate was concentrated in vacuo to afford the product as a yellow solid Yield: 3.0 g, 19 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 7.14 (br s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.78-2.86 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 0.83-0.90 (m, 2H), 0.59-0.65 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2C(O)=O)=O)=[CH:3][CH:2]=1.Br[C:18](=[CH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OC(=O)C)(=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:10]3[N:9]([C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:13][CH2:12][CH2:11]3)=[CH:26][CH:27]=1
Reactant: O=C(O)C1CCCN1C(=O)c1ccncc1
Reactant: CCOC(=O)C(Br)=Cc1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c(-c2ccncc2)n2c1CCC2
Temperature: 150 °C

Procedure:
A mixture of 1-(pyridine-4-carbonyl)pyrrolidine-2-carboxylic acid (example 19A, b; 60%, 1.5 g, 4.1 mmol), ethyl 2-bromo-3-(4-fluorophenyl)propenoate (example 19A, c; 1.0 g, 4 mmol) and acetic anhydride (10 ml) are heated under reflux for 21 h in an oil bath maintained at a temperature of 150° C. After cooling and concentrating in vacuo (Rotavapor), needles deposit. The concentrated crystal suspension is treated with ether/ethyl acetate (1:2) and the crystals are filtered off with suction. The mother liquor is completely concentrated and the residue is purified by cc (Al2O3— ether/THF 9:1):
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Si:13]([O:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C1CC(O)c2ccc(F)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of 3-hydroxy-6-fluoro-1-indanone (4.09 g, 24.6 mmoles) in dimethylformamide (10 mL) was added to a solution of tert-butyldimethylsilyl chloride (4.60 g, 30.5 mmoles, Aldrich) and imidazole (4.22 g, 62.0 mmoles, Aldrich) in dimethylformamide (20 mL). The solution was stirred at ambient temperature for 18 hours and evaporated in vacuo. The residue was dissolved in dichloromethane (200 mL) and washed with water (6×75 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane: ethyl acetate (95:5). The fractions containing the major spot were combined and evaporated in vacuo, and the residue was dried in a vacuum at ambient temperature for 18 hours to give 4.14 g (60%) of 3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanone as a white solid, mp 56°-58° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:23]5[CH2:24][CH2:25][CH2:26][C:22]=5[C:21]([C:27]([O:29]CC)=O)=[N:20]4)=[C:15]([C:32]([F:35])([F:34])[F:33])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.[NH3:39].Cl>CO>[NH2:39][C:27]([C:21]1[C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2[N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH:9]([C:7]3[NH:6][C:5]4[CH:37]=[CH:38][C:2]([Cl:1])=[CH:3][C:4]=4[N:8]=3)[CH3:10])=[O:36])=[CH:14][C:15]=2[C:32]([F:35])([F:34])[F:33])[N:20]=1)=[O:29]
Reactant: N
Reactant: CCOC(=O)c1nn(-c2ccc(C(=O)NC(C)c3nc4cc(Cl)ccc4[nH]3)cc2C(F)(F)F)c2c1CCC2
Agent: Cl
Solvent: CO
Product: CC(NC(=O)c1ccc(-n2nc(C(N)=O)c3c2CCC3)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 65 °C
Reaction time: 17 h

Procedure:
130 mg (0.19 mmol) of rac.-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[3-(ethoxycarbonyl)-5,6-dihydro-4H-cyclopentapyrazol-1-yl]-3-trifluoromethylbenzamide is dissolved in 5 mL of methanol, combined with 6 mL of concentrated ammonia solution, and stirred for 17 hours at 65° C. in a Schlenk flask. The cooled reaction solution is poured onto ice water, adjusted to pH 7.5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phases are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/ethanol (0%-5%). Yield: 50 mg (51%); Rf value: 0.38 (silica gel; ethyl acetate/ethanol=9:1); C24H20ClF3N6O2 (516.91); mass spectrum: (M−H)−=515/517 (chlorine isotope).