Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:5]
Reactant: CCCCCCCBr
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: O
Solvent: CC#N
Product: CCCCCCCOC(=O)c1cc(O)ccc1O

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (28 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (27.6 g), 1-bromo-heptane (39 g) and acetonitrile (380 ml) was heated, under reflux for 18 h. The cooled reaction mixture was added to water (1000 ml) and extracted with ethyl acetate (3×400 ml). The combined organic layers were washed with 1N-hydrochloric acid (300 ml) and water (2×400 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (40 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (9:1) as eluent, to give heptyl 2,5-dihydroxybenzoate.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])=[CH:25][CH:24]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2c2cc[nH]c12
Yield: 22.7 %

Procedure:
This compound is prepared according to synthesis 25, from 300 mg (0.92 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 112 μL (1.1 mmol) of 4-fluoro-aniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in water then diethyl ether, 45 mg (12%) of 8-(4-fluorophenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23]1)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The product from Example 92B and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. MS (ESI+) m/z 410 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:1]([C:13]1[S:12][C:11]([Cl:10])=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([C:13]1[S:12][C:11]([O:26][C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cccs1
Product: CC(C)(C)c1ccc(Oc2ccc(C(=O)c3ccccc3)s2)cc1
Product: O=C(c1ccccc1)c1ccc(Cl)s1

Procedure:
2-benzoyl-5-chlorothiophene was synthesized via Friedel-Crafts acylation of benzoyl chloride with 2-chlorothiophene. This was reacted under standard conditions with 4-t-butyl phenol to produce 2-benzoyl-5-(4-t-butyl-phenoxy)thiophene. It was discovered by thin layer chromatography that the displacement of the acyl chlorine proceeds completely with no side reactions. Complete nucleophilic displacement demonstrates that this reaction meets the requirements necessary for high polymer formation via a step growth reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH:18]3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[NH2:37][C:38]1[CH:48]=[CH:47]C(Br)=[CH:45][C:39]=1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41]>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[NH2:37][C:38]1[CH:48]=[CH:47][C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)=[CH:45][C:39]=1[C:40]([N:42]([CH3:43])[CH3:44])=[O:41]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(C3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g, 3 mmol), 2-amino-5-bromo-N,N-dimethyl-benzamide 0.8, 3.3 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (110 mg, 0.2 mmol) in THF/Acetonitrile/saturated NaHCO3 (5 ml/5 ml/5 ml) was stirred at 100° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (1.1 g, 71% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.89 (s, 6H), 3.77 (s, 3H), 6.74 (d, 1H), 7.03 (m, 1H), 7.14 (d, 1H), 7.29 (s, 1H), 7.34-7.41 (m, 4H), 7.55 (d, 1H), 7.94 (s, 2H), 8.01 (d, 2H), 8.54 (s, 1H). MS: m/z 541.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:22]=1[NH2:23]>C(O)CO.O>[CH3:19][C:4]1[N:3]=[C:2]([NH:23][C:22]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=2[CH3:20])[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=1.[CH3:19][C:4]1[N:3]=[C:2]([NH:23][C:22]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=2[CH3:20])[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:23][C:22]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=3[CH3:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(CO)cc2)c(Cl)n1
Solvent: O
Solvent: OCCO
Product: Cc1cc(C)c(NCc2ccc(S(=O)(=O)c3ccc(C)nc3Nc3c(C)cc(C)cc3C)cc2)c(C)c1
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(CO)cc2)c(C)c1
Yield: 5.3 %

Procedure:
[4-(2-Chloro-6-methylpyridine-3-sulfonyl)-phenyl]-methanol (1.15 g, 3.86 mmol) and 2,4,6-trimethyl aniline (3.13 g, 23.2 mmol) were heated at reflux in ethylene glycol (3.5 mL) for 16 h. After cooling the mixture was diluted with water (50 mL) and extracted with ethyl acetete (2×200 mL). The combined organic extracts were washed with brine, dried and stripped in vacuo. The residue was purified by column chromatography on silica gel (40% EtOAc/hexanes eluent) to give the product {4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-methanol as an amorphous solid (836 mg, 55% yield for the two steps) and (6-methyl-3-{4-[(2,4,6-trimethylphenylamino)-methyl]-benzenesulfonyl}-pyridin-2-yl)-(2,4,6-trimethyl-phenyl)-amine (53 mg, 3.5% yield). mass spec. (AP+): m/z 397 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]([N:11]([S:18]([CH2:21][CH2:22][CH2:23][F:24])(=[O:20])=[O:19])S(CCC)(=O)=O)=[CH:9][CH:8]=[C:7]([F:25])[C:3]=1[C:4]([O-:6])=[O:5].[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[C:10]([NH:11][S:18]([CH2:21][CH2:22][CH2:23][F:24])(=[O:19])=[O:20])=[CH:9][CH:8]=[C:7]([F:25])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)[O-])c1F)S(=O)(=O)CCCF
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
2,6-Difluoro-3-(N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate (38 g, 120 mmol) was dissolved in 5:2 THF/MeOH (250 mL), and a solution of lithium hydroxide (8.77 g, 366 mmol) in water (50 mL) was added. The reaction mixture was stirred at room temperature for four hours. The majority of the organic solvents were then removed in vacuo. 2.5N HCl (500 mL) was slowly added to the mixture, and the resulting solid was filtered and rinsed with cold ether to give 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid as a solid (29.3 g, 81% yield). 1H NMR (400 MHz, CDCl3 ppm) 9.85 (s, 1H), 7.54 (dt, 1H), 7.21 (dt, 1H), 4.54 (td, 2H), 2.20-2.00 (m, 2H), 3.24-3.18 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]([O:24]C(=O)C)[CH3:23])[CH2:17][CH2:16]1)=[N:8][N:7]=[CH:6]2.CCOCC>[OH-].[Na+].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]([OH:24])[CH3:23])[CH2:17][CH2:16]1)=[N:8][N:7]=[CH:6]2
Reactant: COc1cc2cnnc(N3CCC(CC(C)OC(C)=O)CC3)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1cc2cnnc(N3CCC(CC(C)O)CC3)c2cc1OC
Yield: 45.1 %

Procedure:
6,7-Dimethoxy-1-[4-(2-acetoxypropyl)piperidino]phthalazine (1 g) was heated at 90° in a mixture of 5 N sodium hydroxide (5 ml) and ethanol (5 ml) for 30 hours. The mixture was then evaporated in vacuo and the residue suspended in water (25 ml) from which it was extracted with chloroform (2×25 ml). The combined chloroform extracts were washed with water (20 ml) and evaporated in vacuo to give a crude oily product, which solidified on trituration with ether (20 ml). Recrystallization from acetonitrile gave 6,7-dimethoxy-1-[4-(2-hydroxypropyl)piperidino]phthalazine (400 mg), m.p. 154°-6°.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-heptylbenzene (0.82 ml, 4 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-heptylbenzoin was obtained as crystal (386.7 mg, 61.5% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:5]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:16][CH:17]=3)[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:3]1[C:4]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:5]2[CH:11]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:16][CH2:17]3)[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(C3=CCN(CC(=O)N(C)C)CC3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(C3CCN(CC(=O)N(C)C)CC3)cc12

Procedure:
A solution of Example 236G (80 mg, 0.185 mmol) in methanol (10 mL) was added to 20% palladium hydroxide on carbon (wet) (40 mg, 0.029 mmol) in a pressure bottle. The mixture was stirred at 50° C. under 30 psi hydrogen for 16 hours and filtered. The filtrate was concentrated and the residue was purified by reverse-phase HPLC on a Phenomenex Luna C8 AXIA column (100 Å) using a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.00-2.20 (m, 2H), 2.21-2.30 (m, 2H), 2.90-2.98 (m, 6H), 2.98-3.45 (m, 5H), 3.75 (s, 3H), 4.21 (s, 2H), 6.09 (bs, 1H), 7.20 (dd, J=8.6, 3.1 Hz, 1H), 7.26 (dd, J=9.1, 4.5 Hz, 1H), 7.29-7.38 (m, 1H), 8.54 (s, 1H), 12.12 (bs, 1H). MS (ESI(+)) m/e 436 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To 5-chloro-2-fluoro-4-iodopyridine (600 mg, 2.331 mmol) was added DMSO (2.2 ml), trans-4-aminocyclohexanol (1074 mg, 9.32 mmol) and TEA (0.390 ml, 2.80 mmol). The resulting reaction mixture was stirred at 75° C. for 24 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (1×), water (1×), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40 g column eluting from 15%-75% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 750 mg of the title compound as free base, which was used in the next step without further purification. LCMS (m/z): 353.0 (MH+), retention time=0.56 min.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([S:15]([CH2:18][CH:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)O)(=[O:17])=[O:16])[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[NH2:39][OH:40].C(O[C:45](=[O:47])C)(=O)C>C1COCC1.C(O)=O>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([S:15]([CH2:18][CH:19]([N:39]([OH:40])[CH:45]=[O:47])[CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)(=[O:17])=[O:16])[CH2:12]2)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc2c(c1)CN(S(=O)(=O)CC(O)C1CCOCC1)CC2
Reactant: NO
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)CN(S(=O)(=O)CC(C1CCOCC1)N(O)C=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-[(7-tert-butyl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-(tetrahydro-2H-pyran-4-yl)ethanol (431 mg, 1.13 mmol) and Et3N (0.38 ml, 2.71 mmol) in anhydrous THF (10 ml) was cooled at 0° C., then methanesulfonyl chloride (0.105 ml, 1.36 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 15 min, then at 60° C. for 20 h00. A 50% aqueous solution of NH2OH (1.0 ml, 16.9 mmol)) was added and the resulting mixture was stirred at 60° C. for 2 h30. Then the reaction mixture was washed with brine (5 ml), dried (MgSO4) and the solvent was removed under reduced pressure to give a yellow oil. A mixture of formic acid (3.2 ml) and acetic anhydride (0.8 ml) was stirred at 0° C. for 30 min., then a solution of the previous oil in anhydrous THF (5 ml) was added and the resulting mixture was stirred at 0° C. for 10 min., then at RT for 30 min. The mixture was evaporated under reduced pressure. The residue was taken up with MeOH (10 ml) and heated at 60° C. for 30 min. The reaction mixture was evaporated under reduced pressure, then the residue was taken up with EtOAc (20 ml) and washed with water (2×10 ml), a saturated aqueous solution of NaHCO3 (10 ml) and brine (10 ml). The aqueous layers were extracted with EtOAc (20 ml). The organic layers were combined, dried (MgSO4) and the solvent was removed under reduced pressure to give a yellow oil. After purification by crystallization in EtOAc/Et2O/pentane, the title compound (66) was obtained as a white powder (175 mg, 36%). HPLC, Rt: 4.0 min (purity: 100%). LC/MS, M+(ESI): 425.3, M−(ESI): 422.9.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[CH:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H].[Na].I[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>O.CN(C=O)C>[F:3][C:4]([F:13])([F:14])[CH:5]([O:12][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC(O)C(F)(F)F
Reactant: [H][H]
Reactant: N#Cc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(Oc1ccc(C#N)cc1)C(F)(F)F

Procedure:
Into 100 ml of dry DMF containing 0.86 g of sodium hydride (purity 60%), were added dropwise 3.9 g of R-form oa 1-trifluoromethyl-heptanol, at room temperature with such a speed not causing too rapid generation of hydrogen, to prepare sodium salt (alkoxide) of R-form oa 1-trifluoromethyl-heptanol After addition was over, stirring was continued further an hour at room temperature, followed by adding thereto 4.80 g of p-iodo-benzonitrile and then refluxing for 2 hours. After cooling, the product was introduced into iced water, and extracted with hexane The hexane phase was washed subsequently with water, 1N-HCl aqueous solution and then water, followed by purifying with silica gel column to obtain 5.16 g of oily oa p-(1-trifluoromethyl-heptyloxy)- benzonitrile.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:10]2([C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:31])[CH:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[F:39])=[O:7])(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:17]([O:16][CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][CH:11]1[C:10]2([C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:31])[CH:9]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])[CH:8]([C:6]([OH:7])=[O:5])[NH:12]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (0.24 g, 0.41 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 g). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a yellow solid (0.25 g, 97%).
Reaction SMILES: C(C1C=CC([C:16]2[NH:17][C:18]3[CH:24]=[C:23](N)[C:22](N)=[CH:21][C:19]=3[N:20]=2)=CC=1)(OC1C=CC=CC=1)=O.C1(S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C1(O)C=CC=CC=1>CO>[N:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][CH:16]=1
Reactant: Nc1cc2nc(-c3ccc(C(=O)Oc4ccccc4)cc3)[nH]c2cc1N
Agent: O=S(=O)(c1ccccc1)c1ccccc1
Solvent: Oc1ccccc1
Solvent: CO
Product: c1ccc2[nH]cnc2c1
Temperature: 250 °C
Yield: 169.3 %

Procedure:
A polymerization flask equipped with nitrogen inlet and outlet tubes and mechanical stirrer was thoroughly flamed and purged with nitrogen. To this was added a mixture containing 5.0 g (14.5 mmole) of 2-[p-carbophenoxyphenyl]-5,6-diaminobenzimidazole and 25 g of diphenyl sulfone. The reaction flask was then slowly heated to 250° C and maintained at that temperature for 6 hours. During this time, phenol sublimed from the reaction mixture, and a precipitate formed. The flask was cooled to 125° C and the polymer suspension poured into 500 ml of methanol. The polymer thus precipitated was collected on a filter frit, washed several times with small portions of methanol, and dried. Reprecipitation from methane sulfonic acid into methanol, followed by successive washings with 5% ammonium hydroxide, methanol and benzene, yielded 2.9 g of benzimidazole polymer as a dark tan powder, exhibiting an inherent viscosity of 1.1 dl/g in methane sulfonic acid (0.35 g/dl).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:18])[NH:16][N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:18])[N:16]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(C2=NNC(=O)C2(C)C)cc1OCC
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCC

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C2) and tert-butyl 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B2*HCl)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8].[C:15]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([N+:28]([O-])=O)=[CH:23][CH:22]=2)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[N:20]([CH2:3][C@@H:2]([OH:1])[CH2:7][OH:8])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:12]([C:9]1([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=3)[CH2:10][CH2:11]1)=[O:14])=[CH:23][CH:22]=2)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc(O)c(O)c4)CC3)ccc2n1C[C@@H](O)CO

Procedure:
(R)—N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(3,4-dihydroxyphenyl)cyclopropanecarboxamide was prepared using an experimental procedure similar to Example 72 from 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid and 2-tert-butyl-5-nitro-1H-indole.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:15]1([C:21]#[C:22][C:9]2[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[CH:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Bubble nitrogen through a mixture of N-[isopropyl]2-nitro-5-bromoaniline (0.34 g, 1.31 mmol), phenylacetylene (0.20 g, 1.96 mmol), palladium(II) acetate (7.3 mg, 0.033 mmol) and triphenylphosphine (17 mg, 0.065 mmol) in triethylamine (5 ml) for 3 minutes, then heat at reflux for 1 hour. Cool to room temperature and concentrate under reduced pressure. Partition the residue between ethyl acetate and saturated aqueous sodium chloride, dry the organic phase over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 9:1 hexane:ethyl acetate to provide the desired compound as a red solid (0.31 g, 85%).