Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.C([CH:40]1[CH2:43][CH:42]([CH2:44][C:45]([OH:47])=[O:46])[C:41]1([CH3:49])[CH3:48])(=O)C.[OH-].[K+]>C(O)C>[C:45]([CH2:44][CH:42]1[CH2:43][CH:40]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[C:41]1([CH3:49])[CH3:48])([OH:47])=[O:46]
Reactant: CC(=O)C1CC(CC(=O)O)C1(C)C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C(CC(=O)O)CC1c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 16 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e 100 mg, 0.256 mmol) was reacted with (3-acetyl-2,2-dimethyl-cyclobutyl)-acetic acid (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (21 mg, 16% yield). MS: 512.31 (M+H+); HPLC Procedure A, retention time=9.07 min.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1(C)C(C)=CC=CC=1>[Cl-:9].[Cl:1][C:17]1[CH:16]=[CH:15][C:11]([C:12]([NH:2][N+:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:13])=[CH:10][CH:18]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C(N[n+]1ccccc1)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
1-Aminopyridinium chloride (104 parts) and -chlorobenzoyl chloride (150 parts) were heated in xylene (750 parts) at 140° C for 4 hours. The solid product was filtered off and recrystallised from n-butanol to give 1-(p-chlorobenzamido)pyridinium chloride (209 parts, 97% yeild), melting point 241° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][C:19](F)=[O:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][C:19](=[O:20])[NH:7][CH2:8][CH2:9][SH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (141 mg, 1.68 mmol) in 8.2 mL water was added 2-aminoethanethiol hydrochloride (102.5 mg, 0.90 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25a (145.6 mg, 0.82 mmol) in 8.2 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 132.8 mg (69% from 24a) of clean 26a as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Reactant: c1cn[nH]c1
Product: Clc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][OH:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][O:24][CH3:27])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: Cc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: COCc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-7-hydroxymethyl-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1([CH2:36][C:37]([O:39]CC)=[O:38])[CH2:31][C:32]([F:35])([F:34])[F:33]>C(O)C.O>[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=4)=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1([CH2:36][C:37]([OH:39])=[O:38])[CH2:31][C:32]([F:34])([F:35])[F:33]
Reactant: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)ccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
Lithium hydroxide (0.114 g, 2.72 mmol) was added to a solution of 14B2 (0.3 g, 0.543 mmol) in 6 mL of ethanol-water (3:1) mixture, and the mixture was stirred at room temperature for 5 h. After the solvent was removed in vacuo, the residue was diluted with water. The aqueous layer was acidified with addition of saturated citric acid solution until pH 3 was attained. The resulting solution was cooled to 0° C., and solids obtained were filtered off and dried under vacuum to afford the title compound (0.2 g, 88%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.47 (s, 1H), 8.98 (dd, J1=1.9 Hz, J2=7.7 Hz, 2H), 8.53 (dd, J1=2.1 Hz, J2=8.7 Hz, 1H), 8.46 (s, 1H), 8.10-7.93 (m, 3H), 7.88 (d, J=8.7 Hz, 1H), 3.26-2.92 (m, 3H), 2.88-2.64 (m, 2H), 2.58-2.42 (m, 2H), 2.17 (m, 1H). ESI-MS m/z: 525 (M+H)+; HPLC purity: 97%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH3:15][C@H:16]1[O:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:22][C@H:20]1[O:21][C@@H:16]([CH3:15])[CH2:17][N:18]([C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)=[O:13])[CH2:19]1
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)N3C[C@@H](C)O[C@@H](C)C3)cc2c1

Procedure:
In a flask were mixed together the above prepared 5-methoxy-benzofuran-2-carboxylic acid (0.428 g, 2.23 mmol), cis-2,6-dimethylmorpholine (0.308 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.18 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.915 mL) in 9 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3 generated 0.614 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 57.7 %

Procedure:
tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (0.74 g, 3.2 mmol) and methyl thiosalicylate (1.1 g, 6.4 mmol) were dissolved in toluene (3 ml). Triethylamine (1.4 ml, 9.7 mmol) was added thereto. The reaction mixture was refluxed for 7.5 hrs, subjected to a silica gel (75 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol-hexane to give the titled compound (0.68 g, 57%) as white crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH3:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27]Cl)=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:11][CH2:10]1.Cl>C1COCC1.C(Cl)Cl>[CH3:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:7]3[CH:6]=[CH:5][NH:4][N:3]=3)=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:11][CH2:10]1
Reactant: c1cn[nH]c1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCc1cc[nH]n1

Procedure:
0.5 g of sodium hydride was added to a solution of 0.68 g of pyrazole in 50 ml of THF. Next, 1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) was added to the solution. The solution was reacted for 24 hours, while it was refluxed. After reaction, 2 N hydrochloric acid was added, acidifying the reaction solution. The solution was washed with 100 ml of methylene chloride. Ammonia water was added to the aqueous layer obtained, alkalizing the solution. Thereafter, the solution was extracted with 100 ml of methylene chloride. The organic layer obtained was dried over magnesium sulfate, and the solvent was removed in vacuo. The product obtained was refined by means of silica gel column chromatography using methylene chloride only. Thereafter, the solvent was removed in vacuo, yielding 0.44 g of N-(trans-4-methylcyclohexyl)-4-(2-pyrazolylethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2Br)ccc2c1OCC1CC21
Yield: 76.5 %

Procedure:
2-Bromobenzenesulfonyl chloride (0.559 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.40 g) in DCM (12 mL) and pyridine (4 mL) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was dissolved in DCM and washed with 2N HCl, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35% to give methyl (1aRS,7bSR)-5-(2-bromo-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.612 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([S:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: Fc1ccc(I)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a mixture of 1-fluoro-4-iodobenzene (448 mg, 2.00 mmol) and sodium benzenesulfinate (755 mg, 1.50 mmol) in DMF (5 mL) under a nitrogen atmosphere was added copper (I) trifluoromethanesulfonate benzene complex (443 mg, 2.70 mmol). The reaction was stirred at 65° C. overnight, diluted with ethyl acetate then washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude material which was purified by flash column chromatography (85:15 to 80:20 hexanes/ethyl acetate) to give 1-fluoro-4-(phenylsulfonyl)-benzene (103 mg, 22%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.99-7.92 (m, 4H), 7.58-7.49 (m, 3H), 7.18 (t, J=8.4 Hz, 1H), 7.21-7.15 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1.[Li+].[OH-]>O.C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1cnccc1-c1cc(F)c(Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnccc1-c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
To a solution of methyl 4-(4-chloro-2,5-difluorophenyl)nicotinate (400 mg, 1.41 mmol) in water:THF (1:1, 8 mL) was added LiOH (67.5 mg, 2.82 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (5 mL) and washed with ethyl acetate (2×5 mL). The aqueous layer was separated and acidified with 1.5N HCl and concentrated under reduced pressure to afford 4-(4-chloro-2,5-difluorophenyl)nicotinic acid (180 mg, 0.541 mmol, 38% yield) as a solid. LC/MS (ESI) m/e 270 [(M+H)+, calcd for C12H7ClF2NO2 270]; LC/MS retention time (method B): tR=1.48 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:6]1.[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:6]1
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCCl)c2cc1OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCI)c2cc1OC
Reaction time: 16 h

Procedure:
2-[1-(3-Chloropropyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)—1H-pyrrolo[2,3-b]pyridine (0.395 g; 753.8 μmol) and sodium iodide (0.169 g; 1.13 mmol) in methyl ethyl ketone (10 ml) are placed in a 50 ml single-necked flask, at reflux. After 16 hours, sodium iodide (0.169 g; 1.13 mmol) is added and reflux is maintained for a further 5 hours. The reaction mixture is evaporated under reduced pressure and the residue is then dissolved in 50 ml of ethyl acetate, transferred into a separating funnel and washed with 2 times 30 ml of distilled water. The organic extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure, to give the crude compound, which is purified by chromatography on silica gel (10 μg, silica 20-40 μm), elution being carried out at 10 ml/min with a mixture of cyclohexane and ethyl acetate (70/30; v/v). The fractions containing the expected compound are combined and evaporated to give 2-[1-(3-iodopropyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in the form of an amorphous solid (0.287 g, 62%), the characteristics of which are as follows:
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([NH:23][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:13])=[O:12])=[CH:22][CH:21]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: CC(=O)Nc1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with N-(3-aminophenyl)acetamide (36 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-60% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 44 mg (40%). 1H-NMR: 10.46 (s, 1H), 9.97 (s, 1H), 8.08 (m, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.23-7.18 (m, 1H), 7.11-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.0 Hz, 2H), 2.04 (s, 3H), 1.67-1.59 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10]Br)=[CH:4][CH:3]=1.[OH:19][C:20]1([CH3:34])[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][C:22](=[O:30])[N:21]1[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10][N:27]2[CH2:28][CH2:29][C:24]3([O:23][C:22](=[O:30])[N:21]([CH2:31][CH2:32][CH3:33])[C:20]3([OH:19])[CH3:34])[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(=CCBr)c2ccc(F)cc2)cc1
Reactant: CCCN1C(=O)OC2(CCNCC2)C1(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN1C(=O)OC2(CCN(CC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)C1(C)O
Yield: 86 %

Procedure:
9.3 g of 3,3-bis(4-fluorophenyl)-2-propenyl bromide dissolved in 50 ml of acetone are portionwise added to a mixture containing 6.85 g of 4-hydroxy-4-methyl-2-oxo-3-n-propyl-1-oxa-3,8-diazaspiro[4,5]decane and 4.2 g of anhydrous potassium carbonate in 68 ml of anhydrous acetone at room temperature during 1 hour while stirring, then the reaction mixture is stirred at room temperature for an additional 1 hour. After filtering off the inorganic salts and evaporating the solvent under reduced pressure, the residue is taken up in benzene, washed with water, dried over anhydrous sodium sulfate and then the solution is evaporated to one tenth its volume under reduced pressure. The product is precipitated by adding n-hexane to the evaporation residue. The crystals are filtered off and dried to give the title compound in 86% yield, m.p.: 128°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](OC)=[O:17])=[CH:12][C:11]=1[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(OC2CCCCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2OC2CCCCO2)c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 26.3 (1.61 g, 4.47 mmol) in THF (10 mL) at 0° C., was added LAH (1.0M solution in THF, 6.70 mL, 6.70 mmol). The reaction was stirred for one hour and then carefully diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to provide 26.4 (0.990 g, 66.7% yield).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[S:26]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])(=[O:28])[NH2:27]>>[S:26]([C:30]1[CH:31]=[C:32]([NH:36][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:33]=[CH:34][CH:35]=1)(=[O:28])(=[O:29])[NH2:27]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 510.2 [(M−H)−]; mp 258° C.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].CC(C)(C)CN[C:19](=[O:43])[C:20]1[CH:25]=[C:24]([CH:26]([OH:41])[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)[CH:23]=[CH:22][C:21]=1[OH:42]>>[ClH:14].[CH2:1]([NH:13][C:19](=[O:43])[C:20]1[CH:25]=[C:24]([CH:26]([OH:41])[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:32][CH2:33]2)[CH:23]=[CH:22][C:21]=1[OH:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: Cc1ccccc1N1CCN(CC(O)c2ccc(O)c(C(=O)NCC(C)(C)C)c2)CC1
Agent: Cl
Product: CCCCCCCCCCCCNC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1O

Procedure:
Following essentially the same procedure but substituting dodecylamine for the neopentylamine above results in the preparation of N-dodecyl-2-hydroxy-5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]benzamide hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:16])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(C(=O)O)n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C)ccc1Br
Temperature: 25 °C
Yield: 40 %

Procedure:
To the title compound of step A (10.3 g, 20 mmol) in MeOH (50 mL) was added thionyl chloride (4.4 mL, 60 mmol). The reaction was heated at reflux overnight, cooled to rt and concentrated. Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.9 g, 40%). MS (ESI) mass calcd. for C8H8BrNO2, 230.1; m/z found 232 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:18]=O)[CH3:13]>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[OH:23])[CH3:13]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: O=C1COc2cc(O)ccc21
Solvent: CO
Product: CCOc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1O
Temperature: 25 °C
Yield: 59.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-ethoxy-4-hydroxybenzaldehyde 1.22 g were dissolved in methanol 75 ml, concentrated -hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.19 g.