Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22](OC(C)C)[NH:21][N:20]=2)=[N:4][C:5]([NH:8][CH:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1.[CH:28]1(C2NN=C(NC3C(F)=CN=C(N[C@H](C4N=CC(F)=CN=4)C)N=3)C=2)CC1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22]([CH3:28])[NH:21][N:20]=2)=[N:4][C:5]([NH:8][CH:9]([C:11]2[N:12]=[CH:13][C:14]([F:17])=[CH:15][N:16]=2)[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Reactant: C[C@H](Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 180 °C
Yield: 61.9 %

Procedure:
A mixture of rac-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 1, 100 mg), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 9, 200 mg) and DIPEA (0.150 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 min) to give 5-chloro-N2-[1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as solid (55 mg). The tile compound was obtained after chiral purification using SFC conditions (Chiralpak AD-H, 20% i-PrOH/80% CO2/0.1% Dimethylethylamine). 1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H) 8.83 (s, 2H) 7.88 (s, 1H) 7.44 (s, 1H) 5.93 (s, 1H) 4.92-5.29 (m, 1H) 2.20 (s, 3H) 1.49 (d, 3H); m/z 350.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N:30]1([C:35]([C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[NH2:39])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:39][C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[C:35]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:36])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: Nc1ccccc1C(=O)N1CCCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCCC3)n2)c(OC)c1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-(pyrrolidin-1-ylcarbonyl)aniline. MS (ES+): m/z 608.35 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[Br:11][C:8]1[CH:9]=[N:10][C:2]2[NH:1][CH:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:7]=1
Reactant: NC(=O)c1cc(Br)cnc1N
Reactant: O=Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1NC(c2cccs2)Nc2ncc(Br)cc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a mixture of 2-amino-5-bromonicotinamide (200 mg, 0.93 mmol), thiophene-2-carbaldehyde (125 mg, 1.11 mmol) in MeOH (15 mL) was added 4-methylbenzenesulfonic acid (16 mg, 0.09 mmol). The mixture was stirred at 60° C. overnight. Then the resulting solid was filtered to give the product of 6-bromo-2-(thiophen-2-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (180 mg, yield: 63%), which was used for the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 8.93 (d, J=2.4 Hz, 1H), 8.42 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.45 (dd, J=4.8 Hz, 1.2 Hz, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.98 (dd, J=4.8 Hz, 3.2 Hz, 1H), 6.10 (t, J=2.4 Hz, 1H). MS (M+H)+: 310/312.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]([S:12]([O:15]C3C=CC=CC=3)(=[O:14])=[O:13])[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[OH-].[Na+:23]>C(O)C>[Na+:23].[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]([S:12]([O-:15])(=[O:14])=[O:13])[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=S(=O)(Oc1ccccc1)c1cccc(-c2ccsc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)([O-])c1cccc(-c2ccsc2)n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of phenyl 6-(3-thienyl)-2-pyridinesulfonate (D8) (634 mg, 2 mmol) and aqueous sodium hydroxide solution (1M, 12 ml) in ethanol (20 ml) was stirred at 60° C. for 18 hours. After cooling to room temperature the solution was concentrated in vacuo. The resulting residue was diluted with water, the pH was adjusted to pH 4-5 with 1M hydrochloric acid and the solution was washed with diethyl ether. The aqueous phase was concentrated in vacuo and the residue purified by reverse phase C18 silica chromatography (water to 1:10 methanol:water) to afford the title product (D9). MS (ES−) m/e 240 [M−Na]−.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Yield: 11.2 %

Procedure:
In the same manner as that described in Example 1(1), a reaction was carried out using commercially available 4-aminobenzonitrile (343 mg, 2.9 mmol), N,N-diisopropylethylamine (1.21 ml, 7.0 mmol), 4-formylbenzoyl chloride (561 mg, 3.33 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 1(1) to afford an oily residue. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (2:1) as the eluant to obtain 4′-cyano-4-formylbenzanilide (81 mg, yield 11%) as a pale yellow solid which was recrystallized from ethyl acetate to give pale yellow powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[C:13]([CH3:15])[N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:6]=2[CH:35]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:16][NH2:17])=[C:13]([CH3:15])[N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:6]=2[CH:35]=1
Reactant: Cc1nc2n(c1CN1C(=O)c3ccccc3C1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc2n(c1CN)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 28, a suspension of 1.00 mmole of 8-chloro-1-(phthalimido)methyl-2-methyl-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine is treated with 5.00 mmole of hydrazine hydrate in 12ml. of absolute ethanol at room temperature for 18 hours to afford, after removal of the phthalazine by-product, 8-chloro-1-aminomethyl-2-methyl-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([Cl:17])[CH:6]=1.[C:18](=[O:20])=[O:19].Cl>O1CCCC1>[Cl:17][C:7]1[CH:6]=[C:5]([C:18]([OH:20])=[O:19])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Br)ccc1-c1ccccc1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 65 °C

Procedure:
Few crystals of iodine are added to tetrahydrofuran (200 mL) containing magnesium turnings (2.8 g, 0.117 mol). The mixture is heated at 60-70° C. A solution of 4-bromo-2-chlorobiphenyl (26 g, 0.097 mol) in tetrahydrofuran (50 mL) is added dropwise to the reaction mixture and refluxed for 1 hr. Reaction mixture is brought to room temperature and then cooled to −20° C. Carbon dioxide gas is passed through the reaction mixture for 45 minutes. The reaction mixture is treated with 3N HCl (125 mL) and extracted with ethyl acetate (2×200 mL). Combined organic layer is dried over sodium sulphate. Removal of solvent under reduced pressure gives a solid which is washed with diethyl ether (2×100 mL) and then dried to furnish 2-chlorobiphenyl-4-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:13]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.ClC1C=CC=C(C(OO)=O)C=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:13]=1)=[O:26]
Reactant: Cc1cn2cc(CSCCCCCl)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: ClCCl
Product: Cc1cn2cc(CS(=O)CCCCCl)ccc2n1
Reaction time: 1 h
Yield: 79.7 %

Procedure:
4.95 g of the 6-((4-chlorobutyl)thiomethyl)-2-methylimidazo[1,2-a]pyridine prepared in the Preparative Example 17 was dissolved in 50 ml of dichloromethane, followed by the cooling of the obtained solution with ice. A solution of 3.18 g of m-chloroperbenzoic acid in 20 ml of dichloromethane was dropped into the resulting solution in 20 minutes. After one hour, 0.16 g of m-chloroperbenzoic acid was further added to the obtained mixture. The obtained mixture was additionally stirred for 30 minutes, followed by the addition of an aqueous solution of sodium thiosulfate. The obtained mixture was vigorously stirred at room temperature for 15 minutes, followed by the addition of an aqueous solution of potassium carbonate. The obtained mixture was extracted with dichloromethane. The organic phase was dried over anhydrous potassium carbonate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1 to 80:1)] to give 4.18 g of the title compound as a pale-pink solid (yield: 79%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[N:12][C:11]([NH2:14])=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cnc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cnc(N)cn2)CC1
Yield: 98.6 %

Procedure:
2-(4-methylpiperazin-1-yl)-5-nitropyrazine (328 mg, 1.47 mmol) was dissolved in MeOH (15 ml) at room temperature. Pd/C (10%) (50 mg) was added while the reaction mixture was stirred. The reaction mixture was placed under a H2 balloon and stirred at rt for 1.5 hrs. The reaction mixture was filtered through celite and washed with MeOH (30 mL). The filtrate was stripped and dried under vacuum after azeotroping with toluene twice to give a light brown gummy material (280 mg, yield 89%).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=1)=[O:10])[CH2:2]2.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]([C:11]1[S:12][C:13]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=1)=[O:10])[CH2:4]2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1CC2CCC(C1)O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(-c2sc(C(=O)N3CC4CCC(C3)O4)nc2-c2ccc(Cl)cc2)cc1
Temperature: 150 °C
Yield: 19.5 %

Procedure:
To a solution of 8-oxa-3-azabicyclo[3.2.1]octan-3-yl(4-(4-chlorophenyl)thiazol-2-yl)methanone (Step 2 of compound 67, 0.7 g, 2.09 mmol) in dimethyl acetamide (10 ml) were added 4-bromobenzenesulfonamide (0.54 g, 2.30 mmol) and potassium acetate (0.41 g, 4.18 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To this was added palladium (II) acetate (0.047 g, 0.20 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 150° C. for 15 hr with stirring. The progress of reaction was monitored by TLC; the reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml). The reaction mixture was washed with water (2×30 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 19.5%). MS: m/z 490 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[CH:17]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO>[CH:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)C(c2ccccc2)C2CCCC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)C(c1ccccc1)C1CCCC1
Temperature: 25 °C

Procedure:
2-(2-Cyclopentyl-2-phenyl-acetylamino)-indan-2-carboxylic acid ethyl ester (268) (1 g, 2.56 mmol) is dissolved in EtOH (50 mL) and set to stir at RT. To this solution is added 5M KOH (3 ml). The reaction mixture is stirred at RT overnight. After concentration in vacuo, the residue is dissolved in water (20 mL) and washed with EtOAc (20 ml). The phases are separated and the aqueous phase is acidified with concentrated HCl to pH 2. The solid precipitate is collected via filtration and dried under vacuum. The desired product (269) is obtained as white solid (710 mg, 71%).
Reaction SMILES: [CH2:1]([C:3]([OH:17])([CH2:15][CH3:16])[CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][OH:6])[CH3:2].Cl[O-].[Na+].Cl([O-])=[O:22].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>P([O-])([O-])([O-])=O.C(#N)C>[C:10]([O:9][C:8]([NH:7][CH:4]([C:3]([CH2:15][CH3:16])([OH:17])[CH2:1][CH3:2])[C:5]([OH:22])=[O:6])=[O:14])([CH3:12])([CH3:11])[CH3:13]
Reactant: [O-][Cl+][O-]
Reactant: CCC(O)(CC)C(CO)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(O)(CC)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 35 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
tert-Butyl 2-ethyl-2-hydroxy-1-(hydroxymethyl)butylcarbamate (5.80 g) obtained in Example 36a) and 2,2,6,6-tetramethyl-1-piperidinyloxy (0.73 g) were dissolved in phosphate buffer (pH 6.8, 100 ml) and acetonitrile (100 ml). While the mixture was warmed to 35° C., an aqueous sodium hypochlorite solution (1.3 ml) and an aqueous solution (20 ml) of sodium chlorite (6.4 g) were simultaneously added dropwise thereto over 2 hours, respectively. The reaction mixture was mixed at 35° C. overnight, and returned to room temperature. The solution was acidified by adding a 5% aqueous citric acid solution and extracted three times with ethyl acetate. The extracts were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column (ethyl acetate/hexane=1/1 to 3/1) to obtain the title compound as colorless powder (0.28 g, 24%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>CCOC(C)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1])[CH2:24][CH2:23]2)=[O:21])=[CH:28][CH:29]=1
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@](O)(C(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of (S)-3,3,3-trifluoro-2-trimethylsilyoxy-2-methylpropanoyl chloride (J. Med. Chem., 1999, 42, 2741-2746) (293 mg, 1.2 mmol) in EtOAc (5 ml) was added to a stirred mixture of 4-(4-fluorobenzoyl)piperidine (207 mg, 1.0 mmol) and triethylamine (0.21 ml, 1.5 mmol) in EtOAc (25 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (10 ml), treated with 1 M hydrochloric acid (2 ml) and the mixture stirred at ambient temperature for 1 hour. The methanol was evaporated, the aqueous layer was extracted with EtOAc (2×25 ml), the EtOAc extracts were washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 10% EtOA/DCM as eluent to give a solid which was recrystallized from EtOAc/hexane to give the title compound as a solid (104 mg, 0.3 mmol). Mp: 78-79° C.; NMR: 1.7 (s, 3H), 1.8-2.0 (m, 4H), 3.2 (dd, 2H), 3.5 (m, 1H), 4.4 (dd, 2H), 5.25 (s, 1H), 7.15 (dd, 2H), 8.0 (dd, 2H); m/z 346.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[CH:21])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:25])[CH2:2][CH3:3].I[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[O:25]=[C:5]1[N:6]([CH2:22][CH2:23][CH3:24])[C:7]2[N:8]=[C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[C:21][C:27]4[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=4)[CH:18]=3)[NH:10][C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C#CCn1cc(-c2nc3c([nH]2)c(=O)n(CCC)c(=O)n3CCC)cn1
Reactant: NS(=O)(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC#Cc4ccc(S(N)(=O)=O)cc4)c3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.4 %

Procedure:
A mixture of 1,3-dipropyl-8-(1-prop-2-ynyl-1H-pyrazol-4-yl)-3,7-dihydro-purine-2,6-dione (200 mg, 0.59 mmol), 4-iodo-benzenesulfonamide (166 mg, 0.59 mmol), copper iodide (10 mg, 0.059 mmol), dichlorobis (triphenylphosphine)-palladium (II) (21 mg, 0.03 mmol), triethylamine (2 ml), DMF (2 ml) was degassed for 10 min. and stirred for 20 hrs at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×10 ml). Organic layer was washed with brine (2×15 ml) and dried over Na2SO4. The organic volatile solvent was evaporated and the crude product was purified using HPLC to obtain pure 4-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzenesulfonamide (4.2 mg, 2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[O:30][CH2:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO.C(O)CCC>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: ClCCCOc1c(Cl)cccc1Cl
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCCCO
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCCOc3c(Cl)cccc3Cl)CC2)cc1

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 m l of 1-butanol containing potassium iodide (0.2 g). The reaction was concentrated to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80° C. A yield of 3.26 g (27.7%) of white, crystalline solid, m.p. 101.5°-103° C., was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(C1C=CC=CC=1C(C1C2C(=CC=CC=2)N(CCCCCCCC)C=1C)=O)(O)=O>>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: O=C1OCc2ccccc21

Procedure:
If the 3-(2'-carboxybenzoyl)-1-ethyl-2-methyl-indole in Example 1 is replaced by an equimolar amount of 3-(2'-carboxybenzoyl)-1-n-octyl-2-methyl-indole, with the procedure otherwise being as described in Example 1, there is obtained 3.8 g of a phthalide compound of the formula ##STR14## which melts at 123°-125° C. This colour former develops on silton clay a blue colour of λ max. 600 nm.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].O=C1CCCCC1C(OCC)=O.[CH3:19][C:20]1[CH:21]=[CH:22][C:23](=[O:26])[NH:24][CH:25]=1.[F:27][C:28]1[CH:40]=[C:39](I)[CH:38]=[CH:37][C:29]=1[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CS(C)=O.[Cu]I>[F:27][C:28]1[CH:40]=[C:39]([N:24]2[CH:25]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]2=[O:26])[CH:38]=[CH:37][C:29]=1[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: Fc1cc(I)ccc1CN1CCOCC1
Reactant: Cc1ccc(=O)[nH]c1
Agent: [Cu]I
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccc(=O)n(-c2ccc(CN3CCOCC3)c(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A mixture of CuI (0.19 g, 1 mmol), Cs2CO3 (6.85 g, 20 mmol) and ethyl 2-oxocyclohexanecarboxylate (0.34 g, 2 mmol) in DMSO (10 mL) was stirred at rt for 30 min under N2. Then to the reaction mixture was added a solution of 5-methylpyridone (1.09 g, 10 mmol) and 4-(2-fluoro-4-iodobenzyl) morpholine (3.21 g, 10 mmol) in DMSO (12 mL) via syringe. The reaction mixture was heated at 100° C. overnight, cooled to rt and filtered. The filtrate diluted with H2O (50 mL) was extracted with CH2Cl2 (50 mL×3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as a white solid (0.70 g, 23%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:18]([O-:20])=[O:19])(=[O:8])=[O:7])(C)(C)C.Cl.[CH3:22]O>>[NH2:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:18]([O:20][CH3:22])=[O:19])(=[O:8])=[O:7]
Reactant: CO
Reactant: CC(C)(C)NS(=O)(=O)c1c(C(=O)[O-])sc2ccccc12
Agent: Cl
Product: COC(=O)c1sc2ccccc2c1S(N)(=O)=O

Procedure:
A solution of 6 g of 3-tert-butylaminosulfonylbenzothiophene-2-carboxylate acid in 100 ml of methanol was saturated with anhydrous hydrogen chloride and then heated to reflux for three hours. The mixture was evaporated in vacuo to half of its volume and the residue poured into 200 g of ice and filtered to yield the desired product melting at 150°-154°. The infrared absorption spectrum shown by this material was qualitatively equivalent to that of the product of Example 4.