Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].C(OCC)(=O)C>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH:1]1([NH:4][C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(NC1CC1)Oc1ccccc1
Yield: 103.1 %

Procedure:
To a solution of cyclopropylamine (500 mg) in chloroform (5 ml) were added pyridine (1.04 mg) and a solution of phenyl chloroformate (1.65 g) in chloroform (2 ml) 0° C. and the reaction mixture was stirred at ambient temperature for 0.5 hour. To the mixture was added ethyl acetate and the solution was washed successively with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give cyclopropylaminocarbonyloxybenzene (1.6 g) as a pale yellow powder.
Reaction SMILES: [I:1][C:2](=[CH:4][CH2:5][C@H:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)O)[CH3:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:32]([C@H:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[CH2:5][CH:4]=[C:2]([I:1])[CH3:3])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(I)=CC[C@@H](O)c1ccc2ncccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(I)=CC[C@H](N=[N+]=[N-])c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
A solution of (5R)-2-iodo-5-(6-quinolyl)-5-hydroxy-2-pentene (1.74 g) in 30 mL of toluene is cooled to 0° C. and treated with diphenylphosphoryl azide (1.65 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 g) for 2 hours. The mix is warmed to ambient temperature and diluted with ethyl acetate. The solution is washed sequentially with water, sat. NaHCO3, and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography.
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[C:38]([O-:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([O-:43])=[O:42].CO[Si](CC[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][NH+:56]=1)(OC)OC.CO[Si](CC[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][NH+:71]=1)(OC)OC.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[C:38]([O-:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([O-:43])=[O:42].[NH+:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:55]=1.[NH+:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:70]=1
Reactant: CO[Si](CCc1cccc[nH+]1)(OC)OC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CCO
Solvent: CO
Solvent: CC(C)=O
Product: c1cc[nH+]cc1
Temperature: 25 °C

Procedure:
4.93 g of phenyltrimethoxysilane, 72.45 g of tetraethoxysilane, 22.06 g of methyltriethoxysilane, 0.57 g of the 30% methanol solution of 2-(trimethoxysilylethyl)pyridinium maleate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.12 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-18):
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])(O)=O.[Na+]>CCOCC.O.CC(N(C)C)=O>[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([C:30]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:28][C:27]=1[CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide (318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde (461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16 mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen overnight. Water (40 mL) and ether (30 mL) were added. The precipitate was filtered off, washed with water then ether, and air-dried. The intermediate 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one was obtained as light brown/beige solid. Yield 474 mg (64%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at 100° C. for 4 h. Excess phosphorus oxychloride was removed under reduced pressure. Ice was added and the solid was collected. The solid was washed with water and ether, and air-dried. 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline was obtained as a light brown solid (yield: 356 mg, 72%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline (192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C (dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate (955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5 h. The mixture was filtered through Celite, washed with MeOH/DCM, purified by column chromatography to give 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg, 25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp 169-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:13][CH2:14][O:15][CH3:16]>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccccc1C=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 16.6 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (6.11 g, 0.05 mol) in DMF (50 ml) under argon in an ice bath was added NaH (2.0 g, 0.05 mol, 60% dispersion in mineral oil), followed 1 hour later by 2-chloroethylmethyl ether (4.73 g, 0.05 mol). The reaction mixture was allowed to stand for about 2 days, then was heated at 70° C. for 7 hours. The reaction mixture was stripped to dryness, the residue was partitioned between water and CHCl3, the layers were separated and the aqueous layer was extracted with CHCl3 (2×75 ml). The product appeared to be in both layers, thus they were concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ether to afford 1.5 g of 2-[2-(methoxy)ethoxy]benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O.[OH-].[Na+]>CC(C)=O.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:11])=[O:8])[S:5][CH:6]=1
Reactant: CC(C)=O
Reactant: O=Cc1cc(Br)cs1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromothiophene-2-carbaldehyde (9.1 g, 48 mmol) in acetone (150 mL) at 0° C. was added Jones' reagent (20 mL of a 2.6 M solution [prepared from CrO3 (26.7 g, 270 mmol) dissolved in H2O (40 mL), and H2SO4 (23 mL)], 52 mmol). After stirring for 30 minutes at 0° C., the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 3 hours stirring at ambient temperature, the reaction was quenched by the addition of 2-propanol. After stirring for 64 hours at ambient temperature, the reaction mixture was diluted with Et2O and filtered through a pad of Florisil. The pad was thoroughly washed with EtOAc, and the filtrate was concentrated under reduced pressure to afford a brown paste. This crude material was dissolved in hot aqueous ethanol, treated with decolorizing carbon and filtered while still hot. Upon cooling an oil separated and formed a suspension. This suspension was treated with solid NaOH (4 g, 100 mmol) and boiled briefly to dissolve the solids. The resulting basic aqueous solution was allowed to cool, and was extracted with Et2O (75 mL). The Et2O extract was discarded. The basic aqueous solution was then acidified by the dropwise addition of concentrated HCl. The acidic aqueous phase was extracted with EtOAc (4×60 mL). The combined EtOAc extracts were washed with brine, and dried over Na2SO4 for 16 hours. The mixture was filtered and concentrated under reduced pressure to afford 4-bromothiophene-2-carboxylic acid as a pale brown solid, which was carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][C:38]([OH:44])=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:45]>CO>[ClH:45].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41]([CH:40]=[CH:39][C:38]([OH:44])=[CH:37]3)=[CH:42][CH:43]=2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccc(O)cc3c2)C1
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1

Procedure:
In an analogous manner to that described in Example 22 (l), from tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained 7-[(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidine-3-yloxymethyl]-naphthalen-2-ol hydrochloride (1:1) as an amorphous, beige foam; MS: 498 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:12]
Reactant: CS(=O)(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)c1ccc(N)c(N)c1

Procedure:
2 G. of 1-amino-4-methylsulfonyl-2-nitrobenzene is treated in 200 ml. methanol with hydrogen at 4 atmospheres pressure in the presence of Raney nickel catalyst. The catalyst is removed by filtration and the filtrate concentrated to yield pure 1,2-diamino-4-methylsulfonylbenzene.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([OH:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([O:21][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])[CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 19 h

Procedure:
1-(2-Chloro-ethoxy)-2-nitro-benzene (10 g) and 5-fluoro-2-nitro-phenol (7.86 g) were dissolved in 50 ml DMF and was stirred for 19 h at 90-110° C. after careful addition of 13.82 g potassium carbonate. The reaction mixture was poured in a mixture of crushed ice and water (500 ml) which was vigorously stirred. The residue was filtered off, washed several times with water and dried. The crude product was suspended in methanol and the pale yellow residue was again filtered off, washed with methanol and dried. Yield: 9.5 g.
Reaction SMILES: C([S:20]/[CH:21]=[CH:22]\[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.[N+]([O-])([O-])=O.[Ag+:39]>O1CCCC1.CO>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23](/[CH:22]=[CH:21]\[S:20][Ag:39])[CH:24]=1
Reactant: [Ag+]
Reactant: C(=C\c1cccnc1)\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: [Ag]S/C=C\c1cccnc1
Temperature: 40 °C
Yield: 109.8 %

Procedure:
To a solution of 3-[(Z)-2-(tritylthio)vinyl]pyridine (690 mg) in a mixture of tetrahydrofuran (3 ml), methanol (5 ml) and pyridine (0.147 ml) was dropwise added a solution of silver nitrate (371 mg) in methanol (20 ml) at ambient temperature. The reaction mixture was stirred at 40° C. in dark. The precipitate was collected, washed with methanol and dried over phosphorus pentoxide to give [(Z)-2-(3-pyridyl)vinylthio]silver (487 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:7][N:6]=1.O1CCCC1.Cl[CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28]>CCOCC>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][N:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1)[C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: COc1ccc(NC(=O)C2CC2)cn1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCN(C(=O)C1CC1)c1ccc(OC)nc1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
Sodium hydride (0.33 g, 0.014 mol) and N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide (92.5 g, 0.014 mol) were added to dry tetrahydrofuran (THF). This mixture was stirred under N2 for one hour when methoxyethyl chloromethyl ether (1.6 g, 0.014 mol) was added dropwise to the stirred mixture. The reaction was stirred overnight and diluted with ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo nto give 2.4 g of a yellow oil of the title compound. The structure was confirmed by mass spectroscopy (MS), IR and NMR analysis.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[CH:19]=3)=[N:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:31](Br)[CH2:32][CH2:33][CH3:34]>C(O)CCC>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:31][CH2:32][CH2:33][CH3:34])[CH:24]=4)[CH:19]=3)=[N:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(O)ccc4c3)s2)cc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(OCCCC)ccc4c3)s2)cc1
Yield: 72.8 %

Procedure:
In a 20 ml-round-bottomed flask, 0.30 g (0.77 mM) of 2-(4-hexylphenyl)-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole, 0.08 g (1.21 mM) of potassium hydroxide was 4 ml of n-butanol were placed and dissolved at about 80° C. To the mixture, 0.12 ml (1.12 mM) of n-butyl bromide was added at 80° C. under stirring, followed by refluxing for 4 hours and 10 minutes under stirring. After the reaction, the reaction mixture was cooled on an iced water bath to precipitate a crystal. The crystal was recovered by filtration and washed with methanol. The resultant crystal was dissolved in toluene and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene-methanol) to obtain 0.25 g of 2-(4-hexylphenyl)-5(6-butoxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 72.8%) ##STR36##
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2[C:9]([CH:15]([CH3:17])[CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[S:4]1(=[O:19])=[O:18].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]1[C:32](=[O:33])[CH2:31][C:30]([C:34]#[N:35])=[N:29]1.[F-].[K+].CN(C=O)C>O>[CH:15]([C:9]1[C:6]2[C:7](=[O:8])[N:3]([CH2:2][O:33][C:32]3[N:28]([C:22]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=4[Cl:20])[N:29]=[C:30]([C:34]#[N:35])[CH:31]=3)[S:4](=[O:19])(=[O:18])[C:5]=2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1)([CH3:17])[CH3:16]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: N#CC1=NN(c2ccc(Cl)cc2Cl)C(=O)C1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C#N)nn1-c1ccc(Cl)cc1Cl)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A mixture of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (410 mg, 1.18 mmol), 2,4-dihydro-2-(2,4-dichlorophenyl)-5-cyano-3H-pyrazol-3-one (300 mg, 1.18 mmol), KF (68.44 mg, 1.18 mmol) and DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and was extracted with ether (3×50 mL). The ether extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 310 mg of 4-isopropyl-6-methoxy-2-[1-(2, 4-dichlorophenyl)-3-cyanopyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =2,4-Cl2 --Ph; R2 =CN; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3), m.p. 183°-184° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:20]1>>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:34])=[O:35])[CH2:20]3)[S:3][C:4]=2[CH:10]=1
Reactant: O=S(=O)(Nc1ccccc1OCC1CCNC1)c1ccccn1
Reactant: Fc1ccc2nc(Cl)sc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OCC1CCN(c2nc3ccc(F)cc3s2)C1)c1ccccn1

Procedure:
Compound 29 is prepared using synthesis method 3 using intermediates 2a and 6b (yield: 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[C:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:35])[CH2:33][CH3:34]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CCC(=O)Cl
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)CC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A177) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([NH:16][C:17]2[N:25]=[C:24]3[C:20]([NH:21][C:22](=[O:36])[N:23]3[C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[NH:32][CH2:31][CH2:30][CH2:29]4)=[CH:19][N:18]=2)[CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:36])[N:23]2[C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[NH:32][CH2:31][CH2:30][CH2:29]3)=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n(-c3ccc4c(c3)CCCN4)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n(-c3ccc4c(c3)CCCN4)c2n1

Procedure:
A solution of tert-butyl 4-fluoro-2-(8-oxo-9-(1,2,3,4-tetrahydroquinolin-6-yl)-8,9-dihydro-7H-purin-2-ylamino)phenylcarbamate (obtained from tert-butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidine-2-ylamino)phenylcarbamate and 1,2,3,4-tetrahydroquinolin-6-amine (J. Org. Chem. (2002), 67, 7890) using procedures outlined in Example 27) was stirred for 45 minutes in 1:1 TFA/DCM and concentrated to afford 2-(2-amino-5-fluorophenylamino)-9-(1,2,3,4-tetrahydroquinolin-6-yl)-7H-purin-8(9H)-one. The 2-(2-amino-5-fluorophenylamino)-9-(1,2,3,4-tetrahydroquinolin-6-yl)-7H-purin-8(9H)-one was stirred for 15 minutes in trimethylorthoformate and concentrated to afford 6-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)-3,4-dihydroquinoline-1(2H)-carbaldehyde, which was purified by silica gel chromatography (2→5% MeOH in DCM). This material was deformylated by refluxing for 1 hour in 11:2 1 M HCl:MeOH to provide the title compound as the HCl salt. 1H-NMR (300 MHz, CD3OD) δ 10.0 (s, 1H), 8.4 (s, 1H), 8.4 (dd, 1H), 7.8 (dd, 1H), 7.8 (s, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.4 (td, 1H), 3.6 (dd, 2H), 3.1 (t, 2H), 2.2 (m, 2H).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[C:36]=3[CH3:50])[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:31](=[O:34])[CH:32]=[C:33]4[C:24]([F:23])=[CH:25][CH:26]=[CH:27][N:28]4[C:29]2=[O:51])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 47.2 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (0.076 g, 0.200 mmol), 5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 37] (0.072 g, 0.182 mmol) and Cs2CO3 (0.118 g, 0.363 mmol) in THF (3 mL) and water (0.75 mL) was bubbled with nitrogen for 2 min, then was treated with PdCl2(dppf) DCM adduct (7.4 mg, 9.09 μmol). Bubbling with nitrogen was continued for 30 sec and the reaction vessel was sealed. The mixture was stirred at room temperature overnight, then was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with DCM. The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give 3-chloro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (0.049 g, 43% yield). Mass spectrum m/z 571 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.52-11.48 (m, 1H), 8.27 (br. s., 1H), 8.15-8.09 (m, 2H), 7.84 (s, 1H), 7.59 (br. s., 1H), 7.56-7.46 (m, 2H), 7.30-7.26 (m, 1H), 7.03-6.97 (m, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.60-6.51 (m, 2H), 5.85 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.46-1.42 (m, 6H).