Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:9])=[O:8])(=O)C.[OH-].[K+].CI>CO>[F:11][C:10]([F:12])([F:13])[CH:6]([CH2:5][S:4][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: CC(=O)SCC(C(=O)O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Product: CSCC(C(=O)O)C(F)(F)F
Temperature: 65 °C
Yield: 72.6 %

Procedure:
To a solution of 2-(acetylthiomethyl)-3,3,3-trifluoropropanoic acid (649 mg, 3 mmol) in MeOH (5 mL) stirring at 25° C. was added pellets of potassium hydroxide (421 mg, 7.50 mmol) in four portions over 5 minutes. Reaction was exothermic. Then MeI was added in once, the reaction mixture was then heated at 65° C. for 18 hours. The reaction was then cooled down and quenched with 2N HCl until acidic, and the aqueous layer extracted with chloroform (4×20 mL). Combined organic layer was dried, concentrated in vacuo, purified with flash chromatography (0-20% MeOH/DCM), to give 3,3,3-trifluoro-2-(methylthiomethyl)propanoic acid (410 mg, 2.179 mmol, 72.6% yield) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 10.95 (s, 1H), 3.49-3.37 (m, 1H), 3.02 (dd, J=13.8, 10.8 Hz, 1H), 2.90 (dd, J=13.8, 4.0 Hz, 1H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 172.04 (q, J=2.8 Hz), 123.55 (q, J=281.2 Hz), 50.89 (q, J=27.5 Hz), 29.62 (q, J=2.3 Hz), 15.85; 19F NMR (376 MHz, CDCl3) δ −67.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:10]=3[NH:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH:26](O)([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([O:20][CH:26]([CH3:28])[CH3:27])=[O:19])=[CH:17][C:10]=3[NH:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1Oc1ccc(C(=O)O)cc1NC2
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: COc1cccc2c1Oc1ccc(C(=O)OC(C)C)cc1NC2
Yield: 90 %

Procedure:
A mixture of 10,11-dihydro-4-methoxydibenz[b,f][1,4]oxazepine-8-carboxylic acid (3 g), isopropanol (30 ml) and concentrated sulfuric acid (0.5 ml) was refluxed for 10 hours and then the solvent used was distilled off. The residue was dissolved in ethyl acetate (50 ml) and, after washing with water, dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from ethanol to give isopropyl 10,11-dihydro-4-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate as colorless needles. (Yield: 90%, m.p. 109.5°-110.5° C.)
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:17]N1C(=O)CCC1=O.O>ClCCl.C(O)(=O)C>[Br:17][C:2]1[S:1][C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: N#Cc1ccc2c(c1)-c1sccc1CCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)-c1sc(Br)cc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carbonitrile (4.58 g) in dichloromethane (30 mL) and acetic acid (30 mL) was added N-bromosuccinimide (3.95 g) and the reaction stirred at room temperature for 16 h. Water (100 mL) was then added and the solid collected by filtration and air-dried to give 2-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3): δ 1.19 (s, 3H), 1.20 (s, 3H), 4.35-4.38 (m, 1H), 6.63 (d, J=9.2 Hz, 2H), 7.24 (m, 2H), 7.35-7.38 (m, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.70-7.73 (m, 1H), 8.51 (bs, 1H), 8.68 (bs, 1H), MS: M/z=431.0 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
100.0 g (0.447 mol) 3-bromobenzoyl chloride was added to an ice cooled solution of 48.9 g (0.491 mol) N,O-dimethylhydroxylamine hydrochloride and 140.0 ml (1.00 mol) triethylamine in 650 ml dry dichloromethane over a period of 30 minutes. After additional stirring for 30 minutes, 370 ml water was added and the organic layer dried over sodium sulfate. Fractionated distillation in vacuo yielded 101.4 g (93%) B1, b.p. 114-129° C./0.07 mbar, as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)([CH3:18])=[O:17].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:17])[CH3:18])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 110 %

Procedure:
To a solution of 4-(4-Nitro-phenyl)-piperidin (206 mg, 1 mmol) in CH2Cl2 (3 mL) is added AcCl (0.106 mL, 1.5 mmol) at 0° C. Then Et3N (0.253 mL, 1.8 mmol) is added slowly. The mixture is stirred at 0° C. for 10 minutes. Then saturated NaHCO3 aqueous solution is added. The aqueous layer is extracted with CH2Cl2, and the organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=0.7:99.3 to 6:93) to give 273 mg of the title compound as yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22])=[O:4].[OH-].[Na+].[CH:25]([O:27][CH2:28][CH2:29][O:30][NH2:31])=[CH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C>[CH:25]([O:27][CH2:28][CH2:29][O:30][NH:31][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22])=[O:4])=[CH2:26]
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1Cl
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
To a solution of 8-(4-bromo-2-chloro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (271 mg, 0.71 mmol) in IMS (10 mL) was added a 1.0 M aqueous solution of sodium hydroxide (0.8 mL, 0.8 mmol). The reaction mixture was heated at 65° C. for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting residue was azeotroped with toluene, and then suspended in THF (10 mL). O-(2-Vinyloxy-ethyl)-hydroxylamine (89 mg, 0.87 mmol), N-N-diisopropylethylamine (0.30 mL, 1.73 mmol), EDCI (166 mg, 0.87 mmol) and HOBt (117 mg, 0.87 mmol) were then added sequentially before the reaction mixture was stirred 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and then brine. The isolated organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a pale yellow solid (210 mg, 65%). LCMS (method B): RT=3.17 min, [M+H]+=451/453.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCCC2
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCCC2
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
118 g (0.73 mole) of 5,6,7,8-tetrahydro-2-naphthol methyl ether are dissolved in 320 ml of methylene chloride, and 177 ml of chlorosulfonic acid in 160 ml of methylene chloride are added. The mixture is stirred for 10 minutes at 5° C. and is poured into ice water. The organic phase is separated off and dried with MgSO4. The solvent is removed by evaporation and the residue is recrystallized from acetone/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.C[C@H](NC)[C@@H](O)C1C=CC=CC=1.O.Cl>C(OCC)(=O)C.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: CN[C@@H](C)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
To a solution of racemic 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (described in Example 107) (100 g, 0.37 mol) in ethyl acetate (1.5 L) and methanol (75 mL) was added solid (1S, 2S)-(+)-pseudoephedrine (61.1 g, 0.37 mol). With efficient agitation the mixture was warmed to reflux, held at reflux for 30 min and slowly cooled to 25° C. After a minimum of 2 h the slurry was filtered and washed with ethyl acetate to yield enriched diastereomeric salt (88.6 g, 0.20 mol, 55%; diastereomeric ratio 80:20 as determined by HPLC). The enriched salt was slurried in 3% methanolic ethyl acetate (2.74 L), warmed to reflux, and held at reflux for 30 min. The slurry was cooled to 25° C. slowly, stirred for 2 h, filtered, and washed with ethyl acetate to provide additional enriched salt (70 g, 0.16 mol, 79%, diastereomeric ratio 95:5 as determined by HPLC) Treatment of the enriched salt with 5% methanolic ethyl acetate using the same procedure yielded highly enriched salt (60.0 g, 0.14 mol, 85%, diastereomeric ratio 99:1 as determined by HPLC). This salt (60 g, 0.14 mol) was added to water (1 L) and the resulting suspension acidified to pH 2-3 with concentrated hydrochloric acid (15 mL) and then extracted with diethyl ether (3×500 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to an oil. Hexane was added and reduced in vacuo to afford enantiomerically enriched acid (36 g, 0.13 mol, 98% recovery, enantiomeric ratio 99:1 as determined by HPLC) as a white solid. Crystallisation from a mixture of hexane (360 mL) and cyclohexane (720 mL) afforded enantiomerically pure (9S,10S)-2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid as a white solid (30 g, 0.11 mol, 81%) mp 172°-173° C. [α]D =+101° (c=2, CHCl3).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:32]=[CH:31][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([Cl:30])=[CH:17][N:16]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C>CCOCC>[N:7]1([C:10]2[CH:11]=[CH:12][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([Cl:30])=[CH:17][N:16]=3)=[CH:31][CH:32]=2)[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(Cl)c(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Solvent: CCOCC
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCNCC4)cc3)ncc2Cl)n1C(C)C

Procedure:
The title compound was prepared from 2-[4-(4-acetylpiperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-5-chloropyrimidine (Example 33; 800 mg) by the method of Example 20. Except that after purification by chromatography on neutral alumina, activity II eluting with MeOH:DCM (3:97) the title compound was isolated as a yellow gum. Trituration with ether gave a foam (50 mg 7%). NMR: 1.34 (d, 6H), 2.45 (s, 3H), 2.82 (m, 4H), 2.96 (m, 4H), 4.82 (septuplet, 1H), 6.85 (d, 2H), 7.41 (s, 1H), 7.42 (d, 2H), 8.49 (s, 1H), 9.43 (s, 1H); m/z 412.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][CH2:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:9]1=[O:28])(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[S:51][C:50]([S:52](Cl)(=[O:54])=[O:53])=[CH:49][CH:48]=1>ClCCl>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[CH2:11][CH2:12][C:13]([F:15])([F:16])[CH2:14][C@@H:8]([NH:7][S:52]([C:50]2[S:51][C:47]([Cl:46])=[CH:48][CH:49]=2)(=[O:54])=[O:53])[C:9]1=[O:28]
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)s3)C2=O)c(OC)c1

Procedure:
[(R)-1-(2,4-Dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (0.85 g, 1.85 mmol) was dissolved in 38 ml dichloromethane. 4 M HCl/1,4-dioxan (20 ml) were added dropwise and the mixture was allowed to react for 1 h. The reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To 291 mg of the resultant hydrochloride salt was added CH2Cl2 (20 ml) followed by the dropwise addition of Hünig's base (0.36 ml, 2.1 mmol). A solution of 5-chlorothiophene-2-sulfonyl chloride (0.21 g, 0.9 mmol) in CH2Cl2 (5 ml) was added and the reaction mixture (pH 8) was stirred for a further 1.5 h. The reaction mixture was purified over silica gel (heptane-ethylacetate, 95:5-0:100): white solid 0.40 g (97%);.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[O:5]
Reactant: CCNCC
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCN(CC)C(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diethylamine
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:40])[C:8]1[N:12]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:14]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:40][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][N:25]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:24][CH2:23]3)=[C:15]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:14]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCNCC3)c2n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
Methanesulfonyl chloride (0.08 mL, 1.03 mmol) was added dropwise to a mixture of the above amine (102 mg, 0.211 mmol) and powdered K2CO3 (263 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 5 hrs. Water was added, the phases were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent was removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-9H-purine (105 mg, 88%): mp 236-239° C.; 1H NMR (CDCl3) δ 7.84 (s, 1H), 7.76 (dd, J=8.4, 0.5 Hz, 1H), 7.42 (t, JHF=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.57 (tt, J=11.7, 4.4 Hz, 1H), 4.38 (br s, 4H), 4.09 (m, 2H), 4.06 (s, 3H), 3.88 (t, J=4.8 Hz, 4H), 2.96 (dt, J=12.5, 2.8 Hz, 2H), 2.88 (s, 3H), 2.35-2.20 (m, 4H); Anal. Calcd. for C24H28F2N8O4S: C, 51.2; H, 5.0; N, 19.9. Found: C, 51.0; H, 4.9; N, 19.7%.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[C:39]1[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=1>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][C:25]=1[C:39]1[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Temperature: 80 °C
Yield: 53.9 %

Procedure:
A stirred mixture of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (99.0 mg, 0.371 mmol), dried potassium phosphate (0.1581 g, 0.745 mmol) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (0.2402 g, 0.743 mmol) in anhydrous N,N-dimethylacetamide (2 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (22.1 mg, 0.0191 mmol) was then added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. under nitrogen for 6.5 h. The mixture was diluted with ethyl acetate and filtered through glass fibre paper, washing the solid with more ethyl acetate. The filtrates were washed with brine (15 ml), and the aqueous layer was extracted further with ethyl acetate (25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 30% EtOAc/isohexane) to give 76.6 mg (54%) of the title compound: mp 168-174° C. (CH2Cl2-EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.43 (1H, t, J 9.0 Hz), 7.57 (1H, td, J 7.8, 1.2 Hz), 7.60 (1H, d, J 7.8 Hz), 7.73 (1H, td, J 7.8, 1.3 Hz), 7.85 (1H, dd, J 7.7, 1.1 Hz), 8.16-8.23 (2H, m), 8.62 (1H, s), 8.81 (1H, s); MS (ES+) m/z 384 [M+H]+. Anal. Found: C, 58.31; H, 2.28; N, 17.74%. Required for C19H9F4N5.0.5H2O: C, 58.17; H, 2.57; N, 17.85%.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCn1cnc3ccccc31)CC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.50 g), benzimidazole (443 mg), and sodium carbonate (760 mg) in DMF (15 ml) was stirred at 70° C. for 8 hr. The reaction mixture was diluted with water and extracted with combined solution of ethyl acetate and THF. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo and the residue was diluted with diethylether and the resultant crystals were removed by filtration. The filtrate was concentrate in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=1:2) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (480 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([S:15]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=3[S:28](=[O:31])(=[O:30])[NH2:29])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)([N:34]1C=CN=C1)=O.N.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([S:15]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:34])=[O:24])=[CH:21][C:20]=3[S:28](=[O:31])(=[O:30])[NH2:29])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(NS(=O)(=O)c2cccc(-c3ccc(Cl)c(Cl)c3)c2)c(S(N)(=O)=O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a solution of 4-[[3-(3,4-dichlorophenyl)phenyl]sulfonylamino]-3-sulfamoylbenzoic acid (0.20 g, 0.39 mmol) in DMF (5 mL) was added carbonyldiimidazole (0.06 g, 0.39 mmol). The reaction mixture was heated at 80° C. for 2 h, then aqueous ammonia solution (30%, 2 mL) was added and the resulting solution was stirred at RT for 2 h. The pH of the reaction mixture was then adjusted to pH 5 using 6N HCl and the resulting white precipitate was collected by filtration. The crude product was purified by preparative HPLC to afford the title compound (13 mg, 7%).
Reaction SMILES: O=C1C(C[N:12]2[CH2:29][CH2:28][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]([CH3:26])[NH:17][C:16]3=[O:27])[CH2:14][CH2:13]2)CCC2NC3CCCC=3C1=2>C(O)C>[CH3:26][CH:18]1[NH:17][C:16](=[O:27])[C:15]2([CH2:14][CH2:13][NH:12][CH2:29][CH2:28]2)[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1NC(=O)C2(CCN(CC3CCc4[nH]c5c(c4C3=O)CCC5)CC2)N1c1ccccc1
Solvent: CCO
Product: CC1NC(=O)C2(CCNCC2)N1c1ccccc1

Procedure:
From 1.7 g of the product of Example 4 and 2.23 g of 2-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one in ethanol there was obtained 1.3 of 8-[(1,2,3,4,5,6,7,8-octahydro-8-oxocyclopent[b]indol-7-yl)methyl]-2-methyl-1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one, mp 234°-6° C.