Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[N:6]1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:29][C:15]([F:14])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH:7]=[N:6]3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCn1ncc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CCCn3ncc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
1-(3-chloropropyl)-1H-benzopyrazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoromethyl phenyl piperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 7.6 g compound (I-59) with a yield of 63.1%. ESI-MS [M+H]+: m/z 389.2.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OC(F)F)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 391.78 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3c2)cc1
Temperature: 85 °C
Yield: 7 %

Procedure:
Followed the coupling procedure described in Example 3, starting from 6-bromonaphthalen-2-ol and 4-boronobenzoic acid, where the reaction was heated at 85° C. for 8 h. After the prep-HPLC purification, a further purification by silica gel column (PE:EA=7:1 to 4:1) gave the compound as a yellow solid (26 mg, 7%). 1H NMR (DMSO-d6 500 MHz TMS): δ 12.97 (brs, 1H), 9.91 (brs, 1H), 8.19 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.87-7.92 (m, 3H), 7.80 (m, 2H), 7.13-7.16 (m, 2H); MS (ESI): m/z 265.1 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1.C1C=C([O:23]O)C(C(O)=O)=C(C(O)=O)C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1)=[O:23]
Reactant: CSc1cc(F)cc(C(=O)c2nccs2)c1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1cc(F)cc(C(=O)c2nccs2)c1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 144.4 %

Procedure:
To a solution of sulfide from Step 1 (0.76 g, 2.99 mmol) in MeOH (1.5 mL) and CH2Cl2 (6 mL) at 0° C. was added the magnesium salt of monoperoxyphthalic acid (1.11 g, 1.80 mmol). The mixture was stirred at 0° C. for 1.25 h and then sat. aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with H2O and dried over anhydrous MgSO4. Evaporation of the solvent and chromatography using toluene:EtOAc (25:75) gave 0.70 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][N:3]=1.[N+:13]([CH2:16][C:17](SC)=[S:18])([O-:15])=[O:14]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:17]([SH:18])=[CH:16][N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1
Reactant: CSC(=S)C[N+](=O)[O-]
Reactant: NCCNCc1ccc(Cl)nc1
Solvent: CO
Product: O=[N+]([O-])C=C(S)NCCNCc1ccc(Cl)nc1
Temperature: 50 °C
Yield: 38.6 %

Procedure:
N-(2-chloro-5-pyridylmethyl)ethylenediamine (2.0 g) and methyl 2-nitrodithioacetate (1.7 g) were dissolved in methanol (40 ml), and the solution was heated at 50° C. for 1 hour in a stream of nitrogen. The solution was cooled to room temperature whereupon crystals were precipitated. The crystals were collected by filtration, washed with a small amount of methanol, and then dried to give the desired N-(2-chloro-5-pyridylmethyl)-N'-(1-mercapto-2-nitrovinyl)ethylenediamine (1.2 g) having a melting point of 136° to 137° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH:32]5[CH2:37][CH2:36][C:35]6(OCC[O:38]6)[CH2:34][CH2:33]5)[CH3:31])=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:42]=2)=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:31])[CH:32]5[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:42]=2)=[CH:6][CH:7]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(Cl)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(Cl)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCC(=O)CC1
Reaction time: 168 h
Yield: 51.5 %

Procedure:
To a solution of 7-(4-chlorophenyl)-N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (180 mg) in THF (15 ml) was added at room temperature 3N hydrochloric acid (1 ml), and the mixture was stirred for 7 days. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless solid, which was recrystallized from ethyl acetate to give colorless crystals of 7-(4-chlorophenyl)-N-[4-[N-methyl-N-(4-oxocyclohexyl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 23) (85.9 mg).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.P(Cl)(Cl)(Cl)=O.C(OCC)C>C(Cl)(Cl)Cl.O>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:4][CH2:1][C:2]#[CH:3]
Reactant: C#CCO
Reactant: C1=COCCC1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C#CCOC1CCCCO1
Yield: 50 %

Procedure:
A solution of propargyl alcohol (5.6 g.) and dihydropyran (8.4 g.) in chloroform (16 ml.) was stirred in an ice-bath while a solution of phosphorus oxychloride (0.05 ml.) in chloroform (1 ml.) was added. After stirring for 2 hours at 10°-20° diethyl ether and water were added. The ethereal solution was separated and washed with water, saturated sodium carbonate solution and brine, dried over anhydrous magnesium sulphate and evaporated. Distillation yielded prop-2-ynyl tetrahydropyranyl ether (7.0 g., b.p. 68°-71°/25 mm).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]1([S:61](Cl)(=[O:63])=[O:62])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and benzenesulfonyl chloride as starting materials in 44% yield. LCMS for C30H31ClN7O3S (M+H)+: m/z=604.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:8][NH:7]1.Cl[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18].[OH-].[Na+]>O1CCCC1.O>[CH2:20]([O:19][C:17]([N:7]1[CH2:8][C@H:9]([O:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][C@H:6]1[CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:18])[CH:21]=[CH2:22]
Reactant: C=CCOC(=O)Cl
Reactant: CS(=O)(=O)O[C@H]1CN[C@H](COCCO)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCO

Procedure:
To a solution of (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (30.5 g) in a mixture of tetrahydrofuran (120 ml) and water (120 ml) was dropwise added a solution of allyl chloroformate (14.5 ml) in tetrahydrofuran (14.5 ml) under ice-cooling with stirring, keeping the pH between 9-10 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for one hour and extracted with ethyl acetate (200 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (400 g) and eluted with a mixture of methanol and dichloromethane (2:98 V/V) to give (2S,4R)-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (28.03 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:15][CH:16]([C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)[CH:17]([C:19]1[CH:34]=[CH:33][C:22]2[N:23]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:24](=[O:27])[N:25]([CH3:26])[C:21]=2[CH:20]=1)[OH:18].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.O>[CH:28]1([N:23]2[C:22]3[CH:33]=[CH:34][C:19]([CH:17]([OH:18])[CH:16]([NH:15][C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[C:35]4[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=4)=[CH:20][C:21]=3[N:25]([CH3:26])[C:24]2=[O:27])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1cccc(C(N)C(O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Reactant: COCCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCCC(=O)NC(c1cccc(C)c1)C(O)c1ccc2c(c1)n(C)c(=O)n2C1CCCC1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a stirred solution of 3-methoxypropionic acid (93.5 μL, 0.99 mmol) in methylene chloride (6 mL) and DMF (200 μL) was added oxalyl chloride (86.8 μL, 0.99 mmol). The resulting clear solution was stirred for 2 hours, then added via canula to a stirred solution of 5-(2-amino-1-hydroxy-2-m-tolyl-ethyl)-1-cyclopentyl-3-methyl-1,3-dihydro-benzoimidazol-2-one hydrochloride (400 mg, 0.99 mmol) and triethyl amine (306 μL) in methylene chloride (4 mL). After 1 hour, LCMS showed complete reaction. Water was added to the reaction mixture and the organic phase was separated and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 433 mg of the amide, which was used without further purification.
Reaction SMILES: [CH:1](/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O1CCCC1>[CH:1](/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:18][NH2:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:8][CH:7]=1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/c1ccc(C2(C#N)CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC/C=C/c1ccc(C2(CN)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a mixture of 1-(4-chlorophenyl)-1-cyclohexanecarbonitrile (100 mg, 0.455 mmol) and 1-pentenylboronic acid (104 mg, 0.910 mmol) in tetrahydrofuran (2 ml) and 1 M potassium carbonate (1.5 ml, 1.500 mmol) was added 1,1′-bis(di t-butylphosphino)ferrocene palladium dichloride (10 mg, 0.056 mmol). The mixture was microwaved at 100° C. in a sealed tube for 20 min, at which point LC/MS analysis showed a new peak. The reaction mixture was diluted with 10 mL of EtOAc and 10 mL of saturated aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with 10 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 100% hexanes followed by a gradient of 0 to 100% EtOAc in hexanes over 10 CV to provide the desired product 1-{4-[(1E)-pent-1-en-1-yl]phenyl}cyclohexanecarbonitrile (83 mg, 0.328 mmol, 72.0% yield). To a 0° C. solution of 1-{4-[(1E)-pent-1-en-1-yl]phenyl}cyclohexanecarbonitrile (75 mg, 0.296 mmol) in tetrahydrofuran (2 ml) was added 1.0 M lithium aluminum hydride in ether (1 ml, 1.000 mmol). The mixture was allowed to warm to room temperature and stirred at this temperature overnight, at which point LC/MS analysis showed complete disappearance of the starting nitrile. The mixture was recooled to 0° C. and quenched by dropwise addition of 30 μl of water, 30 μl of 15% NaOH, and 80 μl of water. The mixture was stirred for 30 min at room temperature, and then filtered, washing the solids liberally with ether. The filtrate was concentrated to provide the title compound (78 mg, 0.303 mmol, 102% yield). Mass spectrum (ESI) 258.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[N:48]([CH2:52][C:53]([C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][C:62]=1[F:68])([OH:60])[CH2:54][N:55]1[CH:59]=[N:58][CH:57]=[N:56]1)[N:47]=[CH:46]2>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([NH:42][C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[N:48]([CH2:52][C:53]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][C:62]=2[F:68])([OH:60])[CH2:54][N:55]2[CH:59]=[N:58][CH:57]=[N:56]2)[N:47]=[CH:46]3)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(Br)cc1
Reactant: Nc1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(Br)cc1)Nc1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Reaction time: 0.5 h

Procedure:
To a solution, of (E)-3-(4-bromophenyl)acrylic acid (0.034 g, 0.15 mmol) in tetrahydrofuran (1 ml) were added 1-hydroxybenzotriazole (0.023 g, 0.17 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.032 g, 0.17 mmol). Then triethylamine (0.045 ml, 0.32 mmol) was slowly added at 0° C., followed by stirring the reaction mixture for 30 min. After the addition of (5-Amino-1H-indazol-1-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.057 g, 0.15 mmol) and 4-N,N-dimethylaminopyridine (0.004 g, 0.03 mmol), stirring at room temperature for 2 hours and concentrated by evaporation in a vacuum condition. The crude product was purified by chromatography on silica gel to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:13]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:8][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:34]=[CH:33]1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][S:37]([C:35]3[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=3)(=[O:39])=[O:38])[CH:15]=2)[CH2:10][CH2:11][CH:12]1[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Ethyl 7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate hydrochloride (100 mg, 0.229 mmol) and DMAP (27.9 mg, 0.229 mmol) were dissolved in CH2Cl2 (15 ml) and 1-methyl-1H-imidazole-4-sulfonyl chloride (41.3 mg, 0.229 mmol) dissolved in CH2Cl2 (15 ml) was added. The reaction mixture was stirred over night at RT. After addition of H2O the phases were separated and the aqueous phase was extracted with CH2Cl2. The organic layer was washed with HCl (1N), NaHCO3 solution and NaCl solution, then dried on MgSO4 and the solvent was removed. To the residue EtOAc/diethylether (1:1) was added, stirred, and the precipitate was separated by filtration to obtain a brown solid of product (100 mg).
Reaction SMILES: I[C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(OC([N:20]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=O)(C)(C)C.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([S:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[NH:20][C:21]([C:2]2[C:3](=[O:12])[NH:4][C:5]4[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:22]3)(=[O:31])=[O:30])[CH2:33][CH2:34]1
Reactant: O=c1[nH]c2ccccc2cc1I
Reactant: CN1CCN(S(=O)(=O)c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)c2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Reaction time: 0.75 h

Procedure:
A solution of 3-iodo-1H-quinolin-2-one (1-3, 1.50 g, 5.53 mmol, 1 equiv), 1-(tert-butoxycarbonyl)-5-[(4-methylpiperazin-1-yl)sulfonyl]-1H-indol-2-ylboronic acid (1-10, 2.00 g, 4.72 mmol, 0.854 equiv), lithium chloride (0.704 g, 16.6 mmol, 3.00 equiv), tetrakis(triphenylphosphine)palladium (0.320 g, 0.277 mmol, 0.050 equiv), and aqueous sodium carbonate solution (2 M, 13.8 mL, 27.6 mmol, 5.00 equiv) in dioxane (50 mL) was heated at 90° C. for 1 hour. 1-(tert-Butoxycarbonyl)-5-[(4-methylpiperazin-1-yl)sulfonyl]-1H-indol-2-ylboronic acid (1-10, 2.00 g total, 4.72 mmol, 0.854 equiv) was then added in two equal portions to the reaction mixture with a 30 minute interval in between additions. Following the last addition, the mixture was heated for 30 minutes. The mixture was then partitioned between brine (150 mL) and EtOAc (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. A solution of the residue in dichloromethane (100 mL) was treated with trifluoroacetic acid (100 mL), and the resulting mixture was stirred for 45 minutes, then concentrated. The residue was purified by reverse-phase liquid chromotography (H2O/CH3CN gradient w/0.1% TFA present) to give 3-{5-[(4-methylpiperazin-1-yl)sulfonyl]-1H-indol-2-yl}quinolin-2(1H)one (1-11) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 12.15 (s, 1H), 8.62 (s, 1H), 8.04 (br s, 1H), 7.77 (m, 2H), 7.56 (t, 1H, J=7.6 Hz), 7.52 (s, 1H), 7.46 (d, 1H) J=8.5 Hz), 7.40 (d, 1H, J=8.1 Hz), 7.28 (t, 1H, J=7.6 Hz), 3.20–2.00 (br m, 11H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[Br:14][C:15]1[C:27]([OH:28])=[CH:26][C:18]2[O:19][C:20]([CH3:25])([CH3:24])[O:21][C:22](=[O:23])[C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:28][C:27]1[C:15]([Br:14])=[CH:16][C:17]2[C:22](=[O:23])[O:21][C:20]([CH3:24])([CH3:25])[O:19][C:18]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OC(=O)c2cc(Br)c(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2cc(Br)c(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzyl bromide (4.88 mL) was added to a DMF (50 mL) suspension of 6-bromo-7-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (9.34 g) and potassium carbonate (7.09 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained solid was washed with diethyl ether to obtain the title compound (9.95 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[C:27]1([CH:33]2[CH2:35][O:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.CCOCC>[C:27]1([CH:33]([OH:34])[CH2:35][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:3]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)([C:4]([F:6])([F:5])[F:7])[C:2]([F:25])([F:26])[F:1])[CH:19]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: COc1ccc(COC(c2cccc(O)c2)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(COC(c2cccc(OCC(O)c3ccccc3)c2)(C(F)(F)F)C(F)(F)F)cc1
Yield: 62.3 %

Procedure:
To 1 g (2.6 mmol) of 3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenol (example 5) in 8 mL of dioxane were added 1.0 mL (8.8 mmol) of 2-phenyl-oxirane. The reaction was split in 2 portions. To each of those was added 4.28 g (13.1 mmol) of Cs2CO3 and each reaction mixture was treated for 30 min at 130° C. in the microwave. The mixtures were combined and water and ether were added. The aqueous phase was extracted with ether and the combined organic phases were washed with brine and dried (Na2SO4). After evaporation of the solvent the crude products were separated by column chromatography to give 810 mg (62%) of rac 1-phenyl-2-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethanol as light yellow oil, MS: 500 (M)+, and 250 mg (19%) of rac 2-phenyl-2-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethanol as light yellow oil, MS: 500 (M)+.