Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]3=[O:30])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(piperazin-1-yl)benzo[d]isothiazole (1.75 g, 8.0 mmol), N-(3-bromopropyl)-phthalimide (1.96 mmol, 7.3 mmol) and K2CO3 (2.21 g, 16.0 mol) in DMF (10 mL) was stirred at 80° C. for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to provide 2-(3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione as an intermediate (1.49 g, 3.67 mmol, 50%).
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][C:8](=[O:25])[C@H:9]([CH2:21][CH2:22]SC)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:6][O:7][C:8](=[O:25])[C@@H:9]1[CH2:21][CH2:22][CH2:2][N:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: COC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (1 ml) of the compound prepared in Example 7 (146 mg), were successively added dropwise at 0° C. in a nitrogen atmosphere benzyl bromide (0.114 ml, 0.96 mmol) and a tetrahydrofuran solution of tetrabutyl ammonium fluoride (0.48 ml, 0.48 mmol). The mixture was stirred for 1 hour at 0° C., poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The resulting reaction mixture was subjected to column chromatography on silica gel and eluted with a 1:1 mixture of ether and hexane to give the titled compound in an amount of 94 mg (yield, 75% based on the starting materials used in Example 7).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([O:1][CH2:2][C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)COc1cccc([N+](=O)[O-])c1C#N
Product: CC(=O)OCC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 231c from 2-(3-hydroxy-2,2-dimethylpropoxy)-6-nitrobenzonitrile (Example 233d) and acetyl chloride in 66% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.04 (s, 6H), 2.00 (s, 3H), 3.95 (s, 2H), 4.02 (s, 2H), 7.70-7.72 (m, 1H), 7.85-7.92 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>C(#N)C>[Cl:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=2)[N:24]=1
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: Clc1ncnc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
To a dry flask containing a magnetic stir bar and a nitrogen atmosphere was added 0.247 g (1.33 mmol) of 3-[(methylsulfonyl)methyl]aniline, 2 mL dry acetonitrile and 0.23 mL (1.3 mmol) of diisopropylethyl amine and resultant mixture cooled in an ice bath. To the cold solution was added a solution of 0.2 g (1.33 mmol) of 2,4-dichloro-1,3,5-triazine in 2.4 mL of dry acetonitrile over 1 min. The reaction mixture was stirred for ca. 16 hrs and 1 gram of silica gel was added. The mixture was concentrated in vacuo to dryness and applied to the top of column of silica gel and eluted with a 15–50% ethyl acetate/ dichloromethane gradient. The proper fractions were combined and concentrated in vacuo to give 0.28 g (70%) of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine as a white solid. HNMR: δ 10.83 (s, 1H), 8.64 (s, 1H), 7.63 (m, 2H), 7.4 (t, 1H), 7.25 (d, 1H), 4.48 (s, 2H), 2.94 (s, 3H); MS (ES+, m/z) 299, 301 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.C[Si]([C:14]#[CH:15])(C)C.C(N(CC)C(C)C)(C)C>[Cu]I.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.CN1CCCC1=O>[C:14]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[CH:15]
Reactant: Nc1ncc(F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cc(F)cnc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of 5-fluoro-3-iodo-pyridin-2-ylamine (751 mg, 3.16 mmol) described in Manufacturing Example 173-1-1, trimethylsilylacetylene (874 μL, 6.32 mmol), copper (I) iodide (60.2 mg, 0.32 mmol), N,N-diisopropylethylamine (1.07 mL, 6.32 mmol), and N-methylpyrrolidinone (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.16 mmol), which was stirred for 3 hours under nitrogen atmosphere at 70° C. This reaction solution was cooled to room temperature, and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography and then silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (129 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:28])[NH:14][C:15](=[O:27])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.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>[CH3:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:16]2[C:15](=[O:27])[NH:14][C:13](=[O:28])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:31]4[CH:32]=[CH:33][S:29][CH:30]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(Br)ccc34)C(=O)NC2=O)c2ccccc21
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(C2=C(c3cn(C)c4cc(-c5ccsc5)ccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Argon was bubbled through a solution of 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (160 mg, 0.37 mmol) in dioxane (15 mL) for 10 min. Tetrakis(triphenylphosphine)palladium (0) (8.5 mg, 0.007 mmol) and thiophene-3-boronic acid (52 mg, 0.41 mmol) and aqueous Na2CO3 (0.37 mL, 2M) were added. The mixture was refluxed for 2 h and more tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.01 mmol) was added. Refluxing was continued for 24 h. The mixture was cooled and evaporated. Chromatography of the residue over silica using 50% EtOAc in hexane gave 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophen-3-yl-1H-indol-3-yl)pyrrole-2,5-dione (117 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([C:28]([F:31])([F:30])[F:29])[C:22]([F:27])([F:26])[C:23](Cl)=[O:24].Cl>ClCCl>[F:26][C:22]([F:27])([C:21]([F:20])([F:32])[C:28]([F:29])([F:30])[F:31])[C:23]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6])=[O:24]
Reactant: N#CCc1ccccc1N
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCc1ccccc1NC(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 2-aminobenzylcyanide (15 g) [Rousseau et al., JACS 72, 3047 (1950)], diisopropylethylamine (16 g) and dichloromethane (400 mL) was cooled in an ice bath under a nitrogen atmosphere. Heptafluorobutyryl chloride (28.9 g) in dichloromethane (100 mL) was added dropwise and the reaction was left to warm gradually to room temperature overnight. A 10% aqueous HCl solution was added and the organic phase was separated and dried over MgSO4. After filtration and concentration with a rotary evaporator, the crude, orange oil (42 g) was purified by high pressure liquid chromatography to give 35.4 g of 2,2,3,3,4,4,4-heptafluoro-N-[2-(cyanomethyl)phenyl]butanamide as a white solid, m.p. 76°-79° C.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH:8][S:9]([OH:12])(=[O:11])=[O:10].[OH:13][OH:14]>>[OH:11][S:9]([OH:12])(=[O:10])=[O:8].[CH3:1][C:2]1([O:13][O:14][C:2]2([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(O)CCCC1
Reactant: OO
Agent: O=S(=O)(O)O
Product: CC1(OOC2(C)CCCC2)CCCC1
Reaction time: 2.5 h

Procedure:
A 250 ml tri-neck round bottom flask was equipped and a 50 ml addition funnel and the flask was cooled <0 C. 30 g of 1-methylcyclopentanol (0.3 M, 1 EQ) was added to the flask. 70% H2SO4 solution was prepared and cooled in an ice bath. The H2SO4 (12.71 ml, 0.91 M, 3 EQ) was added drop wise over 15 minutes and the reaction mixture was stirred for ˜2.5 hours in order to allow all the 1-methylcyclopentanol to dissolve. With the reaction stirring, 8.11 ml of H2O2 35% (wt) (0.24 M, 0.8 EQ) was added drop wise over 15 minutes. The reaction was left stirring overnight. The reaction mixture was transferred to a separation funnel and extracted three times with 50 ml of pentane each time. Organic layers were collected and the aqueous was set aside. The organic layers were extracted 3 times with 50 ml of 1N NaOH each time to remove excess acid. The organic layer was collected, dried and concentrated. The residue was purified by chromatography on a silica column using pentane as the mobile phase. The product fractions were concentrated to yield 973 mg of di(1-methyl-cyclopentyl)peroxide as a colorless oil. 13C-NMR (CDCl3) δ 24.43, 24.75, 37.13, 89.23
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[N:25]1([CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)O)[CH:29]=[CH:28][N:27]=[CH:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CO.C(Cl)Cl>[N:25]1([CH2:30][C@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: OC(Cn1ccnc1)c1ccccc1
Reactant: O=C1CCCc2c1ccc(O)c2CN1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CN1C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
To a slurry of 2-(2-Hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-isoindole-1,3-dione (862 mg, 2.68 mmol) in THF (17 mL) was added ®-2-imidazol-1-yl-1-phenyl-ethanol (606 mg, 3.22 mmol) and triphenylphospine (846 mg, 3.22 mmol). After 15 min, diethylazodicarboxylate (0.51 mL, 3.22 mmol) was added and the reaction became homogenous. The reaction was stirred for 2 days and concentrated to give a reddish-brown foam. Purification by chromatography (10-20% acetone/CH2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a light brown foam (1.15 g, 2.35 mmol, 87%). The structure was confirmed by NMR and mass spectrometry. MS m/z 492 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:15])([F:14])[C@H:11]([OH:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:13][C@H:11]([CH3:12])[C:10]([F:15])([F:14])[F:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: Fc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C[C@@H](Oc1ncccc1Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of 3-chloro-2-fluoropyridine (500 mg, 3.8 mmol) and (2R)-1,1,1-trifluoropropan-2-ol (75 wt % solution in TBME, 752 mg, 4.9 mmol) in DMSO (7 mL) was added Cs2CO3 (1.6 g, 4.9 mmol) at room temperature under N2. The resulting mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added another 500 mg of (2R)-1,1,1-trifluoropropan-2-ol and the mixture stirred at the same temperature for another 2.5 hours. The reaction mixture was cooled to room temperature, and partitioned between water and EtOAc. The organic phase was separated, washed with brine (2×30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as colourless oil. The crude product was purified by silica gel column chromatography eluting with 0-30% EtOAc in heptane to give the title compound (365 mg, 43%) as colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ncccc1B(O)O
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: COc1ncccc1-c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Yield: 93 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 93% yield, starting from 2-methoxypyridine-3-boronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate. The reaction mixture was irradiated in a microwave at 150° C. for 1 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (dd, 1 H), 7.25-7.34 (m, 9 H), 7.16-7.24 (m, 2 H), 7.04-7.14 (m, 2 H), 6.76 (d, 1 H), 6.68 (d, 1 H), 4.25-4.35 (m, 1 H), 4.05 (t, 1 H), 3.80 (s, 3 H), 3.55-3.70 (m, 4 H), 2.93-3.04 (m, 1 H), 2.55-2.84 (m, 1 H), 2.27-2.38 (m, 1 H); MS (ESI) m/z 437[M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH:19]1([CH2:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][CH:19]1[CH2:21][CH2:20]1)[CH3:29])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CN(CCCCN)CC1CC1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN(C)CC3CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and N1-(cyclopropylmethyl)-N1-methylbutane-1,4-diamine (Step 1), the title compound was obtained; MS (Found M+1=398). 1H NMR (CDCl3, 300 Hz): 8.05-7.94 (m, 3H), 7.40-7.36 (m, 1H), 7.26-7.23 (m, 2H), 3.93 (s, 3H), 3.75-3.71 (t, 2H, J=6 Hz), 2.48-2.43 (t, 2H, J=6 Hz), 2.29-2.22 (m, 5H), 1.85-1.78 (m, 2H), 1.76-1.65 (m, 2H), 0.87-0.85 (m, 1H), 0.50-0.45 (d, 2H, J=2.4 Hz), 0.09-0.05 (d, 2H, J=4.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:5]([O:7][CH3:8])=[O:6].CC1(C)[SiH2][SiH]=NC(C)(C)C1(C)C.[Na].[S:36]1[C:40]2[C:41]3[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=3[O:43][CH2:44][CH2:45][C:39]=2[CH:38]=[C:37]1[C:50](Cl)=[O:51]>C1COCC1>[Si:16]([O:15][CH2:14][CH2:13][N:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:1])[C:50]([C:37]1[S:36][C:40]2[C:41]3[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=3[O:43][CH2:44][CH2:45][C:39]=2[CH:38]=1)=[O:51])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: COC(=O)c1ccc(NCCO[Si](C)(C)C(C)(C)C)c(Cl)c1
Agent: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a soln. of methyl 3-chloro-4-(2-(tert-butyldimethylsilyloxy)ethylamino)benzoate (1.3 g 3.78 mmol) pretreated with 1M of sodium hexamethyldisilazine in THF (3.46 ml) in tetrahydrofuran (12.2 ml) was added at room temperature 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (1.00 g, 3.79 mmol) portion-wise. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the residue taken into ethyl acetate and washed with water, then saline and dried (Na2SO4) to give 1.37 grams of crude methyl 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate. MS: (ESI+)=572.1
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.[H-].[Na+]>C1COCC1>[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH:32][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:26][CH:25]=1
Reactant: NCCOCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: ICCCOCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CCOCCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1

Procedure:
To a solution of 1-iodo-3-(2-phenylethoxy)propane (0.566 g; 1.95 mmol) in dry THF (9 ml) is added 2-[4-(benzoxazol-2-yl)benzyloxy]ethylamine hydrochloride (0.59 g; 1.9 mmol). NaH (78 mg; 1.9 mmol) is then added at room temperature. The reaction mixture is heated at reflux for 30 minutes, then cooled, concentrated in vacuo, and the residue column chromatographed with 10% MeOH/CH2Cl2The product is dissolved in EtOH acidified with HCl/EtOH concentrated to a solid and recrystallized from CH2Cl2 /petroleum ether to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-3-(2-phenylethoxy)propanamine hydrochloride. (m.p. 134°-135° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]=O.[CH:14](=[O:17])[CH2:15][CH3:16].[Cl-].[Na+]>O.C(O)(=O)C.CO>[CH3:16][C:15](=[CH:5][CH:4]([CH3:3])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=[O:17]
Reactant: CC(C=O)Cc1ccccc1
Reactant: CCC=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C=O)=CC(C)Cc1ccccc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
Into a 2 L Morton flask equipped with a mechanical air stirrer, temperature probe, Nitrogen inlet, autojack, and cooling bath was placed methanol (350 mL) and NaOH (31.25 g, 0.78 mol) dissolved in water (93.75 mL). 2-Methyl-3-phenyl-propanal (100 g, 0.68 mol) was added to the resulting mixture with stirring at 20° C. Over a period of 5 hours at an exponentially decreasing rate, propionaldehyde (48.82 mL, 39.25 g, 0.68 mol) was added to the mixture via a syringe pump while maintaining the reaction temperature at 14-20° C. The following propionaldehyde addition rate profile was used: 0.179 mL/min for two hours; 0.162 mL/min for one hour; and 0.147 mL/min for two hours. The reaction mixture was stirred for an additional 20 min at 14-20 ° C. Acetic acid (47 mL) was then added to the reaction mass followed by 100 mL of a saturated aqueous solution of sodium chloride. The mixture was extracted with two 100 mL portions of MTBE. The organic layers were combined and washed with two 100 mL portions of a saturated aqueous solution of sodium bicarbonate solution then with a saturated aqueous solution of.sodium chloride, dried (MgSO4), filtered, and roto-evaporated to give 2, 4-dimethyl-5-phenylpent-2-enal as a yellow liquid isomeric mixture (118.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[C:43]4[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=4)[N:37]=[CH:36][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccnc4cc(Cl)ccc34)ccc2n1-c1ccc(OC(F)(F)F)cc1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (100 mg, 0.22 mmol; see step (b) Example 9), 4,7-dichloroquinoline (66 mg, 0.33 mmol), K2CO3 (60 mg, 0.43 mmol) and DMF (2 mL) was stirred at 100-110° C. for 3 h, cooled, diluted with H2O (20 mL) and extracted with Et2O (30 mL). The extract was washed with H2O, dried (Na2SO4, concentrated and purified by chromatography to give the title compound. Yield 48 mg (36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][C:22](O)=[O:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][CH2:22][OH:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Solvent: C1CCOC1
Solvent: CSC
Product: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OCCC2CCO
Temperature: 0 °C

Procedure:
To a solution of [7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-acetic acid (1.5 g, 4.28 mmol) in THF 40 ml) was added BH3 Me2S (0.41 ml, 4.32 mmol) at 0° C. The mixture was stirred in the ice bath for 30 minutes and then at room temperature overnight. The mixture was quenched with MeOH and the solvent was removed. The residue was dissolved in EtOAc, washed with brine, dried with MgSO4, filtered and concentrated to give 2-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-ethanol as a clear syrup: 1.35 g; MS: 337.2 (M+H)+, 378.2(M+CH3CN+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[Br:10]Br>[OH-].[Na+]>[Br:10][N:4]1[C:3]([CH2:2][Cl:1])([CH3:9])[CH2:7][O:6][C:5]1=[O:8]
Reactant: CC1(CCl)COC(=O)N1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Product: CC1(CCl)COC(=O)N1Br
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
A solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (2.70 g, 18.1 mmol) in 1.0 M NaOH (20 ml) was cooled to 0° C. Bromine (1.0 ml, 20 mmol) was added dropwise, and stirred for 30 min. The precipitate was filtered off to give the title compound (2.32 g, 10.2 mmol, 56%). 1H NMR (CDCl3, 400 MHz) δ 1.44 (s, 3H), 3.49 (d, J=12.0 Hz, 1H), 3.65 (d, J=12.0 Hz, 1H), 4.22 (d, J=8.8 Hz, 1H), 4.57 (d, J=8.4 Hz, 1H). LRMS (ESI/APCI): 228 [M+H]+.