Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]([OH:26])[CH:12]=3)=[CH:4][CH:3]=1.[CH2:27](O)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:16]3[C:11](=[C:12]([CH3:27])[C:13]([OH:26])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)COc3cc(O)ccc32)cc1
Product: COc1ccc(C2c3ccc(O)c(C)c3OCC2c2ccc(O)cc2)cc1

Procedure:
2.5 g of the product of step 8, 10% Pd/Al2O3 0.4 g and 50 ml of ethanol were combined in a 2-neck 100 ml round bottom flask. The reaction was hydrogenated at low pressure using standard conditions for 3 hours. The reaction was filtered through Celite to remove the catalyst, rinsed through with ethanol (100 ml). The filtrate was concentrated to ˜15 ml before being poured into chilled, stirred water (300 mL). A pale orange precipitate formed which then formed a brown oil. The mixture was then extracted with diethyl ether, the combined organic layers washed with water (3×100 ml), brine (1×100 ml), dried over anhydrous magnesium sulphate and filtered. The solvent was removed in vacuo to give red/brown oil. The product was recrystallised from diethyl ether (˜15 ml), to give brown solid which was rinsed with chilled diethyl ether to give off-white crystals. 4 crops of (IV), ˜1 g. The 1H NMR spectrum and numbering scheme being shown below.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: OC[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Reactant: N
Agent: O=C=O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](CO)C1
Temperature: 90 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of trans-[3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (172.6 mg, 0.475 mmol) in dioxane (3 mL) and iPrOH (3 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈2 mL, then the tube was sealed and heated to 90° C. overnight. The solvents were evaporated, water was added to the residue, and the pale yellow solid was filtered off and dried in vacuo to give the title compound as a pale yellow solid. The compound was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 2.41-2.52 (m, 2H), 2.52-2.64 (m, 3H), 3.83 (d, J=6.3 Hz, 2H), 5.30-5.40 (mc, 1H), 5.60 (brs, 2H), 7.29 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 345.1 (100) [MH+]. HPLC: tR=1.9 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCC.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[CH:25]=[CH:26][C:21]([OH:27])=[CH:22][CH:23]=2)[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(C(O)c2cccc3ccccc23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc(C(c2ccc(O)cc2)c2cccc3ccccc23)cc1
Reaction time: 3 h

Procedure:
A solution of compound (4-methoxyphenyl)-naphth-1-yl-carbinol of formula II (3.0 gm, 0.011 mol) and phenol (5.4 gm, 0.057 mol) in a mixture of anhydrous benzene and anhydrous hexane (40.0 ml), 1:1) was gradually added to a mixture of phenol (1.5 gm, 0.061 mol) and anhydrous aluminum chloride (1.5 gm, 0.011 mol) at 0° C. under stirring. After the addition was over, the stirring was continued at room temperature for 3 hrs, the reaction was decomposed by adding crushed ice with conc. HCl (0.5 ml) and extracted with ethyl acetate. The organic layer was washed with water, 5% NaOH, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel to yield the title compound of formula I. Yield 2.3 gm (59.3%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[N:23]1([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O.CCN(CC)CC>[N:23]1([C:28]2[CH:36]=[CH:35][C:31]([C:32]([N:3]3[CH2:8][CH2:7][CH:6]([NH:9][C:10]4[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=4)[CH2:5][CH2:4]3)=[O:33])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24]1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCNCC2)nc1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)c3ccc(-n4cccc4)cc3)CC2)nc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
To a suspension of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (500 mg) in DMF (5 ml) was added 4-(1H-pyrrol-1-yl)benzoic acid (309 mg), EDCI HCl (317 mg), HOBt (223 mg), Et3N (0.63 ml), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-[6-({1-[4-(1H-pyrrol-1-yl)benzoyl]-4-piperidyl}amino)-3-pyridyl]acrylate (686 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([C:17]2[S:18][C:19]([I:23])=[C:20]([CH3:22])[CH:21]=2)=[CH:8][S:9][C:10]=1[NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])=[O:5])C.[H-].[Na+]>C1COCC1.CN(C=O)C>[OH:5][C:4]1[C:6]2[C:7]([C:17]3[S:18][C:19]([I:23])=[C:20]([CH3:22])[CH:21]=3)=[CH:8][S:9][C:10]=2[NH:11][C:12](=[O:16])[C:13]=1[C:14]#[N:15]
Reactant: CCOC(=O)c1c(-c2cc(C)c(I)s2)csc1NC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)sc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To 5′-(2-Cyano-acetylamino)-5-iodo-4-methyl-[2,3′]bithiophenyl-4′-carboxylic acid ethyl ester (1.7 g, 3.7 mmol, Example 222 d) in THF : DMF (1:1, 18.5 ml) under N2 at 0° C. was added NaH (95%, 442 mg, 18.5 mmol). The suspension was allowed to warm to rt with stirring overnight. The reaction was quenched with H2O. The mixture was placed in a separatory funnel, overwhelmed with H2O and extracted with EtOAc. Most of the color is removed with this washing step. The aqueous layer was acidified with 6 M HCl and a solid ppt out which was collected by filtration to give 4-hydroxy-3-(5-iodo-4-methylthien-2-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (880 mg, 2.1 mmol, 58%); MS (ESI) m/z 415.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[F:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccccc1F
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4F)cc3CC[C@@H]12
Yield: 81.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-fluorophenylboronic acid (109 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 172 mg (82%) of the title compound as a foam. mp 142°-150°. FDMS: m/e=323. α[D]589 =+77.89 (c=0.69, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]2[S:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.C(N(C(C)C)CC)(C)C.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[CH:15]=[N:16][S:17][C:18]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:32]
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (328 mg, 0.79 mmol) and diisopropylethylamine (0.41 mL, 2.37 mmol) in DMF (2 mL) were added O-(2-vinyloxy-ethyl)-hydroxylamine (163 mg, 1.58 mmol), EDCI (303 mg, 1.58 mmol) and HOBt (213 mg, 1.58 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, and washed with water then a saturated aqueous solution of sodium hydrogen carbonate, then brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, TBME in cyclohexane) to afford the title compound as a yellow foam (194 mg, 49%). LCMS (method B): RT=3.99 min, [M+H]+=500.
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH:35][C:2](=[O:3])[CH3:1])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1ccc2nnc(Cl)n2n1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2nnc(Cl)n2n1
Reaction time: 6 h

Procedure:
0.11 cm3 of acetic anhyhdride is added to a mixture of 202 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine in 5 cm3 of pyridine at 0° C. The temperature is allowed to rise to 20° C. over 6 h, then 0.05 cm3 of acetic anhydride is again added and stirring is maintained for 24 h. The precipitate formed is spin-filter-dried and then washed with ethyl ether and pentane. This solid is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μM), elution being carried out with a gradient of dichloromethane/methanol of 100/0 to 90/10. 41 mg of N-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][NH2:31].C(O)C>CO>[C:1]1([S:7]([CH2:10][C:11]2[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:30][NH2:31])=[O:22])[CH2:16][CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1
Reactant: NN
Solvent: CCO
Solvent: CO
Product: NNC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{29} (1.16 g, 2.77 mmol, 1 equiv.), anhydrous hydrazine (0.26 mL, 8.32 mmol, 3 equiv.), ethanol (15.6 mL), methanol (10 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{29} (0.88 g, 79%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.10 (br s, 1H), 7.66 (dd, 2H, J=0.5, 8.0 Hz), 7.64-7.61 (m, 1H), 7.47 (t, 2H, J=8.0 Hz), 7.24 (dt, 1H, J=1.0, 7.5 Hz), 7.17-7.12 (m, 2H), 6.95 (d, 1H, J=7.5 Hz), 4.80 (s, 2H), 3.83 (br s, 2H), 3.40 (s, 2H), 3.04 (s, 2H), 2.47 (br s, 4H), 2.35 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 138.6, 138.0, 133.7, 132.6, 131.1, 128.9, 128.7, 128.5, 128.0, 127.5, 61.1, 60.5, 59.1, 53.6, 53.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[CH3:23])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3)c2cc1OC

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to quantitatively give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([OH:22])=O.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([Cl:25])=[O:22]
Reactant: O=S(Cl)Cl
Reactant: CC1(C2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(CC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
To a solution of (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid (21.8 g., 0.0623 mole) in chloroform (150 ml) and dimethylformamide (1 drop) is added thionyl chloride (25 ml). The reaction mixture is heated at reflux for 3 hours, cooled and concentrated at reduced pressure. The crude (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetyl chloride, thus obtained, is dissolved in methylene chloride (75 ml) and added over 0.5 hour to a mixture of ether (100) ml) and methylene chloride (75 ml) which has been saturated with ammonia.
Reaction SMILES: C(O[CH:5]([C:9]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]2[C:10]=1[CH2:11][N:12]([CH3:27])[C:13]2=[O:26])[CH2:6][CH:7]=[CH2:8])(=O)C.[Br-].[Br-].[Br-].[In+3].[CH2:32]([Si](C)(C)C)[CH:33]=[CH2:34]>C(Cl)Cl>[CH2:8]=[CH:7][CH2:6][CH:5]([C:9]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[C:14]2[C:10]=1[CH2:11][N:12]([CH3:27])[C:13]2=[O:26])[CH2:34][CH:33]=[CH2:32]
Reactant: C=CC[Si](C)(C)C
Reactant: C=CCC(OC(C)=O)c1ccc(NC(=O)OC(C)(C)C)c2c1CN(C)C2=O
Agent: [Br-]
Agent: [In+3]
Solvent: ClCCl
Product: C=CCC(CC=C)c1ccc(NC(=O)OC(C)(C)C)c2c1CN(C)C2=O

Procedure:
To a solution of 1-{7-[(tert-butoxycarbonyl)amino]-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl}but-3-en-1-yl acetate (Compound 243E, 895 mg, 2.39 mmol) in DCM (30 mL) were added indium tribromide (85 mg, 0.24 mmol), followed by the addition of allyltrimethylsilane (550 mg, 4.8 mmol) in DCM (0.5 mL). The resulting mixture was refluxed under nitrogen overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 10-50% EtOAc/Heptane) to give the desired product as a white solid, 180 mg. The unreacted starting material was recovered and resubjected to the reaction using 2.0 eq. allyltrimethylsilane and 0.2 eq. InBr3. The mixture was refluxed overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 10-50% EtOAc/Heptane) to give the desired product as a white solid, 125 mg. Totally 305 mg, 36% yield. 1H NMR (CDCl3): 1.53 (s, 9H), 2.34-2.47 (m, 4H), 2.67 (m, 1H), 3.16 (s, 3H), 4.27 (s, 2H), 4.92-4.99 (m, 4H), 5.55-5.64 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 9.52 (br s, 1H). MS (ES+): m/z=379.13 [MNa+]. HPLC: tR=4.83 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][S:2]SC.[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([S:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([S:11](=[O:13])([S:2][CH3:1])=[O:12])=[CH:7][CH:6]=1
Reactant: CSSC
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 229.3 %

Procedure:
In accordance with the method described in the literature (Synthesis 2002, 343), into a solution (12 mL) of 400 mg (4.25 mmoL) of dimethyl disulfide in methylene chloride were added 2.42 g (13.6 mmoL) of sodium p-toluenesulfinate and 2.16 g (8.50 mmoL) of iodine, followed by stirring at room temperature for 1 hour. The reaction solution was diluted with methylene chloride (12 mL), and a 1 M aqueous sodium thiosulfate solution was added thereto until the iodine color disappeared. The organic layer was washed with water (10 mL), dried over anhydrous magnesium sulfate, and filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1.97 g of the heading compound as a colorless powdery substance (yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[C:28]1([N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:40][CH:37]2[CH2:38][CH2:39][N:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:35][CH2:36]2)=[CH:4][CH:3]=1
Reactant: NC1CCN(c2ccccc2)CC1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Oc1cc(NC2CCN(c3ccccc3)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-phenylpiperidin-4-amine (86 mg, 0.49 mmol, 1.49 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[(1-phenylpiperidin-4-yl)amino]quinolin-2-ol as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=1.[Na].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CN(C=O)C>[N:28]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:26]=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCn2cncn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2.16 g ethyl 6-[p-(5-bromopentyloxy]-phenoxy)-2,2-dimethylhexanoate in 10 ml DMF, was added with stirring 0.55 g sodium salt of 1,2,4-triazole at room temperature, and stiring was continued overnight. DMF was distilled off under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water, dried and concentrated. The crude product thus obtained was purified by silica gel column chromatography, affording 1.21 g of ethyl 6-[p-[5-(1,2,4-triazol-1-yl)pentyloxy]phenoxy]-2,2-dimethylhexanoate.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[OH-].[Na+]>CO>[NH:1]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 96.9 %

Procedure:
Boc-IleGly-OEt (17.4 g, 55.5 mmole) was dissolved in methanol (60 ml), and 2N NaOH (33 ml, 66.6 mmole) was added dropwise thereto while cooling and stirring. The cooling bath was removed, and the solution was stirred for 1 hour at about 15° C. and then neutralized with 6N HCl. Methanol was distilled off, and the solution was adjusted to pH~2 and extracted with ethyl acetate. The thus-obtained ethyl acetate layer was washed with water and dried with MgSO4. Ethyl acetate was distilled off therefrom,, and the thus-obtained oily residue was crystalized with ethyl acetate/n-hexane to give the object product (15.5 g, 98%).