Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13]C)=[O:11]>C1(C)C=CC=CC=1>[C:10]([O:12][CH3:13])(=[O:11])/[CH:15]=[CH:2]/[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCCC=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/CCCC(=O)OC
Yield: 48 %

Procedure:
A solution of methyl 5-oxopentanoate (1.9 g, 14.6 mmol) and (carboethoxymethylene) triphenylphosphorane (5.0 g, 14.9 mmol) in toluene (50 mL) was refluxed for 8 hours. Solvent was removed under vacuo and the crude was purified by flash chromatography on silica gel (eluant: AcOEt/hexane 2/8) to give 1.32 g (48% yield) as colorless oil of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20](Cl)(=[O:22])=[O:21])=[C:4]([O:24][CH3:25])[CH:3]=1.N1C=CC=CC=1.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20]([N:33]([CH3:32])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:22])=[O:21])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: CNc1ccccc1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzenesulfonyl chloride (100 mg, 0.24 mmol) in dichloromethane (3 mL), was added pyridine (0.04 mL, 0.48 mmol), followed by addition of N-methylaniline (0.05 mL, 0.48 mmol). The mixture was stirred at r.t. for 16 hrs, then poured into 1 N HCl solution (10 mL). The product was extracted with ethyl acetate and the organic layer was washed with 1N HCl and water, then was dried over MgSO4. Concentration gave 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-N-phenyl-benzenesulfonamide 15-1, (108 mg). MS: 482.0 (M+H)+; tR=8.76 min (method 2).
Reaction SMILES: [CH3:1][C:2]([CH:9]1[C:14]([CH3:16])([CH3:15])[CH:13]2[CH2:17][CH:10]1[CH2:11][CH2:12]2)([CH2:5][C:6]([CH3:8])=[CH2:7])[CH2:3][OH:4]>CCCCCCC>[CH3:7][C:6]1([CH3:8])[CH2:5][C:2]([CH3:1])([CH:9]2[C:14]([CH3:16])([CH3:15])[CH:13]3[CH2:17][CH:10]2[CH2:11][CH2:12]3)[CH2:3][O:4]1
Reactant: C=C(C)CC(C)(CO)C1C2CCC(C2)C1(C)C
Solvent: CCCCCCC
Product: CC1(C)CC(C)(C2C3CCC(C3)C2(C)C)CO1
Yield: 95.2 %

Procedure:
Similar to Example 4, 33.4 g of the alcohol from Example 52 at a purity of 96.8% (0.136 mole), 0.5 g of Amberlyst-15 and 150 ml of heptane were refluxed for 12 hours. After the usual work-up, 35.6 g of crude tetrahydrofuran was distilled to afford 31.8 g of purified product (98% yield). BP 75° C./0.08 mmHg; 1H-NMR (300 MHz), δ 1.01 (3H, s), 1.05 (3H, s), 1.21 (3H, s), 1.24 (3H, s), 1.31 (3H, s), 1.1-1.3 (2H, m), 1.35-2.05 (9H, m), 3.58 (2H, m); 13C-NMR (75 MHz), δ 23.67, 26.36, 26.63, 28.04, 29.24, 29.41, 32.22, 37.19, 41.65, 43.64, 48.23, 50.08, 58.60, 63.23, 77.49, 80.10; IR (Neat), 2980, 1460, 1370, 1060 cm-1 ; MS (m/e), 236 (M+), 221, 205, 193, 163, 149, 135, 125, 109, 43 (Base);
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][C:20](OC)=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][OH:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)CC1CCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of LAH (0.94 g, 24.69 mmol) in dry THF (100 mL) was added solution of compound 36 (3.0 g 12.34 mmol) in THF (40 mL) at 0° C. and stirred at rt for 16 hours. The reaction mixture was quenched with brine solution and filtered through a Celite® bed. The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM to provide liquid compound 37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-chloro-benzenesulfonyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (46%, colourless oil). HPLC-MS m/z=402.1(M+1), Rt: 4.65 min.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[N:26]4[CH:27]=[CH:28][N:29]=[C:25]4[CH:24]=[CH:23][CH:22]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Cl:39])C(=O)C1.O>C(O)C>[Cl:39][C:27]1[N:26]2[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:13])([F:12])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)=[CH:22][CH:23]=[CH:24][C:25]2=[N:29][CH:28]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4nccn34)no2)cc1C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCO
Product: CC(Oc1ccc(-c2nc(-c3cccc4ncc(Cl)n34)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (150 mg) in ethanol was added NCS (67 mg) at room temperature, followed by stirring at 80° C. for 15 hours. To the reaction solution was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25) to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (110.4 mg) as a white solid. To a solution of 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (100 mg) in methylene chloride (2 ml) was added dropwise 10 equivalents of 4M HCl/dioxane at room temperature. After stirring at room temperature as it was for 1 hour, it was concentrated under reduced pressure. It was powdered/washed with diisopropyl ether, and then collected by filtration to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine hydrochloride (102.6 mg) as a white solid.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[C:64]([O:69][CH2:70][CH3:71])(=[O:68])/[CH:65]=[CH:66]/[CH3:67].S([O-])([O-])=O.[Na+].[Na+]>O.C(O)(C)(C)C>[O:22]1[C@H:66]([CH3:67])[C@H:65]1[C:64]([O:69][CH2:70][CH3:71])=[O:68]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C/C(=O)OCC
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C
Temperature: 3 °C
Reaction time: 25 h
Yield: 50.4 %

Procedure:
AD-mix-β [Produced by ALDRICH company] (213 g) was added to a mixture of tert-butanol (760 ml) and water (760 ml). To the mixture was added methanesulfonamide (14.5 g). Under ice cooling, ethyl crotonate (17.4 g) was added, and the mixture was stirred for 5 hours at 0 to 6° C. and 25 hours at room temperature. Sodium sulfite (225 g) was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate (1 litter)for 22 hours by using liquid-liquid extraction apparatus. The ethyl acetate layer was taken, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether (300 ml), and insolubles were filtered off. The filtrate was concentrated under reduced pressure. To the residue was added 30% a solution of hydrogen bromide in acetic acid (125 ml), and the mixture was stirred for 1 hour at 45° C. After the mixture was cooled to room temperature, ethanol (280 ml) was added. The mixture was stirred for 21 hours at 45° C. and poured into a mixture of sodium hydrogencarbonate (168 g) and water (500 ml) under ice cooling with cautiously. The mixture was extracted five times with diethylether (200 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 ml). To the solution was added DBU (23.4 g). The mixture was stirred for 1 hour at room temperature, diluted with dichloromethane (300 ml) and washed with water (100 ml) and 0.5 N hydrochloric acid (200 ml). The aqueous layer was extracted twice with dichloromethane (50 ml). The dichloromethane layers were combined, and to the layer was added triethylamine (1 ml). The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to distillation under reduced pressure to give ethyl (2S,3R)-2,3-epoxybutanoate (10.0 g) as colorless liquid (Yield: 50%). Optical purity based on the analysis of HPLC of the product was 95% ee.
Reaction SMILES: [Cl:1]C1C(CC)=NC=C(CC)N=1.[CH:12]1([CH:15]2[NH:20][C:19](=O)[CH:18]([CH:22]3[CH2:24][CH2:23]3)[NH:17][C:16]2=O)[CH2:14][CH2:13]1>>[Cl:1][C:19]1[C:18]([CH:22]2[CH2:24][CH2:23]2)=[N:17][CH:16]=[C:15]([CH:12]2[CH2:14][CH2:13]2)[N:20]=1
Reactant: CCc1cnc(CC)c(Cl)n1
Reactant: O=C1NC(C2CC2)C(=O)NC1C1CC1
Product: Clc1nc(C2CC2)cnc1C1CC1

Procedure:
Following the procedure for the preparation of 3-chloro-2,5-diethylpyrazine but substituting 3,6-dicyclopropylpiperazine-2,5-dione and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 0.99–1.13, 1.94–2.03, 2.38–2.47; MS (ESI+) for C10H11N2 m/z 195 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[CH:27]/[C:28]([O:30]C)=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CCOCC>C1COCC1.CO>[CH:20]1([N:19]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)=[CH:16][C:17](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[N:18]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C(O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
To a solution of ester 2.3 (55 mg, 0.132 mmol) in 4.5 ml of THF/MeOH (8:1) was added 1N LiOH (2 ml), and the mixture was stirred for 24 h at rt. Concentration to remove solvent gave a residue that was taken Et2O and extracted with 0.1 N NaOH and H2O (2×). The combined aqueous extracts were acidified with concentrated HCl and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, dried (Na2SO4). The crude product was triturated with hexanes to afford 45.8 mg (86%) of acid 2.4. HRMS (ESI) calc'd for C25H27N2O3 403.1943; found 403.2019 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=16.1, 1H), 7.49–7.34 (m, 5H), 7.28 (d, J=8.8, 2H), 7.07 (d, J=8.8, 2H), 6.46 (s, 1H), 6.38 (d, J=15.7, 1H), 5.13 (s, 2H), 4.14–4.04 (m, 1H), 2.03–1.82 (m, 6H), 1.28–1.24 (m, 4H).
Reaction SMILES: Cl[CH2:2][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].[C:16]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:17]
Reactant: CC(C)C[C@H](CCl)NC(=O)OC(C)(C)C
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](COc1cccc(C#N)c1)NC(=O)OC(C)(C)C

Procedure:
2.35 g (9.97 mmol) of t-butyl (1R)-2-chloro-1-(2-methylpropyl)ethylcarbamate was reacted with 2.42 g (20.3 mmol)) of 3-cyanophenol and 2.72 g (19.7 mmol) of potassium carbonate in dimethylformamide. After the treatment in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:26])/[CH:21]=[CH:22]\[C:23]([OH:25])=[O:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: c1ccncc1
Product: O=C(O)/C=C\C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
A 15 ml portion of pyridine was added to 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine and 0.6 g of maleic anhydride. After stirring overnight, the solvents were removed on the rotary evaporator. The solid was taken up in about 400 ml of hot ethanol and the insoluble material filtered to give 0.33 g of 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(Z)-2-butenoic acid: mass spectrum (m/e): M+H 413, 415.
Reaction SMILES: C[C:2]1[C:3]([CH3:16])=[C:4]([C:7]([C:9]2SC=C(C)C=2C)=[O:8])[S:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:3]1[CH:2]=[CH:6][S:5][C:4]=1[C:7]([CH3:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(C(=O)c2scc(C)c2C)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1sccc1CBr
Reaction time: 4 h
Yield: 73 %

Procedure:
A mixture of methyl 3-methyl-2-thienylketone (14 g., 0.10 mole), N-bromosuccinimide (18 g., 0.10 mole), α,α-azobisisobutyronitrile (AIBN, 0.3 g.), and carbon tetrachloride (300 ml.) was heated cautiously to reflux under a nitrogen atmosphere. After stirring 4 hours at reflux, the mixture was cooled, filtered to remove succinimide, washed first with sodium bicarbonate solution, then with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated at reduced pressure to obtain a pale yellow solid which was recrystallized from hexane to obtain 16 g. (73%) of the desired product as colorless crystals, M.P. 62°-64° C. 1H--NMR (CDCl3), ppm. (δ): 7.5 (d, J=5, aromatic-H), 7.2 (d, J=5, aromatic-H), 4.9 (s, CH2Br) and 2.55 (s, CH3). This compound is a strong irritant.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:15](=[O:19])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCCCCc1ccccc1
Product: CCOP(=O)(CCCCc1ccccc1)OCC
Temperature: 185 °C
Yield: 84.1 %

Procedure:
A mixture of 4-phenylbutyl chloride (8.0 g, 47.5 mmole) and triethylphosphite (15.0 ml, 72 mmole) was heated at reflux (bath temperature 185° C.) under argon for 41.5 hours. Distillation of the mixture gave pure diethyl (4-phenylbutyl)phosphonate (10.8 g, 84%) as a colorless liquid, b.p. 152°-154° C. (1.0 mmHg). TLC (EtOAc) single spot Rf =0.55.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=O)[O:34][C:32](=[O:33])[C:31]2=[CH:37][CH:38]=1.O.CCCCCC>C1(C)C=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][N:1]2[C:35](=[O:34])[C:30]3=[CH:29][C:28]([Cl:27])=[CH:38][CH:37]=[C:31]3[C:32]2=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: O=C1c2ccc(Cl)cc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Yield: 75.5 %

Procedure:
A suspension of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (0.58 g, 1.7 mmol) and 4-chlorophthalic anhydride (0.31 g, 1.7 mmol) in toluene (10 mL) was refluxed for 3.5 hours using a Dean-Stark water separator. The reaction mixture was left standing for cooling at room temperatures, to which was added hexane. The resulting solid was collected by filtration, which was recrystallized from chloroform-hexane to give 0.66 g (yield 75%) of the titled compound, m.p. 237°-238° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[OH:11][CH2:12][C:13]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][O:11][CH2:12][C:13]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: Fc1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(F)cc(Br)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-fluorobenzene (0.8 g, 3.0 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.72 g, 2.5 mmol) were combined in dimethylformamide (8 mL) and cooled to 0° C. The reaction was treated with sodium hydride (120 mg, 4.98 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.2 g (84%). 1H-NMR (CDCl3, 500 MHz) δ 7.34-7.38 (m, 4H), 7.24-7.25 (m, 1H), 7.08-7.10 (m, 1H), 7.01 (s, 1H), 6.70-6.72 (m, 1H), 4.29 (s, 2H), 3.74-3.77 (m, 2H), 3.38 (s, 2H), 3.00-3.06 (m, 2H), 2.17-2.20 (m, 2H), 1.84-1.90 (m, 2H), 1.44 (s, 9H). Mass spec.: 501.32 (MNa)+.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.B(Cl)(Cl)Cl>ClCCl>[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([N:12]2[C:11]3[CH:10]=[C:9]([OH:8])[CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:27]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccnc(-n2c3ccccc3c3ccc(OCc4ccccc4)cc32)c1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(-n2c3ccccc3c3ccc(O)cc32)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(benzyloxy)-9-(4-tert-butylpyridin-2-yl)-9H-carbazole 9 (3.00 g, 7.38 mmol, 1.0 eq) and pentamethylbenzene (3.33 g, 22.14 mmol, 3.0 eq) in dichloromethane (74 mL) was cooled to −78° C. in a dry ice-acetone bath, then BCl3 (18.45 mL, 18.45 mmol, 1.0 M in dichloromethane) was added dropwise. After that, the mixture was stirred at −78° C. for 30 minutes, then quenched with methanol. The dry ice-acetone bath was removed and the mixture was warmed to room temperature. The pH of the solution was adjusted to about 6-7 using Et3N, then the solution was washed with saturated NaHCO3 solution until there was no gas to generate, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-3:1) first, then dichloromethane/methanol (10:1) as an eluent to obtain the desired product, 9-(4-tert-butylpyridin-2-yl)-9H-carbazol-2-ol 10, as a grey solid (2.27 g in 97% yield). 1H NMR (DMSO-d6, 400 MHz): δ 1.40 (s, 9H), 6.79 (dd, J=8.0, 2.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.25 (t, J=7.2 Hz, 1H), 7.32-7.36 (m, 1H), 7.50 (dd, J=5.6, 1.6 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 8.63 (d, J=5.6 Hz, 1H), 9.62 (s, 1H).
Reaction SMILES: [CH2:1]([C@@H:4]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][OH:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:6][CH2:5][C@@H:4]([CH2:1][CH:2]=[CH2:3])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:29])=[O:28]
Reactant: C=CC[C@H](CO)CCCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@@H](CCCCOCc1ccccc1)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (-)-2(R)-allyl-6-(benzyloxy)-hexan-1-ol (5.0 g, 20 mmol) in methylene chloride (85 ml) at 0° C. is added triethylamine (4.6 ml, 33 mmol) followed by methanesulfonyl chloride. The mixture is allowed to stir at 0° C. for 2 hours and then quenched using saturated sodium bicarbonate solution. The organic layer is separated, dried, filtered and evaporated to give (-)-2(R)-allyl-6-(benzyloxy)hexan-1-yl methanesulfonate (mesylate ester) which is used as is.
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCCC1.[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28]N=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C1(C)C=CC=CC=1>C(O)C>[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:10]1([C:16]([NH:18][C:19]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][CH:1]=3)=[CH:37][CH:38]=2)=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C(N=C=S)C1CCCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
1-Cyclohexanecarbonyl isothiocyanate was prepared using commercially available 1-cyclohexanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclohexanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 47%).