Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>O1CCOCC1.[Pd]>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:44][CH:45]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1SC(Cc2ccc(OCCn3ccc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCn3ccc4ccccc43)cc2)S1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 2.05 g of 5-{4-[2-(Indol-1-yl)-ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 14) in 100 ml of dioxane was stirred in an atmosphere of hydrogen and in the presence of 3.1 g of 10% w/w palladium-on-charcoal, first at room temperature for 30 minutes, then at 60° C. for 2 hours and then at 80° C. for 3 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.06 g of the title compound, melting at 42.3°-44.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:7]2.[CH:28](=O)[CH3:29].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:12]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:28][CH3:29])[CH2:7][CH:8]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:9]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2N(Cc2ccccc2)C1=O
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1cccc2c1N(Cc1ccccc1)C(=O)C(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 8-amino-1-benzyl-1,2,3,4-tetrahydro-2-oxoquinolin-3-ylcarbamate (1.0 g) was dissolved in methanol (10 mL), and acetaldehyde (599 mg), acetic acid (10 mg), and sodium cyanoborohydride (171 mg) were sequentially added to the solution under cooling on ice. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure. The thus-recovered residue was dissolved in ethyl acetate, and the solution was sequentially washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, and solvent was evaporated under reduced pressure. The recovered residue was purified through silica gel column chromatography (ethyl acetate: n-hexane=1:3), whereby the title compound (600 mg) was yielded.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])=[O:3].[C:11]([O:15][C:16](=[O:44])[NH:17][C:18]([C:20]1[S:21][C:22]([S:42][CH3:43])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH2:41])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:44])[NH:17][C:18](=[NH:19])[C:20]1[S:21][C:22]([S:42][CH3:43])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)CCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Reaction time: 24 h
Yield: 86.3 %

Procedure:
4-Methanesulfonyl-butyryl chloride (0.333 g, 1.81 mmol) [example 209, step a] was added to a solution of {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.468 g, 0.905 mmol) [example 25, step c] and triethylamine (1.83 g, 18.1 mmol) in dichloromethane at room temperature. The reaction was stirred for 24 hours and then evaporated. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.520 g, 78%) as a solid. ESI-MS (m/z): Calcd. for C29H35N3O7S4: 665.14; found: 665.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:31][C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=O)[O:27]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 85.2 %

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) (245 mg, 0.75 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (190 mg, 0.825 mmol) according to the general procedure K. Obtained as a yellow oil (318 mg).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](C(C)(C)C)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:32]1[CH:37]=CC=C[CH:33]=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:33][CH2:32][CH3:37])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: CCCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M-15,1), 251(17), 250 (100), 163 (6), 121 (34), 114 (9), 107 (6), 90 (17), 78 (9), 77 (10), 71 (17).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:8][C:3]([CH3:9])([C:4]([F:6])([F:5])[F:7])[C:2]([F:10])([F:11])[F:1])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(C)(C(F)(F)F)C(F)(F)F
Yield: 74.8 %

Procedure:
7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows.
Reaction SMILES: [F:1]/[C:2](=[CH:5]\[CH2:6][CH3:7])/[CH:3]=[O:4].[Br-].[Mg+2].[CH:10]#[CH:11].[Br-].Cl>O1CCCC1>[OH:4][CH:3](/[C:2](/[F:1])=[CH:5]/[CH2:6][CH3:7])[C:10]#[CH:11]
Reactant: C#C
Reactant: CC/C=C(\F)C=O
Agent: Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: C#CC(O)/C(F)=C/CC
Reaction time: 0.5 h

Procedure:
After 13.0 g of (Z)-2-fluoro-2-pentenal was dissolved in 30 ml of dry tetrahydrofurane, a tetrahydrofurane solution of acetylene magnesium bromide (the molar amount of acetylene magnesium bromide was 1.5 times that of the said aldehyde) was added to the solution dropwise while it was cooled with ice and maintained at a temperature of 10° C. or below. The mixture was stirred for 30 minutes while being cooled with ice and then stirred at 20° C. for one hour. The reaction solution was poured into ice-cooled 5% dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was distilled under reduced pressure, thereby obtaining 9.5 g of the desired substance as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[N:21]2)[CH:10]=[C:11]([F:19])[C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]([N:20]2[CH:24]=[C:23]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[N:22]=[N:21]2)[CH:10]=[C:11]([F:19])[C:12]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: OCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (0.1 mL, 2.23 mmol) was added dropwise to a solution of [1-(3,5-difluoro-4-morpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-yl]-methanol (0.6 g, 2.02 mmol), obtained in Example 1, and Et3N (0.6 mL, 4.4 mmol) in CH2Cl2 (30 mL) at 0° C. After stirring for 45 min the reaction mixture was washed successively with water, aqueous NaHCO3 and brine and dried over sodium sulfate. Evaporation of volatiles left the title compound as oily liquid (0.7 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:13][NH2:14].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C1COCC1>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][CH3:13])=[O:5]
Reactant: Nc1c(C(=O)O)ccc(F)c1Br
Reactant: CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)c(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a slurry of 2-amino-3-bromo-4-fluorobenzoic acid (719; 0.690 g, 2.95 mmol) in 5 mL EtOAc was added methanamine (2.0 M in THF; Aldrich, St. Louis, Mo.; 5.90 mL, 11.79 mmol) to give a solution. 1-propanephosphonic acid cyclic anhydride 50 wt % in EtOAc (Matrix Scientific; 1.911 mL, 3.24 mmol) was added. The reaction became warm. The reaction was sealed and stirred rapidly at RT. After 30 min, additional methanamine 2.0 M in THF (Aldrich, St. Louis, Mo.; 5.90 mL, 11.79 mmol) was added. After 1 h, the reaction was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with sat'd NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-amino-3-bromo-4-fluoro-N-methylbenzamide (0.57 g, 2.30 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (1H, d, J=3.9 Hz), 7.57 (1H, dd, J=8.8, 6.3 Hz), 6.89 (2H, br. s.), 6.57 (1H, t, J=8.6 Hz), 2.74 (3H, d, J=4.5 Hz). MS (ESI, pos. ion) m/z: 246.9/248.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([O:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:7])([O-])=O>C(O)(=O)C.C1COCC1.[Pd]>[C:6]([O:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])(=[O:7])[C:5]1[C:4](=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:1]
Reactant: O=C(OCN1C(=O)c2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)OCN1C(=O)c2ccccc2C1=O

Procedure:
Phthalimidomethyl o-nitrobenzoate (10 g) dissolved in a mixture of 60 ml acetic acid and 150 ml THF was hydrogenated with 10% palladium on charcoal catalyst (0.5 g) in a Parr shaker apparatus for 1 hour. The solution was filtered and the filtrate concentrated in vacuo. The crystalline product precipirated and was filtered off yielding 7.0 g, m.p. 160°-162° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10]C2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)c(Nc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 56.6 %

Procedure:
To a stirred solution of 5-acetyl-2-chloro-phenylaniline (which was obtained in Example 22) (7.40 g, 43.5 mmol) in CH2Cl2 (200 mL) and pyridine (40 mL) at 0˜5° C. was added dropwise methanesulfonyl chloride (5.0 g, 43.6 mmol) in 50 mL of CH2Cl2. After 1 hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature for another hour. The solvents were removed and the residue was dissolved in CH2Cl2(500 mL). The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (6.1 g, 57%); 1H NMR (300 MHz, DMSO-d6) δ 2.58 (s, 3H), 3.08 (s, 3H), 7.69 (d, J=8.3 Hz, 1H), 7.83 (dd, J=8.3, 2.1 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 9.69 (s, 1H); MS (ES) m/z: 245.9 ((M−H)−, 100%); HRMS Calcd. for C9H11ClNO3S(MH+): 248.0148. Found: 248.0135.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=3)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: CCOC(=O)c1ccc(N2CCN(c3ccccc3)CC2)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 125.2 %

Procedure:
A mixture of 3.72 g (0.02 mol) of ethyl 6-chloronicotinate and 6.44 g (0.04 mol) of N-phenylpiperazine was stirred at 100° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was stirred with isopropanol. 7.8 g of a yellow solid were obtained.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:32]=[C:31](Cl)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>O1CCCC1>[Cl:22][C:23]1[N:32]=[C:31]([NH:14][CH2:13][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NCC1(c2ccccc2)CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of C-(1-phenyl-cyclohexyl)-methylamine (0.28 g; 1.48 mmol) in tetrahydrofuran (10 mL) at room temperature was treated with triethylamine (0.3 mL; 2.2 mmol) and 2,4-dichloro-quinazoline (0.32 g; 1.62 mmol). The reaction was stirred at room temperature 12 h at which time the solvent was removed by rotary evaporation. The crude residue was portioned between ethyl acetate and 10% aqueous HCl. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated. The product was recrystallized from methylene chloride to give (2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine as a white solid. LCMS m/z=352.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:22][CH3:23])[CH:9]=[CH:10][C:11]=2[S:13][CH2:14][CH:15](OCC)OCC)[C:6]([S:24][CH2:25][CH:26](OCC)OCC)=[CH:5][CH:4]=1.ClCCl>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:11]3[S:13][CH:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:22][CH3:23])[C:7]=2[C:6]2[S:24][CH:25]=[CH:26][C:5]=2[CH:4]=1
Reactant: CCOC(CSc1ccc(OC)c2c(SCC(OCC)OCC)ccc(OC)c12)OCC
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: COc1cc2ccsc2c2c(OC)cc3ccsc3c12
Temperature: 25 °C

Procedure:
Polyphosphoric acid (0.29 g) was solubilized in chlorobenzene (10.0 mL) and heated at reflux for 3 hours under nitrogen. A solution of compound 3 (0.225 g, 0.464 mmol) in chlorobenzene (3.0 mL) was added dropwise to the reaction mixture. The mixture was stirring was continued at reflux overnight. After the mixture was cooled down to room temperature, dichloromethane (100 mL) was added, and the mixture was washed with NaHCO3 (saturated, 2×50 mL) and brine (50 mL). The solution was dried over Na2SO4 and concentrated under vacuum. The residual was refluxed in isopropanol (30 mL) for 2 hours. After cooling down to room temperature, compound 4 was obtained by filtration as a pale yellow solid (120 mg, 86%). 1H NMR (500 MHz, CDCl3): δ 7.59 (d, J=5.5 Hz, 2H), 7.45 (d, J=5.5 Hz, 2H), 7.44 (s, 2H), 4.19 (s, 6H).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:39])=[O:40]
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-Methoxy-4-methylbenzenesulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (7.8 mg). MS m/z 373 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[O:2]1[CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH:1]1[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cc(C=O)cnc1C(=O)OC
Reactant: OCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2OCCCCO2)cnc1C(=O)OC
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 5-formyl-2,3-pyridinedicarboxylic acid, dimethyl ester, 5-dimethyl acetal (1.3 g, 0.0048 mol), a catalytic amount of p-toluenesulfonic acid, 1,4-butanediol and toluene is heated at reflux temperature for 2 hours and 30 minutes. The reaction mixture is cooled to room temperature, made basic with sodium bicarbonate and concentrated in vacuo to give a liquid. The liquid is partitioned between methylene chloride and 5% sodium bicarbonate solution. The layers are separated and the aqueous layer is extracted with methylene chloride, the combined methylene chloride extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (2:1 to 1:1) as eluant to give the title compound as a clear oil (0.88 g, 62%), identified by IR and NMR spectral analyses.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([Br:7])[CH:4]=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>CCOC(C)=O.CCCCCCC>[Br:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1cc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)On1cc(Br)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (89%, oil). HPLC-MS m/z=298.0 (M+1), Rt: 3.77 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCC#Cc1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C#CCBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A solution of 3-(4-fluorophenyl)prop-2-yn-1-ol (1 g, 6.80 mmol) in DCM (13.6 mL) under N2 was cooled in a ice bath at 0° C. 2.70 g (8.2 mmol, loading 3mmol/g) of triphenylphosphine polymer supported was then added followed by 2.70 g (8.2 mmol) of carbon tetrabromide. The reaction mixture was stirred 15 min at 0° C. and warmed to room temperature for 90 min. After filtration through celite, the solvent was evaporated under reduce pressure. The crude product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.44 g of 1-(3-bromoprop-1-ynyl)-4-fluorobenzene as a yellow oil (Yield: 99%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([CH3:9])[C:6](O[Si](C)(C)C)=[C:5](O[Si](C)(C)C)[CH:4]([CH3:20])[CH2:3]1.[ClH:21].Cl.[NH2:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[ClH:21].[ClH:21].[NH2:27][C:25]1[CH:24]=[N:23][C:6]2[CH:7]([CH3:9])[CH2:8][N:2]([CH3:1])[CH2:3][CH:4]([CH3:20])[C:5]=2[N:26]=1
Reactant: N=C(N)CN
Reactant: CC1CN(C)CC(C)C(O[Si](C)(C)C)=C1O[Si](C)(C)C
Agent: Cl
Product: CC1CN(C)CC(C)c2nc(N)cnc21

Procedure:
This compound was prepared analogous to Example 22 from 1,3(R,S),6(R,S)-trimethyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:37]([O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28])=[O:35])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc(CN2C(=O)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 101.7 %

Procedure:
A solution of 1-(3-hydroxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.13 g), ethyl bromoacetate (0.21 g), potassium carbonate (99 mg) and potassium iodide (catalytic amount) in acetonitrile (10 ml) was refluxed for 9 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-(3-ethoxycarbonylmethoxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.16 g).