Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=O.[Br-].[CH3:18][O:19][C:20]([C:22]1[CH:47]=[CH:46][C:25]([CH2:26][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:24][CH:23]=1)=[O:21].[O-][CH2:49]C.[Li+]>CCO>[CH2:18]([O:19][C:20](=[O:21])[C:22]1[CH:47]=[CH:46][C:25]([CH:26]=[CH:8][C:7]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][O:15][CH3:16])=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=2)=[CH:24][CH:23]=1)[CH3:49]
Reactant: CC[O-]
Reactant: COCOc1ccc(C=O)cc1OCOC
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)c1ccc(C=Cc2ccc(OCOC)c(OCOC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a mixture of 3,4-bis-methoxymethoxy-benzaldehyde (100 mmol) and (4-methoxycarbonyl-benzyl)-triphenyl-phosphonium bromide (100 mmol) in of EtOH (300 mL) at 0° C. was added slowly of a lithium ethoxide solution (101 mL, 1 M in EtOH). Upon the completion of the addition, the cold bath was removed and the reaction was allowed to warm to room temperature. The stirring was continued for additional 2 h. The solvent was then removed by rotary evaporation and residue was taken up to 500 mL of EtOAc and washed with ammonium chloride solution (2×100 mL) and water. The organic layer was dried over Na2SO4 and the crude product was purified on silica (hexane:EtOAc=2:1) to afford a clear sticky solid (yield 99%). NMR indicated the purified product is a mixture of cis/trans isomers containing ethyl and methyl esters. 1H-NMR (300 MHz, CDCl3) δ 8.02 (d, J=0.84, 1.5H), 7.93 (d, J=0.84, 0.5H), 7.91 (s, 0.3H), 7.55 (s, 0.75H), 7.52 (s, 0.75H), 7.38-7.33 (m, 1.25H), 7.17-7.12 (m, 2.25H), 7.03-6.98 (m, 1.25H), 6.84 (m, 0.25H), 6.61-6.52 (m, 0.5H), 5.29-5.05 (m, 4H), 4.41-4.25 (m, 1H), 3.90 (s, 1.5H), 3.56-3.39 (m, 6H), 1.40 (q, J=6 Hz, 1.5H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:4]=[N:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cnc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
3-(bromomethyl)quinoline, 6-methyl-2-sulfanylpyrimidin-4-ol (853 mg, 6 mmol) and triethylamine (1 mL, 7 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (1.7 g, 99% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.54 (s, 2H), 6.01 (s, 1H), 7.58 (m, 1H), 7.70 (m, 1H), 7.94 (m, 2H), 8.35 (s, 1H), 8.96 (s, 1H); M+ 284.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]1([CH3:23])[CH:17]=[CH:16][C:15]([S:18]([O:21]C)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:23])[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH3:12][N+:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][C:3]=1[S:2][CH3:1]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nc2ccccc2s1
Product: CSc1sc2ccccc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
In the first step, 2-methylthiobenzothiazole (Aldrich Chemical Company, Milwaukee, Wis.) is quaternized by heating at 120° C. with an equivalent of methyl p-toluenesulfonate to yield N-methyl-2-methylthiobenzothiazolium p-toluenesulfonate (Compound 1A is also commercially available from TCI, Portland, Oreg.). N-(3-iodopropyl)-4-methylpyridinium iodide (Compound 1 B) is prepared by heating 4-methylpyridine (1.00 g) with 5 mL of 1,3-diiodopropane without a solvent at 120° C. for about 1 hour. Ethyl acetate is added and the product is filtered. Compounds 1A and 1B are condensed to yield 1'-(3'-iodopropyl)-3-methyl-4'-thiacyanine iodide (Compound 1C) using methods known in the art [e.g. Brooker, et al. J. AM. CHEM. SOC. 64, 199 (1942)]. For instance when 2.93 g of 1A is stirred with 3.3 g of 1 B with the addition of 1.15 mL of triethylamine in 20 mL of CH2Cl2 for 16 hours at room temperature followed by the addition of 80 mL of ethyl acetate about 1.1 g of 1 C is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][CH2:25][C:26](=[O:28])[CH3:27].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(O)(=O)C>[O:28]=[C:26]([CH3:27])[CH2:25][NH:24][C:20](=[O:22])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CNC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
t-Butyloxycarbonyl-p-nitrophenylalanine (4.42 g, 14.26 mmol, aminoacetone hydrochloride (1.56 g, 14.26 mmol), triethylamine (1.44 g, 14.26 mmol), 1-hydroxybenzotriazole (1.69 g, 12.55 mmol), were dissolved in ethyl acetate (400 ml). 1,3-Dicyclohexylcarbodiimide (3.23 g, 15.68 mmol) in ethyl acetate (25 ml) was added and the solution allowed to stir for 18 hours. Glacial acetic acid (0.2 ml) was added and the solution was filtered. The filtrate was extracted with saturated salt solution (100 ml), 1N HCl solution (3×100 ml), saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml). The organic phase was dried over MgSO4, filtered and concentrated to 50 ml. Petroleum ether (50 ml) was added and the solution was cooled to 0° C. for 12 hours. The precipitated product was collected and dried under vacuum.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:38](O)=[O:39])=[CH:24][C:25]=3[N:26]3[CH2:32][CH:31]([OH:33])[CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:41][N:42]([CH3:47])[S:43]([NH2:46])(=[O:45])=[O:44]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:38]([NH:46][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])=[O:39])=[CH:24][C:25]=3[N:26]3[CH2:32][CH:31]([OH:33])[CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=4[C:27]=23)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.5 mg, 0.06 mmol) was added to a solution of (±)13-cyclohexyl-6,7-dihydro-6-hydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (7.5 mg, 0.02 mmol) and DMAP(7.4 mg, 0.06 mmol) in DMF (0.5 mL) and CH2Cl2 (0.5 mL) at 22° C. The vial was shaken for a minute at 22° C. N,N-Dimethylsulfamide (4.9 mg, 0.04 mmol) was then added. Stirring was continued for 18 hr. The solution was filtered and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white film (3.0 mg, 30%). ESI-MS m/z 482 (MH+); 1H NMR (500 MHz, MeOD) δ 1.26–1.34 (m, 1 H) 1.40–1.55 (m, 2 H) 1.63 (m, 1 H) 1.82 (m, 2 H) 1.96 (m, 1 H) 2.01–2.19 (m, 3 H) 2.36 (m, 1 H) 2.95–3.08 (m, 2 H) 3.03 (s, 6 H) 3.76 (dd, J=15.26, 3.36 Hz, 1 H) 4.41–4.69 (m, 2 H) 7.40–7.50 (m, 4 H) 7.60 (m, 1 H) 7.93 (m, 1 H) 8.11 (m, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@@H:13]([NH2:14])[CH2:12][CH2:11][CH2:10][C:9]1([F:16])[F:15])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>ClCCl>[F:21][C:20]([F:23])([F:22])[C:18]([O-:24])=[O:19].[F:21][C:20]([F:23])([F:22])[C:18]([O-:24])=[O:19].[F:15][C:9]1([F:16])[CH2:10][CH2:11][CH2:12][C@H:13]([NH3+:14])[C@H:8]1[NH3+:7]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@@H](N)CCCC1(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+][C@@H]1[C@@H]([NH3+])CCCC1(F)F
Reaction time: 8 h

Procedure:
A mixture of tert-butyl[(1R,6S)-6-amino-2,2-difluorocyclohexyl]carbamate (5 g, 19.98 mmol) and TFA (6.16 mL, 80 mmol) in dichloromethane (50 mL) was left to stir overnight, and concentrated to afford the title compound as a brown oil. 19F NMR (CDCl3, 564 MHz) −81.07 (s, 6F); −99.7-−100.1 (d, 1F); −111.1-−111.5 (d, 1F).
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])[CH3:3].CC([O-])(C)C.[K+].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][Cl:29]>CS(C)=O>[ClH:29].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[CH:4]([N:2]([CH3:1])[CH3:3])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccc(CCl)c1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)C(c1ccccc1)C1CCCCC1OCc1cccc(F)c1
Product: Cl
Temperature: 100 °C
Yield: 16.8 %

Procedure:
1.00 g (4.29 mmole) of the 2-(dimethylaminophenyl-methyl)cyclohexanol prepared according to Example 1 (3rd stage) were dissolved in 5 ml dimethylsulfoxide, analytical grade, and 503 mg (4.48 mmole) potassium tert-butylate were added at 50° C. The mixture was then heated to 100° C. and 323 μl (2.61 mmole) 3-fluorobenzyl chloride were added. This addition was repeated twice more after in each case two hours, and the reaction mixture was then heated at 100° C. for a further 15 hours. Working up was carried out according to Example 1 (4th stage), as a result of which 166 mg {[2-(3-fluorobenzyloxy)cyclohexyl]phenylmethyl}-dimethylamine hydrochloride (11% of theoretical), which decomposes from 203° C. on heating, were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)([Cl:19])=O.Cl>C(Cl)(Cl)Cl>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:19])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A mixture of 3-pyridinesulfonic acid (50.0 g), phosphorus pentachloride (80.0 g) and phosphorus oxychloride (100 mL) was stirred at 120° C. for 8 hr. Under a nitrogen atmosphere, the mixture was cooled to room temperature, and chloroform (dehydrated, 330 mL) was added. Hydrogen chloride was blown in, and the precipitated crystals were collected by filtration and washed with chloroform (dehydrated) to give the title compound as a white solid (yield 54.7 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.NN>CCO>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(I)ccc1Cl
Agent: NN
Solvent: CCO
Product: Cl
Product: NCc1cc(I)ccc1Cl
Yield: 149.5 %

Procedure:
Compound 63 (350 mg, 0.88 mmol) was dissolved in dry EtOH (15 mL) and hydrazine (0.1 mL) was added. The stirred mixture was refluxed for 24 h, cooled and the EtOH evaporated. The residue was dissolved in Et2O (3 mL) and treated with HCl/Et2O. The precipitated hydrochloride salt was filtered and triturated with dry Et2O (3×2 mL), obtaining 200 mg of product (yield 75%). 1H NMR (D2O, 300 MHz) δ 7.88 (s, 1H), 7.80 (dd, J=8.4, 1.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 4.27 (s, 2H). MS (m/e) (positive FAB) 268.1 (M−Cl)+, m.p. 207-210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(N2Cc3c(NCc4ccco4)cccc3C2=O)C(=O)N1
Reaction time: 24 h
Yield: 29.5 %

Procedure:
To a stirred suspension of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.52 g, 2.0 mmol) in methanol (50 ml) was added furan-2-carbaldehyde (0.200 g, 2.05 mmol). The mixture was heated to reflux for 4 hours. The solvent was evaporated in vacuo and the residue was dissolved in acetic acid (20 ml). Sodium triacetoxyborohydride (0.450 g, 2.05 mmol) was added to the reaction mixture. The reaction mixture was stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×100 ml), saturated aqueous NaHCO3 (2×100 ml), brine (1×100 ml), and dried over MgSO4. The solvent was evaporated in vacuo and the residue was partially purified by chromatography (100% ethyl acetate) to give an off-white solid which was recrystallized from ethanol to give 0.20 g of product as a white solid: mp 248-250° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 7.57 (s, 1H), 7.27 (t, J=7.6 Hz, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.36 (d, J=11.2 Hz, 2H), 6.22 (t, J=5.4 Hz, 1H), 5.12 (dd, J=4.9 and 13.1 Hz, 1H), 4.37 (d, J=5.5 Hz, 2H), 4.27 (d, J=17.2 Hz, 1H), 4.14 (d, J=17.2 Hz, 1H) 3.00-2.86 (m, 1H), 2.65-2.59 (m, 1H), 2.37-2.23 (m, 1H), 2.08-1.99 (m, 1H); 3C NMR (DMSO-d6) δ 172.83, 171.16, 168.70, 152.82, 143.06, 142.00, 132.09, 129.02, 126.76, 112.35, 110.63, 110.33, 107.08, 51.50, 45.73, 31.20, 22.75; Anal. Calcd. For C18H17N3O4: C, 63.71; H, 5.05; N, 12.38. Found: C, 63.41; H, 5.03; N, 11.98.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:60][C:61]1[S:62][CH:63]=[CH:64][N:65]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[C:8]([NH:60][C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Yield: 58.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid (170 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 4 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-N-thiazol-2-yl-propionamide (123 mg, 58.3%) as a white solid: mp 172-173° C.; EI-HRMS m/e calcd for C25H30N2O2S (M+) 422.2028, found 422.2023.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:42])[NH:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[C:21]([C:23]5[N:28]=[CH:27][C:26]([CH2:29][N:30]([CH2:38][CH2:39][O:40][CH3:41])C(=O)OC(C)(C)C)=[CH:25][CH:24]=5)[S:22][C:15]=34)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[C:21]([C:23]5[CH:24]=[CH:25][C:26]([CH2:29][NH:30][CH2:38][CH2:39][O:40][CH3:41])=[CH:27][N:28]=5)[S:22][C:15]=34)=[CH:11][N:12]=2)=[O:42])[CH2:2][CH2:3]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1
Yield: 57.8 %

Procedure:
A solution of 28 (754 mg, 1.27 mmol) and TFA (5 mL) in DCM (25 mL) was stirred at RT for 5.5 hr. The TFA was removed by co-evaporation with DCM, dissolved in a minimum of methanol, diluted with water, and the pH was adjusted to around 13 with 1N NaOH. The resulting sticky suspension was extracted with DCM in the presence of traces of methanol. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by Biotage (SiliaSep 40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 10/90 over 20 CV) to produce a material that upon trituration with MeOH afforded the title compound 29 (360 mg, 0.734 mmol, 67% yield over 2 steps) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.23 (bs, 1H), 8.56 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.27-8.20 (m, 2H), 7.89 (dd, J=8.2, 2.2 Hz, 1H), 7.79-7.72 (m, 2H), 7.66 (bd, J=9.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J=5.9 Hz, 2H), 3.24 (s, 3H), 2.68-2.57 (m, 3H), 0.74-0.60 (m, 2H), 0.52-0.39 (m, 2H), one NH is missing. MS (m/z): 491.6 (M±H).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1>>[ClH:1].[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29][CH2:28]2)[CH2:23][CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN1CCC(C2CCNCC2)CC1
Product: CN1CCC(C2CCN(C(=O)N3c4ccccc4C(=O)Nc4cccnc43)CC2)CC1
Product: Cl
Yield: 21 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-(1-methyl-4-piperidinyl)piperidine in a yield of 21% of theory. Colourless crystals, m.p. 254°-255° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([N:21]=[C:22]=[S:23])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=[S:23])[NH:10][S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: NS(=O)(=O)c1ccccn1
Reactant: COc1nc(N=C=S)nc(OC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(NC(=S)NS(=O)(=O)c2ccccn2)nc(OC)n1

Procedure:
A mixture of 1.58 g of 2-pyridinesulfonamide, 2.04 g of 4,6-dimethoxy-2-isothiocyanato-1,3,5-triazine and 1.5 g of anhydrous potassium carbonate is stirred in 75 ml of acetone for 60 hours at ambient temperature. The reaction mixture is then poured into 500 ml of cold water, acidified with hydrochloric acid and the precipitated product removed by filtration.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ncccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 151.9 %

Procedure:
Using General Procedure B: To a stirred solution of 2-methyl-pyridine-3-carbaldehyde (75 mg, 0.62 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (246 mg, 0.62 mmol) and AcOH (40 uL, 0.62 mmol) in THF (6.2 mL) was added NaBH(OAc)3 (394 mg, 1.86 mmol) and the mixture was stirred at room temperature overnight. Purification of the crude white foam (280 mg) by column chromatography on silica gel (200:3:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (116 mg, 37%) as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl.C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]([C:18]3[CH:13]=[CH:14][C:15]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:17]=3)[N:20]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Yield: 75.5 %

Procedure:
A 250 mL one-necked round-bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 3-(4-chlorophenyl)-3-ketopropionaldehyde (18.3 g, 0.1 mol), 4-sulfonamidophenylhydrazine hydrochloride (11.2 g, 0.05 mol) and 100 mL of absolute ethanol. The solution was heated to reflux for 15 hour and then diluted with 100 mL of water and allowed to stand whereupon a white solid formed that was isolated by filtration on a Buchner funnel and air dried to provide 12.6 g, 76% of 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide, mp 185°-187° C. 1H nmr (CDCl3 /300MHz ) 7.89 (d, J=8.7 Hz, 2H), 7.76(d, J=1.8 Hz, 1H), 7.43(d, J=8.7 Hz, 2H), 7.34(d, J=8.7 Hz, 2H), 7.17(d, J=8.7 Hz, 2H), 6.53(d, J= 1.8 Hz, 1H), 4.93(brs, 2H), mass spectrum MH+=334.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>O>[C:1]([O:9][C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([O:17][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[C:27]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1cc(Cl)c(O)c(Cl)c1)c1ccccc1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1cc(Cl)c(OCc2ccc(F)c(Oc3ccccc3)c2)c(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
A reaction vessel was charged with 1.54 g of 3,5-dichloro-4-hydroxyphenyl benzoate, 0.83 g of potassium carbonate, 1.53 g of 4-fluoro-3-phenoxybenzyl bromide, and 10 ml of N,N-dimethylformamide, followed by stirring at room temperature for 5 hours. The reaction mixture was poured into water, and extracted twice with 50 m of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.32 g of 3,5-dichloro-4-(4-fluoro-3-phenoxybenzyloxy)phenyl benzoate (88% yield).