Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].[C:16]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:29][CH:28]([OH:30])[CH2:27][O:26][C:16](=[O:25])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:9])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C(C=Cc1ccccc1)OCC1CO1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Product: COc1ccc(C=CC(=O)OCC(O)COC(=O)/C=C/c2ccccc2)cc1OC
Reaction time: 15.5 h

Procedure:
3,4-dimethoxy cinnamic acid (140; 3.82 g; 18.37 mol) was dissolved in 60 mL of dioxane and heated under reflux (60°-70° C.). A catalytic amount (22.5 mg; 0.7 mmol) of tetrabutylammonium bromide and 1.5 g (7.35 mmol) of glycidyl cinnamate (130) were consecutively added to the solution of 3,4-dimethoxy cinnamic acid (140). The resulting mixture was heated to 100°-105° C. with continuous stirring for 15-16 h and then distilled under reduced pressure to yield compound (Id). 1H-NMR (CD3OD) δ 3.81 (s, 3H), 3.83 (s, 3H), 4.14 (m, 1H), 4.27 (d, 4H, J=8 Hz), 6.42 (d, 1H, J=16 Hz), 7.64 (d, 1H, J=16 Hz), 7.15 (dd, 1H, J=8 Hz, 2 Hz), 6.92 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=2 Hz), 6.53 (d, 1H, J=16 Hz), 7.70 (d, 1H, J=16 Hz), 7.35 (m, 3H), 7.56 (m, 2H)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: OCCn1ccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A stirred solution of 2-imidazol-1-yl-ethanol (J. Med. Chem., 39(10), 1991, (1996)) (3.9 g, 35 mmol) in dimethylformamide (75 mL) at 15° C. was treated portionwise with 60% sodium hydride (0.84 g, 35 mmol) and stirred at room temperature for 30 minutes. The mixture was rechilled and 4-fluoro-1-nitrobenzene (4.93 g, 35 mmol) added dropwise. The mixture was stirred cold for 30 minutes and heated at 35-40° C. for 30 minutes. A little water was added and the volatiles were removed on a pump. The residue was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and evaporated. Chromatography on silica gel and eluting with methanol/triethyl-amine/dichloromethane (2:2:96) and crystallization of the purified product from dichloromethane/ether gave 3.4 g (42%) of 1-[2-(4-nitro-phenoxy)ethyl]-1H-imidazole as a colorless solid, mp 55-57° C. Mass spectrum (LR-APCI) MH+=234.
Reaction SMILES: [CH:1]([C:5]1[C:6]([CH3:20])=[CH:7][C:8]([I:19])=[C:9]([CH:18]=1)[O:10][C:11](=[CH:14][N:15]([CH3:17])C)[C:12]#[N:13])=[CH:2][CH:3]=[CH2:4].Cl.N[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1>C(O)C>[CH:1]([C:5]1[C:6]([CH3:20])=[CH:7][C:8]([I:19])=[C:9]([CH:18]=1)[O:10][C:11](=[CH:14][NH:15][C:17]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)[C:12]#[N:13])=[CH:2][CH:3]=[CH2:4]
Reactant: Nc1ccccc1
Reactant: C=CC=Cc1cc(OC(C#N)=CN(C)C)c(I)cc1C
Agent: Cl
Solvent: CCO
Product: C=CC=Cc1cc(OC(C#N)=CNc2ccccc2)c(I)cc1C

Procedure:
To the crude crude 2-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-3-dimethylamino-acrylonitrile of step 3 was added aniline hydrochloride (2.54 g, 19.59 mmol) and ethanol (25 mL). The mixture was heated to reflux for 16 hours under nitrogen atmosphere. The mixture was cooled and concentrated under reduced pressure to yield crude 2-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-3-phenylamino-acrylonitrile, which was used in the same flask directly in the following step.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:22][CH2:21][CH2:20][CH2:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=2[CH:27]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:22]([CH:1]=[O:2])[CH2:21][CH2:20][CH2:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=2[CH:27]=1
Reactant: O=CO
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCC1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CCC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Formic acid (5.96 ml) was added to acetic anhydride (12.2 ml) at 0° C. and then the mixture was stirred under nitrogen atmosphere at 55° C. for 2 hours. After cooling to 0° C., THF (150 ml) was added, and further a solution of methyl 8-bromo-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (8.5 g) in THF (100 ml) was added dropwise under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 5 hours, after which the solvent was distilled off under reduced pressure. The reaction material was diluted with ethyl acetate, followed by washing with saturated sodium bicarbonate, water and saturated brine. The resultant was dried with magnesium sulfate, after which the solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane to give methyl 8-bromo-1-formyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (8.3 g) as colorless crystals.
Reaction SMILES: [OH-].[Na+].[C:3]([NH2:6])(=[O:5])[CH3:4].[C:7]([O:10][CH2:11][CH2:12]Cl)(=[O:9])[CH3:8]>CN(C)C(=O)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:7]([O:10][CH2:11][CH2:12][NH:6][C:3](=[O:5])[CH3:4])(=[O:9])[CH3:8]
Reactant: CC(N)=O
Reactant: CC(=O)OCCCl
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC(=O)N(C)C
Product: CC(=O)NCCOC(C)=O
Yield: 74.6 %

Procedure:
Ten grams of sodium hydroxide was suspended in 50 ml of N,N-dimethylacetamide, followed by a further addition of 12 g of acetamide, 0.05 g of phenothiazine and 36 g of 2-chloroethyl acetate. A reaction was allowed to take place at 40° C. for 4 hours with stirring. After the completion of the reaction, the reaction solution was filtered to separate off all the undissolved materials. Under reduced pressures, N,N-dimethylacetoamide and unreacted 2-chloroethyl acetate were distilled off. After adding 100 ml of benzene and 50 ml of distilled water to the residue, the mixture was thoroughly agitated and separated into two layers. The aqueous solution layer was extracted twice with 50 ml of benzene. The benzene layers were combined and dried with magnesium sulfate. The thus-dried benzene layer was subjected to a distillation under reduced pressure. A fraction was collected at 138-140° C./ 2 mmHg, thereby obtaining 22 g of N-acetoxyethylacetamide (yield: 74%). The reaction system in the above reaction contained water of the order of 5000 ppm or so.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[N:15]1([C:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH:12]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCCC2)CC1
Temperature: 25 °C

Procedure:
A mixture of Boc-4-piperidone (5.5 g, 27.6 mmol), pyrrolidine (2.42 ml, 29 mmol) and PTSA (30 mg) in cyclohexane (30 mL) is refluxed overnight with a Dean-Stark trap to remove water. The mixture is cooled to rt and the solvent is removed in vacuo and the thick oil obtained is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH3:30])[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[N:33]1>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[S:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)(=[O:39])=[O:38])[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNCc1cccc(C(CNC(=O)OC(C)(C)C)C2(c3ccc(Cl)cc3)CCC2)c1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(Cc1cccc(C(CNC(=O)OC(C)(C)C)C2(c3ccc(Cl)cc3)CCC2)c1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C

Procedure:
tert-Butyl (2-[1-(4-chlorophenyl)cyclobutyl]-2-{3-[(methylamino)methyl]phenyl}ethyl)carbamate (35 mg, 0.082 mmol) was dissolved in dichloromethane (0.8 mL). 4-Dimethylaminopyridine (10 mg, 0.082 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (16 mg, 0.09 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with aqueous hydrochloric acid (1 N, 5 ml, twice) and sodium bicarbonate. The organic layer was dried (magnesium sulfate) and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography (silica, ethyl acetate, n-heptane). Yield: 36 mg (0.063 mmol, 77%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2]>CC[O-].[Na+].C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: [Ni]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1CCC(O)CC1
Yield: 64.3 %

Procedure:
115 g 4-hydroxy-phenylacetic acid ethyl ester is hydrogenated in a mixture of 10 ml one molar sodium ethylate solution and 350 ml ethanol for 72 hours at 160° C. and 200 bar using Raney-Nickel. The preparation is subsequently evaporated and the remaining oil is distilled in a high vacuum. 76.4 g 4-hydroxycyclohexane-acetic acid ethyl ester is obtained with a boiling point of 120°-121° C./2 mm Hg. TLC (mobile solvent: dichloromethane/methanol 9:1). Rf=0.8.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.CO.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Ethyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxlate (495 g, 1.24 mol) was dissolved in 4.95 L of tetrahydrofuran and 2.48 L of methanol. Crystals were formed by adding a potassium carbonate (342 g, 2.47 mol) solution in 4.2 L of water and the mixture was heated under reflux for 6.5 hours. Under reflux, 1.85 L of a 3N hydrochloric acid was dropped to form crystals. After cooling, 84 ml of a 6N hydrochloric acid was added at room temperature (pH 2-3) and stirred for 1 hour while cooling in ice. After filtration, the residue was washed with 2.97 L of a mixed solution of tetrahydrofuran/methanol/water=1/1/3 . After vacuum drying (40° C.), 443 g (Yield 96%) of 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid was obtained as pale yellowish white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)(=O)C.CCO>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NN=Cc1ccc(C(F)(F)F)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 4-hydroxybenzhydrazide (0.3 g, 0.002 mol) and 4-trifluoromethylbenzaldehyde (0.35 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give beige solid 0.58 g, in 94% yield, mp: 260.5° C. 1H NMR (CD3OD) δ 8.35 (s, 1H), 7.99 (d, 2H), 7.83 (d, 2H), 7.70 (d, 2H), 6.87 (d, 2H). 13C NMR (CD3OD) δ 167.0, 163.0, 147.7, 1139.6, 131.0, 129.1, 126.7, 126.6, 124.5, 116.4. Anal. Calcd for C15H11F3N2O2. ¼H2O: C, 57.60; H, 3.54; N, 8.95, F; 18.22. Found: C, 57.71; H, 3.77; N, 8.67, F; 18.43.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[CH3:32])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[CH2:16][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 1 c], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one (example 1 a]) was treated with triethylsilane in trifluoroacetic acid to yield the title compound as colorless liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[OH:26]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc2ccccc2c1
Product: COc1cc2nccc(Oc3ccc4ccccc4c3)c2cc1OC
Temperature: 180 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (45 mg) and commercially available β-naphthol (144 mg) were mixed and stirred at 180° C. for 2 hours, and the reaction mixture was then purified in the same manner as described in Example 2 to obtain 45 mg of the title compound (yield: 68%).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.O>[Br:18][CH2:19][C:20]([NH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21]
Reactant: NC1CCCCCC1
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a −20° C. solution of cycloheptylamine (6.37 mL, 50.0 mmol) and diisopropylethylamine (9.58 mL, 55.0 mmol) in methylene chloride (250 mL) was slowly added bromoacetyl bromide (4.78 mL, 55.0 mmol). The reaction mixture was warmed to room temperature over 20 minutes and stirred for an addition 30 minutes. The reaction mixture was diluted with water (100 mL) and stirred for an additional 30 minutes. The rganic layer was separated, washed with water (3×100 mL), dried over magnesium sulfate and concentrated in vacuo to afford a beige solid (10.5 g). The crude material was further purified by silica gel flash column chromatography using hexane-ethyl acetate (1:1) as the eluent to give the purified title compound as a white solid (9.77 g, 83%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][CH:20]([S:22]([C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:29][C:25]([S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])=[CH:26][N:27]=2)[CH2:31][CH2:32]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)C(C)C)s2)CC1
Yield: 67 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(propane-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 67%). MS (m/e): 516.3 (M+H+, 100%), 533.3 (M+NH4+, 85%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([CH2:35][C:17]([CH3:22])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([O:20][CH3:21])=[O:19])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COC(=O)C(C)c1ccccc1
Reactant: BrCC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC1CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 184.2 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 3.04 mL, 3.04 mmol, 1 equiv) under a N2 atmosphere was cooled to 0° C. and treated with a solution of methyl 2-phenylpropionate (0.500 g, 3.04 mmol, 1 equiv) in dry tetrahydrofuran (2 mL). The reaction was stirred at 0° C. for 2 hrs, then cooled to −78° C. and treated with hexamethylphosphoric triamide (0.4 mL) and bromomethylcyclopentane (0.745 g, 4.568 mmol, 1.5 equiv). Stirred the reaction at −78° C. and allowed the bath to slowly warm to room temperature overnight. After 15 hrs, the reaction mixture was quenched with 10% aq NH4Cl (50 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with H2O (50 mL) and brine, then dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was purified by SiO2 flash chromatography with 2:3 dichloromethane/hexanes to give the product as colorless oil (1.38 g, 5.60 mmol, 92%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.90-1.12 m, 2 H) 1.32-1.72 m, 10 H) 1.97-2.12 (m, 2H) 3.58 (s, 3 H) 7.19-7.35 m, 5 H); MS (APCI+) m/z 247 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([OH:21])=O)=[O:12].Cl.C[N:24](C)CCCN=C=NCC.N>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:24][C:19]([C:15]1[S:16][CH:17]=[CH:18][C:14]=1[NH:13][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])=[O:21]
Reactant: O=C(Nc1ccsc1C(=O)O)c1cnc2ccccc2n1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N
Solvent: ClCCl
Product: NC(=O)c1sccc1NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A mixture of 3-[(2-quinoxalinylcarbonyl)amino]-2-thiophenecarboxylic acid (0.70 g, 2.3 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 2.24 g, 11.5 mmol), and 4-(dimethylamino)pyridine (DMAP, 1.43 g, 11.5 mmol) in CH2Cl2 (100 mL) was stirred at room temperature for 2 h. To the reaction mixture was added aqueous ammonia (40%, 5 mL), and the stirring continued for another 12 h. The solvent was evaporated to dryness and the resulting solid was washed with satd NH4Cl solution (3×), NaHCO3 solution and H2O. The organic phase was evaporated to dryness resulting in a white powder (0.32 g, 46%). HPLC/MS: (M+H)+ 299.4 m/z
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1I>>[Br:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: Fc1ccc(I)c(Br)c1
Product: Fc1ccc(Sc2ccccc2)c(Br)c1

Procedure:
Prepared from benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])[N:10]=2)[CH:7]=1.[Br-].[CH3:27][O:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:30]>CO>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:12][C:11]=1[C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[O:28][CH3:27])=[CH:37][CH:36]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1)N1CCCC1
Reactant: COC(=O)Nc1ccc(B(O)O)cc1
Agent: [Br-]
Solvent: CO
Product: COC(=O)Nc1ccc(-c2cnc3nc(-c4cc(NC(=O)N5CCCC5)ccc4Cl)cn3c2)cc1

Procedure:
Compound 24 was synthesized using N-(3-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)-4-chlorophenyl)pyrrolidine-1-carboxamide (I-15) as the bromide and (4-((methoxycarbonyl)amino)phenyl)boronic acid using a suzuki coupling protocol as described in the synthesis of I-11. The residue was redissolved in methanol and precipitation yielded the compound. m/z (ESI) of 24: 491.2 (M+H+), 1H NMR (600 MHz, DMSO-D6) δ 9.86 (s, 1H), 9.30 (d, J=2.6, 1H), 8.94 (d, J=2.6, 1H), 8.55 (s, 1H), 8.47 (d, J=2.8, 2H), 7.73 (m, 3H), 7.62 (d, J=8.5, 2H), 7.41 (d, J=8.8, 1H), 3.70 (s, 3H), 3.40 (t, J=6.5, 4H), 1.86 (t, J=6.4, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)OC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OC(C)C)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 60.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.52 g, 5 mmol) was reacted with isopropyl morpholine-3-carboxylate hydrochloride (1.05 g, 5 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (1.79 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:18])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:1][C:2]1[C:3]([NH:18][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[N:6][CH:7]=1
Reactant: COc1ccccc1COc1ncc(F)c(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1COc1ncc(F)c(NS(=O)(=O)c2ccccc2)n1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-amine (500 mg, 2.01 mmol) in dry THF (10 mL) was added 1M LiHMDS solution in THF (3.21 mL, 3.21 mmol) causing a slight exotherm. After stirring for 5 min, benzenesulfonyl chloride (0.346 mL, 2.71 mmol) was added and after 10 min the orange solution turned light orange and turbid. The mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the resulting viscous gold oil was diluted in EtOAc (10 mL), poured into a separatory funnel containing EtOAc (100 mL) and washed with 1N HCl aqueous solution (4×50 mL) and brine solution (1×50 mL). The organic extract was dried over Na2SO4, filtered, and evaporated to yield N-(5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-yl)benzenesulfonamide (714 mg, 91% yield) as a light tan solid. MS (ESI) m/z 387.99 (M−H)−.