Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][N:29]([C:33]([CH3:40])([CH3:39])[C:34](OCC)=[O:35])[CH2:28]6)[N:25]=[CH:24][CH:23]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:41]=2)=[N:7][C:6]([CH3:42])=[N:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][N:29]([C:33]([CH3:40])([CH3:39])[CH2:34][OH:35])[CH2:28]6)[N:25]=[CH:24][CH:23]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:41]=2)=[N:7][C:6]([CH3:42])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)N1CCCC(n2nccc2-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCN(C(C)(C)CO)C4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(3-(5-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylpropanoate (150 mg, 0.26 mmol) in Tetrahydrofuran (2.00 mL) at 0° C. was added Lithium Aluminum Hydride (1 mol/L) in THF (0.52 mL, 0.5238 mmol) dropwise. The reaction mixture was slowly allowed to warm up to room temperature and was stirred for 2 hours. LC-MS analysis of the reaction mixture showed no more starting material and the formation of the desired product. The reaction mixture was quenched by the addition of MeOH, filtered and the concentrated. The resulting oil was purified by rHPLC to give 266. 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.3 Hz, 1H), 7.98-7.86 (m, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.22 (dd, J=8.3, 1.4 Hz, 1H), 7.09 (s, 1H), 6.39 (t, J=6.8 Hz, 1H), 5.83 (dt, J=13.2, 6.6 Hz, 1H), 4.54 (d, J=15.0 Hz, 4H), 4.36-4.15 (m, 2H), 3.24 (d, J=4.9 Hz, 2H), 3.08 (d, J=8.5 Hz, 1H), 2.93 (t, J=15.9 Hz, 1H), 2.62-2.52 (m, 2H), 2.26 (s, 3H), 2.11 (t, J=10.8 Hz, 1H), 1.92 (s, 2H), 1.73 (d, J=13.1 Hz, 1H), 1.57-1.42 (m, 6H), 0.91 (s, 6H). LCMS: 531.3
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br.O>CO>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(C)c(S(N)(=O)=O)c1
Reactant: BrBr
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)CBr)cc1S(N)(=O)=O
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
21.3 Grams (0.1 M) of 5-acetyl-2-methylbenzenesulfonamide was dissolved in 180 g of methanol, while the resulting solution was kept at 35°-40° C., 16.0 g (0.1 M) of bromine was added dropwise by taking 1.5 hours. The reaction mixture was stirred for 10 minutes after the dropwise addition, 80 g of water was added to the reaction mixture and the whole reaction mixture was stirred for further 30 minutes at room temperature. A part of methanolwater was removed by evaporation, then the crystals formed were collected by filtration, washed with water and dried to obtain 28.0 g of 5-bromoacetyl-2-methylbenzenesulfonamide in the form of white crystals. Melting point: 146.5°-147.5° C Yield: 95.9%.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:7]1([CH3:18])[CH3:17])=[O:5])C.CCO.[OH-].[Na+]>O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:8]2[C@H:6]([C:4]([OH:5])=[O:3])[C:7]2([CH3:18])[CH3:17])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2cccc(OC)c2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc([C@H]2[C@H](C(=O)O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.6 %

Procedure:
Trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acid ethyl ester (15.22 g, 61 mmol) was added to a mixture of EtOH (200 mL) and 2M aqueous NaOH (100 mL). Solid NaOH (5.0 g, 125 mmol) was added, and the reaction mixture was stirred under N2 atmosphere for 15 hours at room temperature. The reaction mixture was diluted with water and extracted twice with a mixture of 1/1 hexanes/diethyl ether and once with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give 11.5 g of trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acid, MS=221 [M+H]+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:14])[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[Na]>C(O)(=O)C>[CH3:5][N:6]([CH3:14])[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:3][CH2:2][C:1]#[N:4]
Reactant: C=CC#N
Reactant: CN(C)c1cccc(O)c1
Agent: [Na]
Solvent: CC(=O)O
Product: CN(C)c1cccc(OCCC#N)c1
Yield: 80 %

Procedure:
A 407 g (7.68 moles) portion of acrylonitrile and 500 g (3.65 moles) of m-dimethylaminophenol were placed in a 3-l, 3-necked flask equipped with a stirrer and reflux condenser with a drying tube. The solution was treated with 4 g (0.17 mole) of metallic sodium, over 0.7 hr., with an observed temperature rise from 10° to 24°. The reaction mixture was heated to reflux over 0.8 hr., refluxed for 22 hrs., cooled, treated with 11 ml of glacial acetic acid and the excess acrylonitrile removed under reduced pressure. The residue was taken up in 3.8-l of ether, decanted from a purple resinous material, stored over Darco overnight and filtered. The filtrate was stripped of ether under reduced pressure to give 590 g (80%) of the desired nitrile (brown).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][C:15]3[C:20]([Cl:21])=[CH:19][C:18]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])=[CH:17][C:16]=3[C:10]=2[CH:9]1[C:31]([OH:33])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([N:36](CC)[CH2:37]C)C.Cl.CNC.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)C>[Cl:21][C:20]1[C:15]2[O:14][C:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]([C:31](=[O:33])[N:36]([CH3:37])[CH3:34])[C:10]=3[C:16]=2[CH:17]=[C:18]([S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: Cl
Solvent: CC#N
Product: CN(C)C(=O)C1c2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of the product obtained from step A (80 mg, 0.16 mmol) in anhydrous acetonitrile (1.5 mL) was added triethylamine (45 μL, 0.32 mmol) followed by dimethylamine hydrochloride (20 mg, 0.24 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (106 mg, 0.24 mmol). After stirring at ambient temperature for 12 h, the resulting solution was concentrated to dryness in vacuo. The reaction mixture was diluted with ethyl acetate (20 mL), washed sequentially with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated in vacuo to give the crude product which was purified by flash column chromatography (SiO2, 9:1 to 3:2 hexanes/ethyl acetate) to afford tert-butyl 6-chloro-1-(dimethylcarbamoyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (60 mg, 71%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.93-7.77 (m, 4H), 7.57-7.48 (m, 3H), 6.19 (s, 1H), 4.53-4.27 (m, 1H), 3.76-3.62 (m, 2H), 3.43 (s, 3H), 3.02 (s, 3H), 2.85-2.80 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>CO>[CH2:1]([O:8][C:9]([C@@H:10]([NH:11][CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[CH:12]([CH3:13])[CH3:14])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of L-valine benzylester in MeOH (12 mL) was slowly added 1,3-propanesultone (604 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with cold MeOH and acetone (2×25 mL). It was dried in the vacuum oven (50° C.), affording the title compound (649 mg, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.47 (m, 5H), 5.41 (d, 1H, J=11.7 Hz), 5.31 (d, 3H, J=11.7 Hz), 4.04 (m, 1H), 3.19 (m, 2H), 2.95 (t, 2H, J=6.8 Hz), 2.35 (m, 1H), 2.14 (m, 2H), 1.04 (d, 3H, J=6.3 Hz), 0.95 (d, 3H, J=6.3 Hz). 13C (D2O, 125 MHz) δ ppm 168.75, 134.81, 129.38, 129.31, 129.17, 69.00, 65.96, 48.24, 46.71, 29.67, 21.40, 18.39, 16.65. [α]D=−7.2° (c=0.0015 in water), ES-MS 330 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:29][CH3:30])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][NH:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:34]=O>>[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:29][CH3:30])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][N:24]([CH3:34])[CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CNC1
Reactant: C=O
Agent: Cl
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CN(C)C1
Yield: 55 %

Procedure:
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-3-carboxamide hydrochloride salt (Example 75) was coupled with aqueous formaldehyde using the same method as for the equivalent step in Example 76 to give 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]-1-methylazetidine-3-carboxamide (55%) as a white powder; 1H NMR Spectrum: (CDCl3) 1.03 (t, 3H), 2.45 (s, 3H), 2.83 (q, 2H), 3.37 (brs, 2H), 3.65 (m, 2H), 3.97 (s, 3H), 4.05 (s, 2H), 5.41 (brs, 1H), 7.16 (m, 2H), 7.22 (s, 1H), 7.47 (brs, 1H), 7.95 (brs, 1H), 8.28 (s, 1H), 8.59 (m, 1H), 8.76 (s, 1H); Mass Spectrum: (M+H)+ 473.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[C:42]([S:44](=[O:64])(=[O:63])[N:45](CC2C=CC(OC)=CC=2OC)[C:46]2[N:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[C:41]([F:65])=[CH:40][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH:22]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:22]=2)=[CH:40][C:41]([F:65])=[C:42]([S:44]([NH:45][C:46]2[N:51]=[CH:50][CH:49]=[CH:48][N:47]=2)(=[O:63])=[O:64])[CH:43]=1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncccn1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnc(N3CCNCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.4 %

Procedure:
tert-Butyl 4-(4-(4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-2-yl)sulfamoyl)-5-fluorophenoxy)-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 122, 360 mg, 0.385 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 20 hours and then concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water both with 0.1% formic acid) to give the title compound (30 mg, 11%) as a white solid.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:7](=[O:25])[N:8]([CH2:21][CH2:22][CH2:23]O)[N:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(Br)([Br:28])=O>O>[Br:28][CH2:23][CH2:22][CH2:21][N:8]1[C:7](=[O:25])[C:6]([Cl:5])=[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]=[N:9]1
Reactant: O=S(Br)Br
Reactant: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCBr
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To 170 ml of chloroform were added 9.9 g of 4-chloro-5-(4'-chlorobenzyloxy)-2-(3'-hydroxypropyl)-3(2H)-pyridazinone (0.03 mol) and slowly added 9.4 g of thionyl bromide (0.045 mol) under stirring for about 2 hours at -5° to 5° C. After reaction, the resulting solution was added little by little with water and the chloroform layer was separated. The layer was washed with water and then with aqueous solution of 5% sodium hydrogen carbonate, and further washed with saturated saline and dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The solid product thus obtained was recrystallized from a mixed solvent of n-hexane-benzene to give 5.2 g of 2-(3'-bromopropyl)-4-chloro-5-(4'-chlorobenzyloxy)-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][C:13]#[CH:14].[OH-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:13][CH2:12][C:11]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#CCCCCl
Reactant: Oc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C#CCCCOc1ccc(Cl)cc1

Procedure:
To a mixture of 51.4 g (0.4 mol) of 4-chlorophenol, 49.2 g (0.48 mol) of 5-chloro-1-pentyne and 7.36 g (20 mmol) of tetra-n-butyl ammonium iodide in 140 mL of ethanol is added a solution of 24.7 g (0.44 mol) of potassium hydroxide in 24 mL of water over 2 minutes. The mixture is heated to reflux and is maintained for 25 hours.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](=O)[CH2:20]Br>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1cccc(-c2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 72 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 3-trifluoromethylphenacyl bromide to obtain methyl 3-[4-(3-trifluoromethylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 72%. Colorless prisms. Melting point: 105 to 106° C.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:29][O:30][CH3:31])[CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH2:27][I:28])(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:32](Cl)(=[O:34])[CH3:33].C(NC(C)C)(C)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[C:32]([N:21]([S:22]([CH2:25][CH2:26][CH2:27][I:28])(=[O:24])=[O:23])[CH2:20][CH:19]([CH2:29][O:30][CH3:31])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCI)COC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCCCCCCCOCC(COC)CN(C(C)=O)S(=O)(=O)CCCI
Temperature: 0 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a cooled mixture of 0.76 g (1.3 mM) of 1-hexadecyloxy-3-(3-iodopropylsulfonylamino)-2-methoxymethylpropane IIk1 and 0.14 ml (2.0 mM) of acetyl chloride in 10 ml of dichloromethane at 0° C., is added 0.39 ml (2.2 mM) of diisopropylamine and the mixture is stirred at 0° C., for 3 hours. The mixture is poured into ice-water and the product is isolated by dichloromethane extraction. The dichloromethane layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by column silica gel chromatography using toluene-ethyl acetate (9:1) mixture and 0.81 g (99% yield) of the titled compound IIk1' is obtained.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]1([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[CH2:1]([NH:3][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: BrCc1ccccc1Oc1ccccc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water (5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02 mmol) in THF (25 ml) was added dropwise and the reaction stirred at ambient temperature for 2 hours. The volatile components were removed at reduced pressure, aqueous sodium hydroxide (IN, 20 ml) was added and the aqueous solution extracted with dichloromethane (2×). The organic layers were dried (MgSO4), evaporated and purified by chromatography (eluant: CH2Cl2/EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as a yellow solid (2.2 g, 51%).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1([CH2:31][CH2:32]OS(C2C(C)=CC=CC=2)(=O)=O)[CH:30]=[CH:29][N:28]=[CH:27]1>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: Clc1ccc(N2CCN=C2Cc2ccccc2)c(Cl)c1
Reactant: Cc1ccccc1S(=O)(=O)OCCn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN=C2C(CCn2ccnc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a stirred solution of 2-(imidazol-1-yl)ethanol (1.9 g, 0.0156 mol), triethylamine (2.8 ml, 0.0187 mol), and 4-N,N-dimethylaminopyridine (20 mg) in dichloromethane (20 ml) at a temperature of -78° C. under nitrogen atmosphere, was added p-toluenesulphonyl chloride (3.6 g, 0.0187 mol) in dichloromethane (10 ml). The reaction mixture was allowed to warm to -10° C. and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. The organic phase was separated and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield colorless crystals of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (4.23 g). n-Butyllithium (3.9 ml, 0.0059 mol, 1.5M in hexane) was added to a stirred solution of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-phenylmethylimidazole (1.5 g, 0.0049 mol) in dry tetrahydrofuran (10 ml) at -78° C. under a nitrogen atmosphere. Copper(I)bromide-dimethyl sulphide complex (50 mg, 0.0024 mol) was added to the reaction mixture. After a period of one hour, a solution of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (2 g, 0.0072 mol) in tetrahydrofuran (7 ml) was added to the reaction mixture. The resulting mixture was allowed to warm to room temperature and allowed to react for 15 hours before being quenched with saturated aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel with ammonia/methanol/ethyl acetate (1:4:45) to yield 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole (1 g) which upon treatment with ethereal hydrogen chloride yielded the hydrochloride salt of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole. (Found C, 49.00; H, 5.03; N, 10.76. C21H22N4Cl4.9/4 H2O requires C, 49.19; H, 5.21; N, 10.93) having the formula ##STR44## The anti-anaerobic activity of the compounds of the present invention is demonstrated by the following examples:
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:7])[C:4](O)=[O:5].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH2:40])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1.[Li+].[OH-].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH:40][C:4](=[O:5])[C@@H:3]([O:2][CH3:1])[CH3:7])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CO[C@@H](C)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
(S)-2-Methoxypropanoic acid (181 mg, 1.74 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (443 mg, 1.74 mmol) and triethylamine (440 mg, 4.35 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H) in DCM (50 mL). The reaction was stirred at room temperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added. The reaction was stirred for 1 hour, and then saturated aqueous Na2CO3 was added (200 mL). The aqueous phase was extracted 3 times with DCM (200 mL), and then the combined organic phases were dried over MgSO4 and concentrated to dryness. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 20-100% CH3CN/water gradient; 20 CV) to yield (S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (131 mg, 48% yield) as a solid.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][C:9]([CH2:11][C:12]2[C:21]([F:22])=[C:20]([F:23])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([F:24])[C:13]=2[F:25])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:34](OCC)(=[O:36])C.O>CN(C)C=O.C[O-].[Na+]>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]([CH:11]([C:12]2[C:13]([F:25])=[C:14]([F:24])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([F:23])[C:21]=2[F:22])[CH2:34][OH:36])=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1c(F)c(F)c(CC(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)c(F)c(C(CO)C(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
In 486 ml of N,N-dimethylformamide was dissolved 8.6 g of methyl 4-diphenylmethoxycarbonylmethyl-2,3,5,6tetrafluorobenzoate. To the resulting solution were added 3.54 g of paraformaldehyde and 61 mg of sodium methylate in this order. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 300 ml of ethyl acetate and 800 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 35.0 g (yield: 67.0%) of methyl 4-(1-diphenylmethoxycarbonyl-2-hydroxyethyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH:13]=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH:15]1([N:21]=[CH:13][CH2:12][CH:9]2[CH2:10][CH2:11][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: CCCCCC1CCC(CC=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCC1CCC(CC=NC2CCCCC2)CC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
(4-Pentylcyclohexyl)acetaldehyde (30.1 g) was dissolved in diethyl ether (40 mL), to which cyclohexylamine (15.2 g) and potassium carbonate (12 g) were added, and the system was stirred at room temperature over night. The resulting suspension was filtered with Celite, and the filtrate was concentrated under reduced pressure. Cyclohexyl-(2-(4-pentylcyclohexyl)ethylidene)amine (40.6 g) in a yellow oily form thus obtained was used in the second step without purification.