Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:3]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)[CH:3]=2)=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Reactant: N#CC1(c2cc(Br)ccn2)CC1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CC2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 1-(4-bromo-pyridin-2-yl)-cyclopropanecarbonitrile (Step 18.3) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 2 h at 100° C., quenched by dilution with EtOAc/H2O, and extracted with EtOAc. The crude product is purified by silica gel column chromatography (Hex/EtOAc, 1:1) to afford 122 mg of the title compound as a white solid: ESI-MS: 357.1 [M+H]+; tR=4.86 min (System 1); TLC: Rf=0.29 (Hex/EtOAc, 1:1).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[CH3:17]I>C(COC)OC>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)Cc1ccc(O[Si](C)(C)C)cc1
Reactant: CI
Solvent: COCCOC
Product: COC(=O)C(C)c1ccc(O)cc1
Temperature: -70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of methyl 2-(4'-trimethylsilyloxyphenyl)ethanoate (34.3 mmole) in dimethoxyethane (10 ml) was added dropwise to the reaction, the temperature rising to -30° C. before cooling to -70° C. This cold reaction mix was added dropwise to a solution of methyliodide (0.16 mole) in dimethoxyethane (20 ml) cooled to -70° C. The mixture was stirred at room temperature overnight before removing the solvent by evaporation. The residue was stirred with dilute HCl and extracted with dichloromethane, washed with saturated NaHCO3 solution, dried (MgSO4) and the product isolated by evaporation. Distillation of the crude product gave MHPP (yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:26]=[O:28])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Temperature: 75 °C
Yield: 72.3 %

Procedure:
To a mixture of 6-(4-amino-phenoxy)hexanoic acid methyl ester 21 (26 grams, 109.7 mmol) and triethylamine (29.2 g, 288.56 mmol) in toluene (390 ml) under nitrogen atm. was added triphosgene (15.6 grams, 52.56 mmol) in one lot. The reaction was exothermic and the internal temperature rose to 60° C. Later, the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temperature for 26 hours. The reaction mixture was cooled to room temperature, the solids were filtered, and the toluene was distilled off under vacuum to get crude 36, which was vacuum distilled to get pure 36 (10 g, 34.7%). M.p: 47-50° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[Cl:16].C[O:18][B:19](OC)[O:20]C.Cl>C1COCC1>[Cl:16][C:8]1[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[CH:11]=[CH:12][C:7]=1[B:19]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(Br)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 1-bromo-2-chloro-4-ethoxybenzene (19.5 mmol, 4.59 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming a white precipitate. The white precipitate (2.25 g, 58%) was filtered and dried to afford (2-Chloro-4-ethoxyphenyl)boronic acid. 1H NMR (CDCl3, 300 MHz): 7.87 (1H, d, J8.4 Hz), 6.88 (1H, d, J 2.5 Hz), 6.84 (1H, dd, J 8.4 and 2.5 Hz), 5.53 (2H, br. s), 4.06 (2H, q, J 7.07 Hz), 1.42 (3H, t, J 7.0 Hz.)
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([Cl:19])=[C:11]2[Cl:20])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[F-].[Cs+].[C:25](B1OC(C)(C)C(C)(C)O1)([CH3:27])=[CH2:26]>COCCOC.CCOC(C)=O>[Cl:20][C:11]1[N:10]([C:4]2[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([C:25]([CH3:27])=[CH2:26])[C:3]=2[O:21][CH3:22])[C:18]2[C:13]([C:12]=1[Cl:19])=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1c(Br)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C=C(C)c1nn(C)c(=O)c(-n2c(Cl)c(Cl)c3ccccc32)c1OC
Temperature: 150 °C
Yield: 92.6 %

Procedure:
6-bromo-4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-pyridazin-3-one (0.600 g, 1.49 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.0608 g, 0.0744 mmol) and cesium fluoride (0.476 g, 2.98 mmol) are suspending in DME (3 mL) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (330 μL, 1.79 mmol) is added. The resulting reaction mixture is heated under microwave irradiation to 150° C. for 20 min. The resulting reaction mixture is diluted with EtOAc (50 mL) and then washed with brine (50 mL). The organic layer was dried (MgSO4) and then concentrated under reduced pressure onto silica. Purification by flash chromatography (combiflash, 0 to 20% EtOAc/isohexane) afforded the desired product 4-(2,3-dichloroindol-1-yl)-6-isopropenyl-5-methoxy-2-methyl-pyridazin-3-one (503 mg, 1.38 mmol, 93%) as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:28].C1COCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:24]([C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:28])[CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1OC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4C(=O)Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (400 mg, 1.182 mmol) and p-nitrophenyl chloroformate (262 mg, 1.300 mmol) in THF (6 mL) DIPEA (245 μL, 1.419 mmol) was added drop wise at RT. The solution was stirred for 1 h at RT before the resulting mixture was concentrated in vacuo and the title compound was used in the following reaction without purification. MS (ESI, pos. ion) m/z: 504 (M+1). Mass cal'd for C26H21N3O8: 503.13.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([O:12]COC)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]1[CH:21]=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[CH:25]=[C:24]([CH2:36][OH:37])[C:23]=2[CH2:38][OH:39])[CH:19]=[CH:18][N:17]=1.Cl>O1CCOCC1.CO>[O:1]=[C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]1[CH:21]=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[CH:25]=[C:24]([CH2:36][OH:37])[C:23]=2[CH2:38][OH:39])[CH:19]=[CH:18][N:17]=1
Reactant: COCOc1cc(=O)n(-c2cc(-c3c(CO)c(CO)cc4cc(OC)c(OC)cc34)ccn2)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(O)c5ccccc54)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
1-[2-(2-Oxo-4-methoxymethoxy-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.39 g) is dissolved in a mixture of dioxane (10 ml) and methanol (5 ml), and thereto is added 2M hydrochloric acid (2 ml). The mixture is warmed to 50° C., and stirred for 7 hours, and then concentrated under reduced pressure to remove the solvent. To the residue are added chloroform and water, and the chloroform layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1) to give 1-[2-(2-oxo-4-hydroxy-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-naphthalene (0.79 g) which is listed in Table 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dimethyl 5-bromoisophthalate (6.2 g, 22.7 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) was added dropwise NaOH (1.0 M in water; 20.4 mL, 20.4 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated. Ethyl acetate was added and the mixture was extracted with water (2×). The combined aqueous layer was adjust to pH=3 using HCl (6.0 M in water). This mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated (4.9 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:15]1([CH:21]=[CH:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:28]2[CH2:27][CH2:26][CH:25]([O:24][CH2:23][CH:22]=[CH:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:30][CH2:29]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C(=Cc1ccccc1)COC1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@](O)(CN1CCC(OCC=Cc2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 48.5 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.198 g, 0.910 mmol) and 4-(3-phenyl-2-propenyloxy)piperidine (0.198 g, 0.910 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(3-phenyl-2-propenyloxy)piperidin-1-yl]propan-2-ol (0.192 g, yield 49%) as a brown oil in the same manner as in Example 254.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17]O)[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CO)N(C(=O)OC(C)(C)C)C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a mixture of the above 2-amino-5-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (2.00 g, 5.20 mmol), phthalimide (0.92 g, 6.24 mmol) and triphenylphosphine (1.64 g, 6.24 mmol) in dry tetrahydrofuran (30 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl azodicarboxylate (DEAD) (0.98 ml, 6.24 mmol). The reaction mixture was allowed to stir overnight, slowly warming to room temperature. Next day the reaction mixture was again cooled to 0° C. and phthalimide (0.46 g, 3.12 mmol), triphenylphosphine (0.82 g, 3.12 mmol) and diethyl azodicarboxylate (DEAD) (0.49 ml, 3.12 mmol) was added in sequence and the reaction mixture was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo and the resultant solid dissolved in dichlorormethane (20 ml). The residue was subjected to flash column chromatography using a mixture of ethyl acetate/hexane (1:2) as eluant. Fractions were collected affording after evaporation in vacuo 1.0 g of the desired compound contaminated with phthalimide. Recrystallization from ethanol gave 0.23 g (9%) of pure 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Br:24]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]([Br:24])[C:8](=[O:21])[C:9]([CH3:19])([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
36.6 g (0.1 mole) of 1,4-bis-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were dissolved in 250 ml of chloroform, and 16.6 g (0.1 mole) of bromine were added dropwise at 20° C. in a manner such that continuous decolorization occurred. After the addition, the mixture was subsequently stirred at room temperature for 30 minutes and was then concentrated by distilling off the solvent in vacuo. 43.2 g (quantitative conversion) of 1,4-bis-(4-chlorophenoxy)-1-bromo-3,3-dimethyl-butan-2-one were obtained as an oil, which was further reacted directly. ##STR43##
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:37]([N:39]([CH2:42][C:43]1[S:47][C:46]([C:48]2[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][NH2:61])=[CH:55][CH:54]=3)[N:49]=2)=[CH:45][C:44]=1[CH3:62])[CH2:40][CH3:41])[CH3:38]>CN(C=O)C>[CH2:37]([N:39]([CH2:42][C:43]1[S:47][C:46]([C:48]2[O:52][N:51]=[C:50]([C:53]3[CH:54]=[CH:55][C:56]([CH2:59][CH2:60][NH:61][C:1](=[O:5])[CH2:2][OH:3])=[CH:57][CH:58]=3)[N:49]=2)=[CH:45][C:44]=1[CH3:62])[CH2:40][CH3:41])[CH3:38]
Reactant: O=C(O)CO
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNC(=O)CO)cc3)no2)cc1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of glycolic acid (15 mg, 202 μmol) and DIPEA (35 mg, 270 μmol) in DMF (5 mL) is added HOBt (27 mg, 202 μmol) and EDC hydrochloride (39 mg, 202 μmol) at 0° C. The mixture is stirred for 15 min at 0° C. Then 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine is added and stirring is continued for 1 h at 0° C. The reaction is quenched with water, diluted with sat. aq. NaHCO3 and the mixture is extracted three times with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (4 mg) as a colourless oil; LC-MS: tR=0.69 min; [M+1]+=429.06.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>ClCCl.CCOC(C)=O>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrBr
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Ex-62A: A solution of 2-hydroxy-4-methoxybenzaldehyde (3.03 g, 20 mmol) in 25 mL of dichloromethane was cooled to 0° C. and treated dropwise with a solution of bromine (3.41 g, 21 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 1.5 hours. The solvent was removed by rotary evaporation to give a residue. The residue was taken up in EtOAc and washed with 3 portions of water. The organic layer was dried over MgSO4. The drying agent was removed by filtration, and solvent was removed by rotary evaporation to give 3.9 g of the desired 5-bromo-2-hydroxy-4-methoxybenzaldehyde as a solid, m.p. 111-115° C.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:11]1[C:2]([NH:17][NH2:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2nc(Cl)c(OC)nc2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(NN)c(OC)nc2c1
Temperature: 50 °C

Procedure:
A mixture consisting of 5 g. (0.022 mole) of 2-chloro-3,6-dimethoxyquinoxaline and 2.8 g. (0.056 mole) of hydrazine hydrate (2.7 ml.) in 75 ml. of ethanol was heated at 50° C. overnight. Upon completion of this step, a further 1.0 ml. of hydrazine hydrate was added to the mixture and the resulting mixture was heated at 50° C. for a period of six hours. At this point, another 1.0 ml. of hydrazine hydrate was added and the final reaction mixture was heated at 50° C. overnight prior to being cooled to room temperature. The spent mixture was then filtered and the recovered precipitate washed with ethanol to ultimately afford 4.1 g. (85%) of pure 3,6-dimethoxy-2-hydrazinoquinoxaline, m.p. 128°-130° C. (decomp.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>C(O)CCC>[OH:20][CH2:19][CH2:21][NH:22][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Reactant: NCCO
Solvent: CCCCO
Product: CCCOc1ccccc1-c1nc(NCCO)cc(=O)[nH]1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.43 g) and ethanolamine (0.3 g) in n-butanol (8 ml) was heated under reflux for 4 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was washed with diethyl ether and then eluted from silica with chloroform: methanol (gradient elution). The combined fractions containing product were evaporated under reduced pressure to yield a crude product which was recrystallised from isopropanol:diethyl ether to yield the title compound, 0.28 g, m.p. 164.5°-65.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19]Cl)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:22].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][Br:22])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: Cc1c(CCl)nc2ccccc2c1OCc1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CBr)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (5.0 g) in THF (50 mL) was added anhydrous lithium bromide (15 g), followed by heating under reflux for 3 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added to the residue, followed by stirring, and the resulting solid was collected by filtration. This solid was dried under vacuum at 60° C. to obtain 5.73 g of 4-(benzyloxy)-2-(bromomethyl)-3-methylquinoline as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH2:27][CH2:28][CH2:29]Cl)(=[O:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:29][CH2:28][CH2:27][S:24]4(=[O:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CN(c2ccc(NS(=O)(=O)CCCCl)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CN(c2ccc(N3CCCS3(=O)=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 100 °C

Procedure:
A mixture of 13.5 mg (0.027 mmol) of 5-chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of DMF is heated at 100° C. for 2 h. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic phase is dried and concentrated. The residue is purified by preparative thin-layer chromatography (silica gel, dichloromethane/methanol, 95:5). Yield: 1.8 mg (14.4% of theory),
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[N:14][CH:15]=1.[Cl-].[Li+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:13]3[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][N:14]=3)[CH:3]=2)=[N:14][CH:15]=1
Reactant: Brc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccc(-c3ccc(C)cn3)c2)nc1
Temperature: 25 °C

Procedure:
A mixture of 1,3-dibromobenzene (1.88 g, 8 mmol), 5-methyl-2-tri-n-butylstannylpyridine (7.18 g, 18.8 mmol), lithium chloride (28 g, 0.67 mol), bis(triphenylphosphine)palladium dichloride (360 mg, 0.5 mmol) and toluene (150 cm3) was degassed by bubbling argon through the mixture for 15 minutes. The reaction mixture was heated under reflux for 24 h. The mixture was then allowed to cool to room temperature and was filtered through small pad of silica gel, which was then washed with ethyl acetate. The filtrate was evaporated to dryness and the product was purified by column chromatography (silica gel, hexane/ethyl acetate, 1/1) to give the title product as a colourless solid. Yield 728 mg, 35%. δH (270 MHz; CDCl3): 2.36 (6H, s, 2×CH3), 7.54 (1H, t, J 8.0, 5-H), 7.56 (2H, dd, J 8.2 and 2.1, 2×py 4-H), 7.72 (2H, d, J 8.2, 2×py 3-H), 7.99 (2H, dd, J 8.0 and 1.8, 4-H, 6-H), 8.52 (2H, d, J 2.1, 2×py 6-H), 8.54 (1H, t, J 1.8, 2-H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)cc(OCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (Chakraporty, T. K. and Reddy, G. V. J. Org. Chem., 57, 1992, 5462) (3.3 g, 18.1 mmol) in dry DMF (30 mL) was added K2CO3 (6.3 g, 45.3 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then ((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and the mixture stirred at 160° C. for 2 hrs. The reaction was cooled down to room temperature and diluted with EtOAc, washed with water and brine, and dried over MgSO4, filtered and concentrated to give the crude product (90%) which was used in the next step without further purification.