Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 86 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 86%. Melting point: 161-163° C. (Ethyl acetate-hexane)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:45][NH:46][CH2:47][CH:48]([CH3:50])[CH3:49].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:47]([N:46]([CH3:45])[C:19]([C:8]1[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=1)=[O:20])[CH:48]([CH3:50])[CH3:49]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: CNCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)N(C)CC(C)C)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (260 mg, 0.91 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (350 mg, 1.8 mmol), 1-hydroxybenzotriazole hydrate (140 mg, 0.91 mmol), CH2Cl2 (5 mL) were added N-methylisobutylamine (120 mg, 1.4 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.4 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by silica gel column (0-60% EtOAc/hexane) to yield a syrup. LC-MS: 354.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[C:5]([N+:22]([O-])=O)=[CH:4][N:3]=1.[NH4+].[Cl-].CCO.O>C(Cl)Cl.[Fe]>[NH2:22][C:5]1[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Br)ncc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Br)ncc2N)C1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a mixture of tert-butyl 3-((2-bromo-5-nitropyridin-4-yl)amino)piperidine-1-carboxylate. (1.24 g, 3.01 mmol, 1.0 eq) and NH4Cl (2.43 g, 45 mmol, 15 eq) was added a 2:1 mixture EtOH/water (30 mL). The reaction mixture was heated to reflux, then iron powder (0.67 g, 12 mmol, 3.5 eq) was added in portions over 15 min and the suspension was continued to be heated at refluxed for 16 h. The reaction mixture was cooled to rt, diluted with CH2Cl2 (300 mL) and filtered through celite. The organic layer was washed with water (50 mL×2) and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (1.2 g, 100%) which was used to next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 7.66 (s, 1H), 6.63 (s, 1H), 4.51-4.39 (m, 1H), 3.89-3.86 (m, 1H), 3.67-3.63 (m, 1H), 3.41-3.10 (m, 4H), 2.09-1.95 (m, 1H), 1.74-1.60 (m, 3H), 1.47 (s, 9H). ESI-MS (M+H+): 371.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([S:10][CH3:11])=[C:7]([C:12](=S)[NH2:13])[CH:6]=1)=[O:4].Br[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([C:25](OC)=S)[S:22][C:23]=1C)=O.[CH3:29]C(C)=O>>[CH3:11][S:10][C:8]1[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[C:12]1[N:13]=[C:23]([C:19]2[CH:17]=[CH:16][CH:25]=[CH:21][CH:20]=2)[S:22][CH:29]=1
Reactant: CC(C)=O
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: COC(=O)c1cc(C(N)=S)c(SC)s1
Product: COC(=O)c1cc(-c2csc(-c3ccccc3)n2)c(SC)s1
Yield: 65 %

Procedure:
5-(Methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (100 mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was dissolved in acetone (20 ml). To this solution, methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (112 mg) as prepared in previous step was added and heated at reflux for 3 h. At this point the solid that precipitated was filtered off and washed with acetone and dried under vacuum to give 82 mg (65%) of methyl 5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxylate. 1H-NMR (CDCl3; 300 MHz) δ2.67 (s, 3H), 3.91 (s, 3H), 7.44-7.49 (m, 3H), 7.61 (s, 1H), 8.03-8.06 (m, 2H), 8.28 (s, 1H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH2:6](N(CC)CC)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](O)=[O:20].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([C:19](=[O:20])[CH2:2][N:3]([O:4][CH3:5])[CH3:6])[CH:22]=1
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CON(C)CC(=O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To a solution of N,O-dimethyl hydroxylamine hydrochloride (1.0 g, 10.25 mmol) in dichloromethane (50 mL) was added triethyl amine (3.10 g, 30.75 mmol). The mixture was stirred at room temperature for 10 min followed by adding 5-bromo-2-chloro-benzoic acid 15a (2.41 g, 10.25 mmol, purchased from Beijing yu xiang hui da chemical co., LTD) and bis(2-oxo-3-oxazolidiny)phosphonic chloride (3.13 g, 12.3 mmol) in turn. The resulting mixture was further stirred for 23 hours. The reaction mixture was quenched with 40 mL of water and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15b as a white solid (2.90 g, 100%). The crude product was used in next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:4][C:3]=1[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]=1.CN(C)C=O.[H-].[Na+].Br[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:5]([C:9]([CH3:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][C:3]=1[C:18]1[N:19]=[C:20]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:23]=1
Reactant: CC(C)(c1ccccc1)c1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)cc1O
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.5 %

Procedure:
To a 500 mL three-necked, round-bottomed flask equipped with a condenser, magnetic stirrer, thermometer, and a nitrogen atmosphere axe charged 4.00 g (8.71 mmol) of the product of Example 9, 50 mL of N,N-dimethylformamide and 0.40 g (10 mmol) of sodium hydride (60% in mineral oil). The mixture is heated to an external temperature of 50° C. and 1.68 g (8.70 mmol) of 1-bromooctane are added. The mixture is stirred at this temperature for six hours and is allowed to cool to room temperature. The mixture is poured into a beaker of water which is extracted four times with chloroform. The combined chloroform layers are washed four times with water and dried over anhydrous magnesium sulfate and filtered. The solvent is removed under reduced pressure to afford a yellow oil. The crude product is purified with medium pressure chromatography with 10:1 heptane:ethyl acetate followed by recrystallization from acetone/water to yield 1.12 g of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O.C(O)C.C(OCC)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)=[CH:16][C:15]=2[NH2:30])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
The product of Example 147B (374 mg, 0.723 mmol), iron powder (248 mg, 4.45 mmol), and ammonium chloride (253 mg, 4.74 mmol) in water (5 mL) and ethanol (10 mL) were heated at 80° for 45 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum provided the title compound as a golden solid (327 mg, 93%).
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)C[C@@H]1c1ccnn1C
Yield: 81.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (171 mg, 0.277 mmol) prepared in Example 133a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (106 mg, 82%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:29][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([S:19]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH2:27][OH:28])(=[O:21])=[O:20])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.[Cl-].[Na+].O>[CH3:41][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:28][CH2:27][C@@H:23]2[CH2:24][CH2:25][CH2:26][N:22]2[S:19]([C:10]2[CH:9]=[CH:8][C:7]3[N:6]4[CH2:29][C:2]([CH3:30])([CH3:1])[CH2:3][N:4]=[C:5]4[C:13]4([O:18][CH2:17][CH2:16][CH2:15][O:14]4)[C:12]=3[CH:11]=2)(=[O:21])=[O:20])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: CC1(C)CN=C2N(C1)c1ccc(S(=O)(=O)N3CCC[C@H]3CO)cc1C21OCCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Yield: 65.8 %

Procedure:
A solution of {(2S)-1-[(3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methanol (0.100 g, 2.300 mmol), p-toluenesulfonyl chloride (0.070 g, 0.340 mmol), N,N-diisopropylethylamine (0.100 ml, 0.580 mmol) and 4-(dimethylamino)pyridine (0.020 g, 0.070 mmol) in CH2Cl2 (5 mL) was stirred at rt for 2 days. The reaction was poured into brine and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound as a white foam (0.132 g, 97% ). Anal: Calc'd for C28H35N3O7S2: C, 57.03; H, 5.98; N, 7.13. Found: C, 56.38; H, 5.65; N, 6.81. NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 590.3 [M+H].
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].[ClH:31]>O1CCCC1.C(O)(C)C>[ClH:31].[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][CH:2]([NH:1][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[OH:24])[CH2:3]2)=[CH:8][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccc2c(c1)CC(N)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a mixture of 1.77 g of 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene and 1.1 g of triethylamine in 25 ml of tetrahydrofurane, there is added slowly 1.94 g of bromoacetophenone in 50 ml of tetrahdryofurane. The reaction mixture is left under stirring at room temperature for 2 hours, then is filtered andevaporated. The residue thus obtained is dissolved in isopropyl alcohol and acidified with a solution of hydrogen chloride in isopropyl alcohol, then it is precipitated with an etheral solution, filtered and dried. To the solution of the residue in 70 ml of methanol, cooled to 4° C., there is added slowly 1.5 g of sodium borohydride. The reaction mixture is stirred at room temperature for an hour, poured into water and acidified with acetic acid. The solution is made alkaline with sodium bicarbonate and the organic phase is extracted with methylene chloride, dried and evaporated to dryness. The oil thus obtained is purified by flash-chromatography using a mixture ethyl acetate/methanol 8/2. After recrystallization from isopropyl alcohol, the 2-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride is obtained. Yield: 30% of the theoretical value.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10].C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CN(C1C=CC=CN=1)C>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OC1Cc2ccccc2C1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC1Cc2ccccc2C1
Reaction time: 18 h
Yield: 77.5 %

Procedure:
2-Indanol (20.00 g, 149.5 mmol) and diisopropylethylamine (21.2 g, 164 mmol) was stirred in dichloromethane (300 mL) at 0° C. Methanesulfonyl chloride (18.78 g, 164 mmol) and dimethylaminopyridine (1.80 g) were added simultaneously and stirring continued at room temperature for 18 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated. This was washed with NaHCO3 (sat) and with citric acid solution (5%) and dried over MgSO4. The filtered solution was concentrated and the resultant solid recrystallized from isopropanol-EtOH (3:1) to give off-white crystals (24.6 g, 78%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1>>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[OH:13])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1nccs1
Product: OC(c1ccc(Br)cc1)c1nccs1

Procedure:
Using the same protocol as described in example 22, step 1, 2-bromothiazole (451 μL, 5.0 mmol) was added to 4-bromobenzaldehyde (1.018 g, 5.5 mmol). The crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][OH:16].C[O-].[Na+].Cl>CCOC(C)=O>[CH3:15][O:16][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.4 %

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.15 g, 665 μmol, prepared according to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) in methanol (2 mL) sodium methoxide (79.0 mg, 1.46 mmol) was added and the reaction refluxed for 5 hours. Another 287 mg (5.32 mmol) sodium methoxide was added and the white suspension was stirred at reflux temperature overnight. After 23 hours the suspension was allowed to cool to room temperature and was poured on saturated 1M HCl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated to give the desired compound as a colorless solid (0.133 g; 90%). MS (ESI): m/z=220.02 [M−H]−.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>>[S:8]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: OCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCCCCO)cc1

Procedure:
By following a procedure of Reference Example 1, 6.2 g (60 mmole) of 1,5-pentanediol and 5.7 g (30 mmole) of tosyl chloride were treated to give 1,5-pentanediol monotosylate as a colorless oily material Yield 4.1 g (yield: 53%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[F:13])(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:7][C:6]=1[F:13])(=[O:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)cc1F
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1F

Procedure:
The product was characterized as 4-acetamido-3-fluorobenzaldehyde 15. 4-Acetamido-3-fluorobenzaldehyde 15 reacts with thiosemicarbazide to yield 4-acetamido-3-fluorobenzaldehyde thiosemicarbazone 16. Compound 16 has been tested and shown to be both non-toxic and highly active against M. Tuberculosis.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10])#[N:2].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])#[N:2]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of 3-(2-cyanophenylsulfonyloxy)-5-methylphenol (580 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (10% ethyl acetate in dichloromethane) to give the title compound as a colorless oil (560 mg, 80%). 1H-NMR (300 MHz, CDCl3) δ 8.11 (m, 1H), 7.94 (m, 1H), 7.77-7.82 (m, 2H), 6.65 (s, 1H), 6.59 (s, 1H), 6.57 (s, 1H), 4.05 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 2.00 (m, 2H), 1.76 (brs, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)C(CC)=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.[CH:32]([Mg]Cl)([CH3:34])[CH3:33].[CH2:37]1[CH2:41]OC[CH2:38]1>[Cl-].[Cl-].[Zn+2]>[CH2:32]([C:34]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:6]2=[N:7][C:2]([CH:37]([CH3:41])[CH3:38])=[CH:3][C:4]([CH3:31])=[C:5]2[N:10]=1)[CH3:33]
Reactant: CC(C)[Mg]Cl
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1nc2c(C)cc(C(C)C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine (75 mg) in THF (2 mL) at -78° C. was sequentially added ZnCl2 (1.58 mL, 1M/ether), iso-propylmagnesium chloride (0.79 mL, 2M/ether), and tetrakis-triphenylphosphinepalladium (15 mg). After complete addition the reaction was warmed to RT and stirred for 16 hours. Extractive workup (EtOAc, from dilute HOAc), and purification (SiO2, 80/20/1 CH2Cl2 /MeOH/NH4OH) gave 43 mg of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:23][N:24]=[C:25]=[O:26]>C(O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[N:8]([C:25](=[O:26])[NH:24][CH3:23])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CN=C=O
Reactant: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Solvent: CCO
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Br)ccc2CC1C
Yield: 84 %

Procedure:
0.84 g (2.33 mmoles) of 8-bromo-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 22, Step D) are reacted with methyl isocyanate according to the method of Example 3. The crude product is suspended in 5 ml of hot ethanol. After filtration and drying, 0.82 g (84%) of the title compound are obtained. M.p.: 197°-200° C.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:37])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].CO>C1COCC1>[CH2:21]([N:17]1[C:18]2[C:13](=[C:12]([OH:37])[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:10])=[N:20][CH:19]=2)[CH:14]=[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[C:16]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2cc3c(O)c(C(=O)NCCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A mixture of 4-{[1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carbonyl]-amino}-butyric acid ethyl ester (38 mg, 0.074 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washes several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a yellow solid. MS: (+) m/z 488.40 (M+1).