Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>CC(N(C)C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 90 °C

Procedure:
Cesium carbonate (14.19 g, 43.56 mmoles, 2 equivalents) was added to a stirred solution of 4-amino-3-nitrophenol (3.35 g, 21.78 mmoles, 1 equivalent) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (6.69 g, 23.96 mmoles, 1.1 equivalent) in anhydrous DMA (30 ml). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6]
Reactant: COc1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CO)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 3-bromo-4-methoxybenzaldehyde (4.98 g) in ethanol (50 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (1.31 g) under ice-water cooling. The mixture was stirred at 0° C. for 2 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with water and brine, and dried over magnesium sulfate. The organic layer was evaporated in vacuo to give 3-bromo-4-methoxybenzyl alcohol as a colorless oil (4.98 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:20][C:19]3[C:18]([CH3:34])([CH3:33])[CH2:17][CH2:16][C:15]([CH3:36])([CH3:35])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][C:19]3[C:18]([CH3:33])([CH3:34])[CH2:17][CH2:16][C:15]([CH3:36])([CH3:35])[C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2CCCO[Si](C)(C)C(C)(C)C)C(C)(C)CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2cc3c(cc2CCCO)C(C)(C)CCC3(C)C)cc1
Yield: 85.3 %

Procedure:
To a solution of 4.0 g (7.7 mmol) of Methyl-4-{(E)-2-[3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate in 20 mL tetrahydrofuran was added a solution of 8 mL (8.08 mmol) tetrabutylammonium fluoride (1.0 M in tetrahydrofuran). After 30 min the reaction mixture was diluted with water and extracted with ethyl acetate. The organic fraction was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate) to give 2.67 g (85%) of Methyl-4-{(E)-2-[3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate (m.p.=109-115.5° C.).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23](O)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[C:34]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.C(OCC)(=O)C.[Cl-].[Na+]>[C:34]1([S:40]([NH:43][C:23]([C:18]2[C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][N:9]4[C:8]5[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=5[N:6]=[C:5]4[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:15]=3)=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)NS(=O)(=O)c2ccccc2)cc1
Temperature: 140 °C

Procedure:
960 mg (2.5 mmol) of 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid are dissolved in 25 ml of methylene chloride, treated with 2 ml of thionyl chloride and heated under reflux for one hour. The solvent is then distilled off and evaporated 2 times after adding methylene chloride. 390 mg (2.5 mmol) of benzenesulphonamide are added to the residue and the mixture is heated for one hour at 140° C. After cooling, the oil obtained is taken up in ethyl acetate/sodium chloride solution and extracted 3 times using ethyl acetate. The combined ethyl acetate phases are dried over sodium sulphate, evaporated and the crude product obtained is purified over a silica gel column using methylene chloride/ethanol as eluting agent.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[O:26]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cccc3ccccc23)ccc1CNCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(-c2cccc3ccccc23)ccc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of Example 20A (1.75 g, 4.95 mmol) in dichloromethane (40 mL) at −78° C. was treated with 1M BBr3 in dichloromethane (15.0 mL, 15.0 mmol), warmed to room temperature, stirred for 5 hours, quenched with water, and extracted with dichloromethane. The extract was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1.C(Cl)Cl>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cccc(-c2cncc(Br)c2)c1

Procedure:
A solution of 3-methoxy-phenylboronic acid (1.0 eq, 300 mg, 1.27 mmol) in DME (3 ml) and 2M sodium carbonate solution (1.2 ml) under an inert atmosphere of argon is treated with 3,5-dibromopyridine (300 mg, 1.27 mmol) followed by PdCl2(dppf).DCM (0.1 eq, 93 mg) and then is heated using microwave radiation at 90° C. for 30 minutes. The mixture is extracted with DCM and the organic extracts are washed with water. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with 0-30% EtOAc in iso-hexane to afford the title compound [M+H]+=265.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[C:19]([I:20])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].[OH-].[Na+].O>[C:21]1([S:27]([N:17]2[C:14]3=[N:15][CH:16]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:12]=[C:13]3[C:19]([I:20])=[CH:18]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(-c2cnc3[nH]cc(I)c3c2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cc1OC
Reaction time: 2 h

Procedure:
Into a Round bottom flask was added 5-(3,4-Dimethoxy-phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine, 133, (0.403 g, 0.00106 mol) and Tetra-N-butylammonium bromide (0.0342 g, 0.000106 mol), in 5.000 M of Sodium hydroxide in Water (2.73 mL). Benzenesulfonyl chloride (0.225 g, 0.00127 mol) in Methylene chloride (0.747 mL, 0.0116 mol) was added dropwise. After 2 h, 30 mL of Methylene chloride and 30 mL of water were added. The organic layer was separated and washed with 1M sodium bicarbonate (aq.) (30 ml×2) followed by water (30 ml) and brine (30 mL). The organic layer was collected and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by chromatography (Silica gel, ethyl acetate/hexanes) to give 295 mg of the desired product as a white solid. MS(ESI) [M+H+]+=521.04
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])=[CH2:28]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:28][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH2:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Bromosuccinimide (52.0 g, 292 mmol) and benzoylperoxide (2.0 g, 8.0 mmol) were added to a solution of isopropenylbenzene (82.0 g, 694 mmol) in carbon tetrachloride (200 mL). The reaction mixture was heated to reflux. After 18 h, additional N-bromosuccinimide (30.0 g, 168 mmol) was added. After 18 h, the mixture was allowed to cool to ambient temperature and the solid in the mixture was filtered off. The filtrate was concentrated and purified by vacuum distillation (95-120° C., 10 torr). The isolated mixture was purified by silica gel chromatography (100% hexanes) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)[N:9]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.11) (0.197 g, 0.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.15 g, 0.6 mmol) according to the general procedure III. Obtained as light yellow solid (0.24 g), which was subsequently deprotected.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]1([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl>O1CCCC1.C(OCC)(=O)C>[C:14]1([S:20]([CH2:23][CH2:24][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(CCn1c2ccccc2c2ccccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.8 g 9H-carbazole and 9.8 g phenylvinylsulphone are suspended in 3 ml of tetrahydrofuran, cooled to 0° C., combined with 60 μl benzyltrimethylammonium hydroxide (40% solution in water) and stirred for 20 minutes. Then the mixture is heated to 115° C. for 7 hours. Then it is divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>CCOC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2-hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (0.8 g; 3.6 mmol) in EtOAc (15 ml) at 0° C. is added NEt3 (610 μl) and methanesulfonyl chloride (340 μl). After addition the mixture is warmed to RT and stirred for 3 days. After completion the reaction mixture is acidified with diluted hydrochloric acid and extracted twice with EtOAc. The organic phase is washed with brine, dried over MgSO4 and evaporated to give methanesulfonic acid 2-tert-butoxycarbonylamino-benzyl ester (0.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[C:5]#[N:6].Cl>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1cc(Cl)cc(C#N)c1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: N#Cc1cc(O)cc(Cl)c1
Temperature: 185 °C
Yield: 76.2 %

Procedure:
3-Chloro-5-(methyloxy)benzonitrile (46.48 g, 277 mmol) and anhydrous Lil (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 mL) under nitrogen and heated to 185° C. for 8 h. The reaction mixture was cooled to RT and solidified upon standing. The solid was broken-up and added to a mixture of 10% HCl and ice. The solution was extracted with EtOAc (3×200 mL), dried over MgSO4 and evaporated. The solid was triturated in hexanes and EtOAc to afford an off-white solid and a second crop of product was obtained from the filtrate. The combined material was dried under vacuum to afford the title compound (32.40 g, 76%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.69 (s, 1H), 7.37 (t, 1H), 7.09-7.13 (m, 2H). MS: m/z 152.1 (M−1).
Reaction SMILES: C[O:2][C:3]([CH:5](C(OC)=O)[N:6]1[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][N:9]([CH2:10][CH2:11][N:12]([CH:20](C(OC)=O)[C:21](OC)=[O:22])[CH2:13][CH2:14]2)[CH2:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:22][CH2:21][CH2:20][N:12]1[CH2:11][CH2:10][N:9]2[CH2:19][CH2:18][N:15]([CH2:16][CH2:17][N:6]([CH2:5][CH2:3][OH:2])[CH2:7][CH2:8]2)[CH2:14][CH2:13]1
Reactant: COC(=O)C(C(=O)OC)N1CCN2CCN(CC1)CCN(C(C(=O)OC)C(=O)OC)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCN1CCN2CCN(CCO)CCN(CC1)CC2

Procedure:
From 4,10-Bis(dimethoxycarbonylmethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.3.6.8) and lithium aluminum hydride.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Br:30])=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+].C(O)(=O)C>CCCCCCC>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Br:30])[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Cl)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCCCCC
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1ccc(Cl)cc1Br
Temperature: 80 °C
Yield: 61.6 %

Procedure:
A 250-mL RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((2-bromo-4-chlorophenyl)amino)phenyl)acrylate (10.4 g, 20.68 mmol) and MeOH (103 ml) to give a thick, yellow suspension. Sodium methoxide (25 wt % in MeOH) (0.894 ml, 4.14 mmol) was added. A reflux condenser was attached, and the flask was heated to 80° C. overnight. The mixture was cooled to room temperature. Acetic acid (1.776 ml, 31.0 mmol) was added, and the mixture was concentrated. The residue was taken up in 2-PrOH and heated to boiling to give a brown solution. The mixture was cooled to room temperature with stirring then was concentrated. The residue was taken up in DCM and loaded onto a 25-g silica gel loading column. The column was eluted directly onto a pre-equilibrated 120-g Redi-Sep silica gel column with 0-50% EtOAc/Heptane to give a solid. The solid was taken up in heptane and filtered. The filtered solid was washed with heptane and dried under a stream of N2 (g) to give 6-(benzylthio)-1-(2-bromo-4-chlorophenyl)quinolin-2(1 H)-one (5.816 g, 12.73 mmol, 61.6% yield) as a tan solid. 1 H NMR (400 MHz, DMSO-d6)□=8.09 (d, J=2.3 Hz, 1 H), 8.01 (d, J=9.5 Hz, 1 H), 7.83 (d, J=2.2 Hz, 1 H), 7.72 (dd, J=2.3, 8.4 Hz, 1 H), 7.56 (d, J=8.4 Hz, 1 H), 7.41 (dd, J=2.2, 8.8 Hz, 1 H), 7.37-7.17 (m, 5 H), 6.71 (d, J=9.6 Hz, 1 H), 6.41 (d, J=8.8 Hz, 1 H), 4.25 (s, 2 H), 3.32 (s, 3 H). m/z (ESI) 456.0 (M+H)+.
Reaction SMILES: C(C1N=C(C2(C)COC2)NC=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12])#N.I[C:25]1[NH:29][C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[C:36]([F:39])([F:38])[F:37].IC1NC(C2(C)COC2)=NC=1C#N>>[CH3:18][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:25]1[NH:29][C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[C:36]([F:39])([F:38])[F:37]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C#N)c1
Reactant: FC(F)(F)c1nc(C2CCOCC2)[nH]c1I
Agent: CC1(c2nc(C#N)c(I)[nH]2)COC1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCOCC3)nc2C(F)(F)F)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 202.4, except 5-iodo-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole (compound 287.1) was used instead of 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cc(C)ccc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloro-5-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6](=[CH:10][C:11]([OH:13])=O)[C:7]([OH:9])=[O:8]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:17][C:16]1[CH:15]=[C:14]2[C:4](=[CH:3][C:2]=1[Cl:1])[O:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:11]2=[O:13]
Reactant: O=C(O)C=C(Oc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C(O)c1cc(=O)c2cc(Cl)c(Cl)cc2o1
Temperature: 70 °C
Reaction time: 14 h
Yield: 29.5 %

Procedure:
2-(3,4-Dichloro-phenoxy)-but-2-enedioic acid (17.98 g, 64.9 mmol) was combined with Eaton's Reagent (140 ml). The mixture was heated at 70° C overnight. After 14 h, the mixture was cooled to ambient temperature and added to ice (600 g). The resulting white precipitate was collected by filtration, washed with copious water, and air-dried. The white solid (16.8 g) was dissolved in hot DMSO and cooled slowly to ambient temperature. The supernatant was recovered and concentrated, and the process was repeated to provide the desired compound (4.96 g, 29%) as a white solid. The crystalline material proved to be the undesired 5,6-dichloro isomer. MS (APCI) m/z 259 [M+H]+; 1H NMR (300 MHz, DMSO-D6) δ ppm 6.96 (s, 1H) 8.16 (s, 1H) 8.26 (s, 1H).
Reaction SMILES: [ClH:1].[ClH:2].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[NH:12][C:13]1[NH:14][CH2:15][CH2:16]N=1.OO>Cl>[ClH:1].[Cl:1][C:9]1[C:10]([Cl:2])=[CH:11][C:6]2[N:5]=[C:4]([N:12]3[CH2:16][CH2:15][N:14]=[CH:13]3)[NH:3][C:7]=2[CH:8]=1
Reactant: c1ccc2[nH]c(NC3=NCCN3)nc2c1
Agent: Cl
Agent: OO
Product: Clc1cc2nc(N3C=NCC3)[nH]c2cc1Cl
Temperature: 80 °C
Yield: 67.4 %

Procedure:
2-(Benzimidazolyl)amino-2-imidazoline dihydrochloride (prepared as described in Example 14) (27.4 g, 0.10 mol) was dissolved in concentrated hydrochloric acid (300 ml). The solution was stirred and heated to 80°C. A 15% solution of hydrogen peroxide (68 ml) was added dropwise to the stirred solution maintaining the temperature at 80°C. A colourless crystalline precipitate was soon deposited. At the end of the addition the solution was filtered, whilst hot and the precipitate washed with water and dried. This first crop (22.8 g), m.p. 275°-285°C, was found to be a mixture of chlorinated products. The second crop of crystals was deposited from the filtrate on cooling and was collected, washed with water and dried. This second crop (4.26g), m.p. 278°-281°C was found to be substantially pure 5,6-dichlorinated product. The first crop was recrystallised from aqueous dimethylformamide. The first (2.28 g), m.p. 297°-298°C, and second (6.42 g) m.p. 282°C crops of this recrystallisation were discarded, but the third crop (11.60 g) m.p. 252°-262°C was found to mainly 5,6-dichlorinated material. Both crops of 5,6-dichlorinated product were combined and recrystallised from boiling water to give 2-(5,6-dichlorobenzimidazolyl-2-imidazoline monohydrochloride (9.83 g; 29%) as colourless microcrystals m.p. 279°-281°C.
Reaction SMILES: [C@@H:1]1([O:12][C@H]2[C@@H](O)[C@@H](CO)O[C@H](OC3C=CC(N)=CC=3)[C@@H]2O)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C([O-])(O)=O.[Na+].O>O.CC#N>[OH:12][C@H:1]1[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ccc(O[C@H]2O[C@H](CO)[C@H](O)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H]2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A mixture of p-aminophenyl 3-O-α-D-galactopyranosyl-α-D-galactopyranoside 22 (11 mg, 0.025 mmol), tetrameric platform 28, and NaHCO3 (3 mg, 0.030 mmol) in 0.15 mL of H2O/CH3CN (1:1) was slightly shaken for 1 h. After addition of 0.15 mL of H2O, the reaction mixture was set at room temperature for 2 d and purified on reversed phase HPLC column eluted at 1 mL/min with a gradient of acetonitrile-water (0 to 30%) over 15 minutes to yield 41 (4.6 mg, 40%) as a white solid: MS (ESI): m/e (M/2+1) Calcd. for C60H95N7O29: 1377.6 obsd: 1377.9.