Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[N:18]O)[CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27]>CO.CCOCC.O[Mo](O)(=O)=O>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27].[NH2:18][CH:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][C:14]([CH3:16])([OH:17])[CH3:15]
Reactant: CC(C)(O)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Agent: O=[Mo](=O)(O)O
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH4-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(C)(O)CC(N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-hydroxy-3-methylbutan-1-one oxime (2 g) in methanol (70 ml) was cooled to -10° C. and molybdic acid (1.67 g) added with stirring. Sodium borohydride (2.7 g) was added portionwise. The temperature of the reaction mixture was maintained at 0° C. for 21/2 hours and then water (200 ml) was added. The reaction mixture was extracted with ether, the extract filtered, and the filtrate washed with water and dried. Removal of the solvents yielded an oil which was dissolved in ether. A solution of maleic acid in ether was added and a gum was formed which solidified to give 4-amino-4-[1-(4-chlorophenyl)cyclobutyl]-2-methylbutan-2-ol maleate (m.p. 139°-144° C. (dec)).
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH2:5][NH2:6])[OH:4].[C:7](OC([O-])=O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].S(=O)(=O)(O)O>O1CCCC1.[Cl-].[Na+].O>[OH:4][CH2:3][CH2:5][NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCO
Yield: 99.8 %

Procedure:
Sodium hydroxide (800 mL of 2M in water) was added to a solution of ethanol amine (100 6, 1.64 mole) in tetrahydrofuran (850 mL). The reaction mixture was placed in a 25° C. water bath and stirred rapidly. A solution of tert-butyl dicarbonate (358 g, 1.64 mole) in tetrahydrofuran (800 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred for a total of 4 hours at which time analysis by TLC indicated that all of the starting material had been consumed. The tetrahydrofuran was removed under reduced pressure to provide an aqueous slurry. The slurry was cooled in an ice bath. The pH was adjusted to pH 2 by the addition of sulfuric acid (1 L of 1M in water). The resulting solution was extracted with ethyl acetate (4×500 mL). The combined extracts were washed sequentially with water (3×500 mL) and brine (2×500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a first lot of crude product. Analysis of the aqueous and brine washes indicated that they contained product so they were extracted with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a second lot of crude product. The two lots were combined to provide 263.8 g of tert-butyl (2-hydroxyethyl)carbamate as a colorless oil.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[CH3:12][NH:13][CH3:14]>C1COCC1>[OH:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][CH2:3][C:2]([N:13]([CH3:14])[CH3:12])=[O:11]
Reactant: CNC
Reactant: O=C1CCc2ccccc2O1
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1ccccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of chroman-2-one (444 mg) in THF (1 mL) was treated with dimethylamine (7.5 mL) and stirred at room temperature for 5 hours. The solution was concentrated. The concentrate was filtered through a small pad of silica gel.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][C@@H:20]([C@H:24]([O:37]C=O)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)[C:21]([OH:23])=[O:22]>CO>[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][C@@H:20]([C@H:24]([OH:37])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=1)[C:21]([OH:23])=[O:22]
Reactant: O=CO[C@H](CCc1ccc(C(F)(F)F)cc1)[C@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)[C@H](O)CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.178 g) was added to a solution of the compound obtained from step h above (0.2 g) in methanol (7 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated, and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 10% methanol in dichloromethane as eluant to afford the title compound (0.090 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@H:11]([NH2:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH2:13])[CH3:12]
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(N)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-(+)-1-(2-napthyl)ethylamine (102.6 mg, 0.599 mmol), 2,4-dichloro-5-fluororo pyrimidine (100 mg, 0.599 mmol) and cesium carbonate (390 mg, 1.2 mmol) was dissolved in 1,4-dioxane (3 ml) and H2O (3 ml) in a 10 ml microwave vial. The mixture was stirred in the microwave reactor at 80° C. for 10 minutes. The residue was dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO4) and concentrated to get the crude intermediate 2-chloro-5-fluoro-pyrimidin-4-yl)-(1-naphthalen-2-yl-ethyl)-amine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=1)=[CH:9][C:8]2=[N:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:26]([O:25][N:24]=[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[O:11][C:10]([C:15]2[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=2)=[CH:9]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C(=O)O)cc12
Temperature: 60 °C
Yield: 83.2 %

Procedure:
A suspension of 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid methyl ester (example 115B) (170 mg, 0.43 mmol) in a mixture of tetrahydrofuran/methanol/water (2.0 ml/0.5 ml/0.5 ml) was treated with lithium hydroxide monohydrate (55 mg, 1.29 mmol) and heated at 60° C. for 2 hours. The solvents were removed and the residue was diluted with water, neutralized to pH 5-6 with a 1N solution of hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to give 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid (135 mg, 84%) as a green solid. A solution of the previous carboxylic acid, (3-Dimethylamino-propyl)-ethyl-carbodiimide, hydrochloride (90 mg, 0.47 mmol), 1-Hydroxybenzotriazole hydrate (68 mg, 0.50 mmol) and triethylamine (250 μl, 1.80 mmol) in dimethylformamide (6.0 ml) was stirred at 0° C. for 1 hour then 4-(2-aminoethyl)-morpholine (52 μl, 0.40 mmol) was added. The mixture was stirred at room temperature for 18 hours. The volatiles were removed under vacuum and the residue taken into ethyl acetate, washed several times with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient ethyl acetate/methanol 0-8%) to yield the title compound as a yellow solid (137 mg, 78%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[CH:12]=[O:13])[CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH2:12][OH:13])[CH:14]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a suspension of the crude 5-morpholino-2-nitrobenzaldehyde in a mixture of tetrahydrofuran and ethanol (100 mL/100 mL) was slowly added sodium borohydride (4.0 g). The mixture was stirred at room temperature for 1 hour, and then was partitioned between ether and saturated ammonium chloride. The aqueous phase was extracted with ether, and the organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product (5-morpholino-2-nitrophenyl)methanol (8.5 g, yield 62.3%, two steps).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.CCCCCC.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to 320 mL of benzene. The reaction was stirred for 48 h at room temperature (rt) and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (˜0.5 mmHg, 115°-118° C.) afforded 38.7 g (76%) of a clear and colorless oil. Upon cooling the product solidifies to give white crystals (2). 1-(Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) was added to 430 mL of tetrahydrofuran (THF). The solution was cooled to −78° C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL, 0.11 mol) was added dropwise to the reaction flask. Upon completion, the reaction was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to the reaction. After the addition was completed the reaction mixture was warmed slowly to rt and then stirred for 24 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane as eluant) afforded a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3). 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to −20° C. A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6 mL, 19 mmol) was added dropwise to the reaction flask. Upon completion the reaction was stirred for 1 h at −20° C. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at rt for 3.5 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) afforded a light yellow oil. Upon cooling the product solidifies to give yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl -5-imidazolecarboxaldehyde (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48](Br)=[N:49][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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]>[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([C:32]2[CH:31]=[CH:30][C:29]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:16](=[O:17])[C:15]4[N:14]=[CH:13][N:12]([C:18]5[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=5)[C:11]=4[N:10]=3)=[CH:34][CH:33]=2)=[N:49][CH:50]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Nc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-phenyl)-methane sulfonamide (10, 0.35 g, 0.57 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 5-amino-2-bromopyridine (0.147 g, 0.850 mmol), cesium carbonate (0.360 g, 1.13 mmol), Pd(dppf)2Cl2 (0.020 g, 0.028 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 12 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to afford N-{3-[2-[4-(5-amino-pyridin-2-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-phenyl}-methane sulfonamide, as a yellow solid. 1H NMR (CD3OD, 400 MHz) δ 8.53 (s, 1H), 7.95 (m, 3H), 7.69 (d, 5H), 7.55 (m, 2H), 7.38 (m, 4H), 7.25 (m, 1H), 3.01 (s, 3H); LC-MS calculated for C29H22ClN7O3S (M+H+) 584.1, found 584.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH3:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:35][CH2:36][CH:37]([NH:40][CH3:41])[CH2:38][CH2:39]2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CNC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CNC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-N-methylpiperidin-4-amine. MS (ESI): mass calcd. for C22H24FN5O2S, 441.16; m/z found, 442.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.21 (d, J=1.4, 1H), 8.12-8.09 (m, 1H), 7.96 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.32-7.30 (m, 1H), 7.28 (s, 1H), 3.49-3.42 (m, 2H), 3.10-3.01 (m, 1H), 2.63 (s, 3H), 2.54-2.42 (m, 2H), 2.00-1.92 (m, 2H), 1.47-1.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61]CC4C=CC(I)=CC=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:70]([O-:72])=[O:71])[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][CH:42]([CH2:43]3)[CH2:41]1)[CH2:47]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)(C)C.ClCCCl>[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:6]5[CH:5]=[CH:4][S:3][C:2]=5[Cl:1])=[CH:15][CH:14]=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:70]([O-:72])=[O:71])[CH2:49][CH:44]3[CH2:43][CH:42]([CH2:48][CH:46]([CH2:45]3)[CH2:47]1)[CH2:41]2
Reactant: O=C(O)c1ccc(-c2ccsc2Cl)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)NCc2ccc(I)cc2)ccc1NCC12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: O=C(NS(=O)(=O)c1ccc(NCC23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(-c2ccsc2Cl)cc1
Reaction time: 8 h

Procedure:
A room temperature mixture of Example 29A (39.4 mg, 0.17 mmol), resin-bound dicyclohexylcarbodiimide (225.0 mg, 1.83 mmol/g), and dimethylaminopyridine (60.0 mg, 4.95 mmol) was treated with a solution of Example 28A (40 mg, 0.11 mmol) in a 1:1 mixture of 1,2-dichloroethane and 2-methyl-2-propanol (3 mL), and agitated overnight on an Argonaut Technologies Quest 210. The mixture was treated with resin bound p-TsOH (990 mg, 1.44 mmol/g), agitated for 1 hour, decanted, and washed with dichloromethane. The combined extracts were concentrated and purified by HPLC using 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 586 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.66 (d, 1H), 8.57 (t, 1H), 7.96 (d, 2H), 7.95 (dd, 1H), 7.71 (d, 2H), 7.59 (d, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.29 (d, 1H), 3.17 (d, 2H), 1.97 (s, 3H), 1.58 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19](I)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:20]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1

Procedure:
N-tert-Butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.74) (0.37 g, 0.86 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.33 g, 1.29 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.2 g) which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][C:8]3[NH:9][C:10]4[C:15]([C:16]=32)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:5][CH:4]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][C@@H:8]3[C@H:16]2[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]3)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)-c1c([nH]c3ccccc13)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)[C@@H]1c3ccccc3N[C@@H]1C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5,6-Dihydro-9-methoxyindeno[2,1-b]indole (0.56 g), as a suspension in glacial acetic acid (25 cm3) at 16° C., was treated with sodium cyanoborohydride (1.0 g) in small portions over 6 hours. The resulting solution was stirred for a further 1 hour, and then poured into ice-water (100 cm3). The solution was separated from a small amount of resinous material and the filtrate treated with sodium carbonate (2.5 g) in small portions with vigorous stirring. The colourless solid which separated was collected and crystallised form ethanol as needles. Yield: 0.31 g, 55% M.p. 129°-130° C. 1H NMR (CDCl3) δ: 3.06 (1H, dd, J=16.5 and 1.5 Hz), 3.2-3.8 (1H, br.s), 3.31 (1H, dd, J=16.5 and 6.0 Hz), 3.76 (3H, s), 4.71 (1H, d, J=8.0 Hz), 4.80 (1H, ddd, J=8.0, 6.0 and 2.0 Hz), 6.5 (1H, d, J=8.5 Hz), 6.58 (1H, dd, J=8.5 and 2.5 Hz), 6.99 (1H, d, J=2.5 Hz), 7.15-7.24 (3H, m), 7.33-7.36 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][CH:11]=[CH:12][CH2:13]Br>>[Br:10]/[CH:11]=[CH:12]\[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrC=CCBr
Product: O=Cc1ccc(OC/C=C\Br)cc1

Procedure:
4-Hydroxybenzaldehyde and 1,3-dibromo-1-propene were processed as described in Example 33B to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[O:10].O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:46])[CH2:44][I:45].Cl>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[I:45][CH2:44][C:43]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[O:10])=[O:29])=[O:46]
Reactant: O=C(CI)NCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)COCCOCCNC(=O)COCCOCCNC(=O)CCCCCCCCCCCNC(=O)CI
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a solution of [2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (194 mg) in 0.1 M sodium carbonate was added acetonitrile (5 ml) followed by a solution of 12-(2-Iodoacetylamino)dodecanoic acid 2,5-dioxopyrrolidin-1-yl ester (260 mg) in acetonitrile (6 ml). After stirring for 45 min, pH was adjusted to 4 with 1 N HCl and the mixture was purified by preparative HPLC: C18, 3 cm column (Gemini), A-buffer 0.1% TFA in MiliQ water, B-buffer: 0.1% TFA in AcCN, flow 20 ml/min, gradient 10-80% B over 30 min. Product containing fractions were pooled and concentrated to give the title compound in 49% yield (180 m). LC-MS, M/z: 674.3 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.CS(O)(=O)=O.C([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[C:33]([C:39]4[S:40][CH:41]=[CH:42][N:43]=4)=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:44][CH3:45])C1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[CH3:45][O:44][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:21]=1[OH:20])[N:28]=[CH:27][CH:26]=[C:25]2[O:31][C:32]1[C:33]([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
Trifluoroacetic acid (1 ml) and methanesulfonic acid (0.1 ml) were added to 7-benzyloxy-6-methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinoline (compound 328) (40 mg), and the mixture was stirred at 80° C. for 1.5 hr. The reaction solution was cooled to room temperature, and a saturated aqueous sodium hydrogencarbonate solution was then added to the reaction solution. The mixture was made alkaline, and the mixture was then extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 70%).