Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27](OCC)(OCC)(OCC)[CH3:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:27]([CH3:28])=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Product: Cc1nnc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (150 mg) was heated in a sealed vessel with triethyl orthoacetate at 90° C. for 3 h. The mixture was cooled to room temperature and concentrated to give a crude residue that was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give 272. 1H NMR (dmso-d6, 400 MHz) δ 7.86 (m, 2H), 7.48 (m, 1H), 7.69 (m, 1H), 7.44 (m, 1H), 7.28-7.23 (m, 2H), 6.57 (s, 1H), 4.22 (t, 2H), 3.00 (t, 2H), 2.18 (s, 3H). MS (ESI) 474.0
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][NH:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:19]([CH3:21])[CH3:20])[CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1
Reactant: CC(C)Br
Reactant: Clc1cc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(Cl)cc(Cl)nc21
Temperature: 18 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred solution of 5,7-Dichloroimidazo[4,5-b]pyridine (5 g, 26.5 mmol.) in DMSO (50 mL) was cooled in an ice bath, and treated with K2CO3 (14.6 g, 106.2 mmol.) and 2-bromopropane (12.47 mL, 132.8 mmol.). The mixture was allowed to warm to 18° C. and stirred overnight. The DMSO was removed in vacuo. A mixture of the residue and water (100 mL) was extracted with AcOEt (3×300 mL). The extractions were combined, washed with brine (300 mL), dried over (Na2SO4) and concentrated. Chromatography of the residue on silica gel with toluene-AcOEt-CH2Cl2 3:1:1 gave 5,7-Dichloro-3-iso-propylimidazo[4,5-b]pyridine. (Yield: 57%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]([OH:12])([CH2:10][CH3:11])[CH2:8][CH3:9].C(N(CC)CC)C>ClCCl>[C:1]([O:12][C:7]([CH2:10][CH3:11])([CH3:6])[CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CCC(C)(O)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OC(C)(CC)CC
Temperature: 25 °C
Reaction time: 14 h
Yield: 63.2 %

Procedure:
To a solution of acryloyl chloride (5.0 g, 55.2 mmol) and 3-methyl-3-pentanol (7.6 ml, 60.8 mmol) in dichloromethane, triethylamine (23 ml, 166 mmol) was added at room temperature under a nitrogen atmosphere. After stirring at room temperature for 14 hours, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate=10:1) to give the titled compound (5.45 g, 63%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:27](OC)([O:30]C)[O:28]C.Cl>C1COCC1.CCCCCC>[C:16]1([C:11]2[C:12]3[C:7]([N:8]=[CH:9][CH:10]=2)=[C:6]2[C:15]([C:2]([B:27]([OH:30])[OH:28])=[CH:3][CH:4]=[N:5]2)=[CH:14][CH:13]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COB(OC)OC
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Temperature: -39 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-7-phenyl-1,10-phenanthroline (1.42 g) is dissolved in THF solvent (15 mL). The mixture is cooled to −39° C. and added over a period of 20 minutes to an n-hexane solution of n-BuLi (1.5 M; 3.12 mL) which has been cooled to −78° C. The reaction mixture is stirred for 30 minutes, followed by the addition of trimethyl borate (0.49 mL) in THF at −39° C. is added over a period of 20 minutes. The reaction mixture is maintained at −78° C. for one hour, then allowed to warn to room temperature over a day. The reaction mixture is acidified with cold 2N HCl extracted with ether. The organic layer is extracted with 1 N NaOH and filtered. To the filtrate is added 2 N HCl at 0° C. to yield a precipitate, which is filtered, washed, dried and re-crystallized from ethanol to give the desired product.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(N-(tert-butyloxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (10 g, 23 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (30 ml) and the mixture was stirred for 1 hour at room temperature. The solution was evaporated under reduced pressure and 10% sodium carbonate solution was added. The product was extracted four times with dichloromethane, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 3.0 g=40% (crude)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28](OC)(OC)OC.C(O)(=O)CC>>[NH:21]1[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=[C:17]1[C:15]([N:12]1[CH2:13][CH2:14][CH:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:26]2[O:27][CH3:28])[CH2:10][CH2:11]1)=[O:16]
Reactant: COC(OC)(OC)OC
Reactant: Nc1cccnc1NC1CCN(C(=O)c2nc3ccccc3[nH]2)CC1
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1C1CCN(C(=O)c2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 9.8 %

Procedure:
(4-((3-Amino-pyridin-2-yl)amino)piperidin-1-yl)(1H-benzo[d]imidazol-2-yl)methanone (520 mg, 1.55 mmol) was combined with tetramethylorthocarbonate (2 mL) and propionic acid (8 mg) and heated at 90° C. for 2 hours. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by silica chromatography to give (1H-benzo[d]imidazol-2-yl)(4-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)methanone (57 mg, 0.15 mmol, 9.8% yield). M+1: 377.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 31.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.14 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.525 g, 31.8%). 1H NMR δ(400 MHz, DMSO-d6) 9.96 (s, 1H), 8.91 (s, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.26 (dd, J=3.2, 9.3 Hz, 1H), 6.18 (s, 1H), 5.86 (m, 1H), 3.67 (m, 2H), 3.37 (m, 4H), 2.54 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.71 (m, 2H), 1.53 (m, 2H), 1.39 (s, 9H), 1.33 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20](=[O:26])(=[O:25])[NH:21][CH:22]3[CH2:24][CH2:23]3)[CH:15]=2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:27]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([S:20]([NH:21][CH:22]3[CH2:23][CH2:24]3)(=[O:25])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[CH:10][C:3]=1[C:4](=[O:5])[C:34]1[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=1
Reactant: CON(C)C(=O)c1cc(-c2cccc(S(=O)(=O)NC3CC3)c2)cnc1N
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)c2cc(-c3cccc(S(=O)(=O)NC4CC4)c3)cnc2N)cc1
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-(3-cyclopropylsulfamoyl-phenyl)-N-methoxy-N-methyl-nicotinamide (Intermediate GA) (0.08 g, 0.21 mmol) in THF (3 ml) is cooled to 0° C. 2M 4-tert Butyl phenyl magnesium bromide in THF (0.32 ml, 0.64 mmol) is added dropwise, and the resulting solution is stirred and allowed to warm to room temperature overnight. The reaction is quenched with 2M HCl (5 ml). The solvent is removed in vacuo and the residue purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA). The solid obtained is dissolved in DCM, washed with 2M NaOH. The solvent is removed in vacuo and the resulting solid is dried in vacuo at 40° C. overnight to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (1H, d), 8.01 (1H, d), 7.97-7.89 (3H, m), 7.78 (1H, d), 7.72-7.67 (5H, m), 7.64 (2H, d), 2.18-2.13 (1H, m), 1.38 (9H, s), 0.47-0.38 (4H, m); MS m/z 450 [M+H]+
Reaction SMILES: Cl.[CH2:2]([S:9]([NH:12][C:13]1[C:14](=[O:28])[N:15]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C>[CH2:2]([S:9]([NH:12][C:13]1[C:14](=[O:28])[N:15]([CH2:20][C:21]([OH:23])=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reaction time: 2 h

Procedure:
HCl gas was bubbled through a stirred suspension of 3-benzylsulfonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.4 g, 3.57 mmol), as prepared in the preceding step, in ethyl acetate (15 mL) at 0° C. until a solution was formed. After 2 h at room temperature, a thick suspension was formed. The mixture was degassed with nitrogen and filtered to give the title compound a white solid (1.1 g, 92%). 1H-NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 7.34 (m, 5H), 7.12 (d, J=7.5 Hz, 1H), 6.10 (d, J=7.6 Hz, 1H), 4.78 (s, 2H), 4.51 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:4]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
Chloroacetyl chloride (4 g, 35.4 mmol) was added to a stirred mixture of 3-aminobenzamide (4.0 g 25.9 mmol), K2CO3 (22 g, 159 mmol), water (40 ml), and dioxane (40 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and 25° C. for 16 hours, resulting in a solid precipitate. The precipitate was collected, washed, and dried to yield 4.1 g (75%) of the desired 3-chloroacetamidobenzamide, mp: 210 (D).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:12][CH:13]=1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Reaction time: 48 h
Yield: 97.6 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (11.78 g, 31.61 mmol) in DCM (150 ml) was added TFA (50 ml). The resulting mixture was stirred for 48 hrs. at room temperature and evaporated in vacuo. To the residue was added water (150 ml) and diethyl ether (50 ml) and the pH was adjusted to 8 by addition of 32% aq. sodium hydroxide. The mixture was stirred for 15 min., the precipitate filtered off, washed with water and dried in vacuo at 50° C. for 18 hrs. affording 8.4 g (98%) of the title compound as a solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH:6]1([CH3:16])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:8](O)[CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][CH:8]1[CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:11][CH:6]([CH3:16])[CH2:7]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OC1CC(C)CCC1C(C)C
Temperature: 150 °C

Procedure:
26 g of acrylic acid, 24 g of menthol and 15 g of p-toluenesulfonic acid in 500 mL of toluene were heated under reflux at an oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixture was then extracted with ether, the organic layers were combined and washed with salt saturated sodium bicarbonate solution and then with an aqueous solution of sodium hydride, salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was evaporated under reduced pressure to obtain menthyl acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>ClCCCl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]3[C:6]([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:23](=[S:24])[NH:22][C:4]=3[C:3]=1[O:2][CH3:1])=[N:7][CH:8]=[N:9]2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=S)N3c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (80 mg, 0.27 mmol) (from Example 1, Step, C supra) in 1,2-dichloroethane (30 mL) was added 1,1′-thiocarbonyldiimidazole (0.58 g, 3.24 mmol) (Fluka). The reaction mixture was heated with stirring at 80° C. for 4 hours. The solvent was evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.04) as eluent to give the desired 8,9-dimethoxy-3-phenyl-1H,3H-1,3,4,6-tetraaza-phenalene-2-thione as a gray solid. (Yield 50 mg (55%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[OH:11].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl>[OH:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH2:9][NH:8][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: COc1cccc(C(O)CN)c1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCC(O)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (52 ml, 0.37 mol) was added to the amine from example 1 (31.3 g, 0.19 mol) in dichloromethane (400 ml) and reaction mixture stirred under an atmosphere of nitrogen gas at 0° C. for 10 minutes. Propionyl chloride (16.3 ml, 0.19 mol) was added and after stirring for 30 minutes, the reaction temperature was raised to room temperature for a further 5 hours. The reaction mixture was quenched 1 N HCl (aq) (100 ml) and then extracted with dichloromethane (2×50 ml). The organic fractions were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a colourless oil that crystallised on standing to white crystals (28 g, 0.13 mol, 67%). 1H NMR (CDCl3, 400 MHz) δ: 1.18 (t, 3H), 2.22 (q, 2H), 2.51 (bs, 1H), 3.31 (m, 1H), 3.71 (dd, 1H), 3.80 (s, 3H), 4.81 (m, 1H), 5.95 (bs, 1H), 6.80 (d, 1H), 6.90 (d, 1H), 6.91 (s, 1H), 7.22 (t, 1H). LRMS: m/z 224. Mpt: 77-78° C. Analysis found C, 63.86; H, 7.82; N, 6.28%. C12H17NO3.0.1H2O requires C, 64.04; H, 7.70; N, 6.22%.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>O1CCCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([O:13][N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 18 h

Procedure:
1.04 Grams of Z-Tyr-OH was dissolved in 30 ml of tetrahydrofuran, to this solution 0.38 g of N-hydroxysuccinimide was added, then the reaction mixture was ice-cooled, 0.68 g of dicyclohexylcarbodiimide was added under ice-cooled condition, and the whole mixture was stirred at 4° C. for 18 hours. The precipitate formed was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, to the residue obtained was added ethyl ether and petroleum ether and was decanted, then dried to obtain the desired product.
Reaction SMILES: I([O-])(=O)(=O)=O.I([O-])(=O)(=O)=O.[Na+].[CH2:12]([OH:15])[CH2:13][OH:14]>P([O-])([O-])([O-])=O.C(O)CC>[O:14]=[CH:13][C@@H:12]([C@H:13]([C@H:12]([C@@H:13]([CH2:12][OH:15])[OH:14])[OH:15])[OH:14])[OH:15]
Reactant: OCCO
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCCO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Periodate oxidations. The polysaccharide (0.3 mM galactose equivalents) was dissolved in phosphate buffer (20 ml) as before and 1-propanol (1 ml) was added followed by aqueous solutions (2 ml) of sodium metaperiodate (0.23 mM/mol hexose unit for guaran and 0.17 mM/mol hexose unit for locust bean gum). The oxidation was conducted at 5° C. in the dark for 15 hr after which it was stopped by addition of ethylene glycol (1 ml). When the oxidation was carried out in smaller solution volumes (~8 ml) the same ropy gels were obtained as in the case of galactose oxidase treatments. The dialdehyde products were isolated after dialysis (3 d).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][C:40]([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([Cl:1])[N:10]=3)([OH:44])[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -30 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (3.5 g, 13.8 mmol) and TMEDA (3.1 mL, 20.7 mmol) in THF (100 mL) at −78° C. was added n-BuLi (8.3 mL, 2.5 M in hexanes, 20.7 mmol). The resulting mixture was allowed to warm to −30° C. over 45 min then cooled back to −78° C. before the addition of a solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 20.7 mmol) in THF (10 mL). The reaction mixture was warmed to r.t. and stirred for 2 h then quenched with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with Et2O and unreacted starting material removed by filtration. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 30-80%) then triturated with cyclohexane affording 3-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 81%). LCMS (method A): RT 3.50 min [M+H]+ 453.3
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:11]=[CH:10]3)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[C:27](Cl)([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:23]([C:4]1[CH:3]=[C:2]([C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[N:11]=[CH:10]3)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3C(=O)OCC(Cl)(Cl)Cl)ccc21
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirring suspension of tert-butyl 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (see WO 2006/071940A2, 0.250 g, 0.70 mmol) and Troc-Cl (0.10 ml, 0.74 mmol) in EtOAc (7 ml) at RT was added sat'd. NaHCO3 (2.9 ml, 2.1 mmol). After 3 h, the completed reaction was diluted with hexanes (35 ml) and filtered. The solid was rinsed well with hexanes and dried to afford tert-butyl 5-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.36 g, 97% yield). MS (ESI) m/z: 532.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].C(O)(=[O:19])C>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: CC(=O)O
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 73.5 %

Procedure:
Into a 300 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,4,5,6-tetrafluorophthaloyldifluoride separated by distillation from the mixture of Example 2, and 100 ml of acetic acid were charged, and the mixture was reacted at 130° C. for 1.5 hours with vigorous stirring. Then, the inorganic substance was removed by filtration, and the residue was separated by distillation to obtain 66.8 g of tetrafluorophthalic anhydride. The yield was 73.5%.