Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[C:6]([NH2:11])[CH:5]=1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CN(C=O)C>[F:13][C:3]([F:2])([F:12])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])=[C:6]([NH2:11])[CH:5]=1
Reactant: N#Cc1ccccc1F
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Sc1ccc(C(F)(F)F)cc1N

Procedure:
Using a procedure analagous to that of Example 3, 4-trifluoromethyl-2-aminothiophenol hydrochloride (11.48 g, 50 mmol) was combined with 2-fluorobenzonitrile in DMF as solvent (100 ml) to give crude 2-(4-trifluoromethyl-2-aminophenylthio) benzonitrile (6.84 g). Hydrolysis and subsequent condensation gave the title compound as off-white crystals from ethanol (1.1 g, m.p. 233°-235° C., Rf 0.21, CH2Cl2 /MeOH 50:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:40][C:41]2[N:42]=[C:43]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[S:44][CH:45]=2)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([O:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:40][C:41]2[N:42]=[C:43]([C:46]3[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=3)[S:44][CH:45]=2)[N:3]=1
Reactant: CC(C)(C)[Si](OCCOC1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1[C@H]1CC[C@@H](OCCO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
43 mg (0.06 mmol) of the compound from Example 7A (cis isomer) are dissolved in 5 ml of dry THF, 22 mg (0.08 mmol) of tetra-n-butylammonium fluoride are added and the mixture is stirred at RT for 20 h. 15 ml of ethyl acetate are then added to the mixture. The mixture is washed twice with in each case 3 ml of saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the crude product is purified chromatographically initially by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5) and then once more on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 200:1→10:1).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]2[CH:11]=[N:12][CH:13]=[CH:14][C:8]2=[N:7][C:6]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CC(C)=O.O1CCOCC1.[Pd]>[C:28]([N:12]1[CH2:13][CH2:14][C:8]2[C:9](=[N:10][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[N:7]=2)[CH2:11]1)(=[O:30])[CH3:29]
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(=O)N1CCc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c(NC(C)C)nc2C1
Temperature: 45 °C
Reaction time: 17 h
Yield: 47.5 %

Procedure:
To a pressure reactor charged with a red-orange solution of tert-butyl 4-(3-(isopropylamino)pyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate (2.0 g, 5.37 mmol) in acetone (100 mL) and dioxane (100 mL) was added palladium, 10 wt % on activated carbon (0.229 g, 2.148 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (5.04 mL, 53.7 mmol) was added at 23° C. The mixture was stirred under hydrogen at 310 kPa for 17 hr at 45° C. The reaction mixture was filtered through Celite™, rinsed with dioxane, and concentrated via rotary evaporation. The crude material was purified via medium pressure chromatography using 10% to 100% gradient of EtOAc in heptane on an NH 60 μM size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (1.068 g, 47.5%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) 6 ppm 1.16-1.21 (m, 6H), 1.42 (s, 9H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.58 (t, J=5.9 Hz, 0.9H), 2.70 (t, J=5.6 Hz, 1.1H), 2.87-2.98 (m, 4H), 3.51 (br s, 4H), 3.67-3.75 (m, 2H), 4.06-4.15 (m, 1H), 4.41 (s, 1.1H), 4.44 (s, 0.9H), 5.50 (d, J=7.8 Hz, 1H), 5.53 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 419.0.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:13][C:12]2[CH:16]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:12]([CH:16]=1)[C:13]([O:15][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
K2CO3 (701 mg, 5.00 mmol) was added to a stirred solution of 5-bromo-2-hydroxybenzoic acid (434 mg, 2.00 mmol) in acetone (30 ml), followed by the addition of (bromomethyl)benzene (855 mg, 5.00 mmol). The mixture was refluxed for 12 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. Flash chromatography over silica gel, using 1:10 ethyl acetate-petroleum ether yielded the title compound as a pure, white powder. 700 mg.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[C:10]1([CH2:16][CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[CH3:4][C:3]1([CH3:5])[S:6][CH:17]([CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=CCc1ccccc1
Solvent: O
Product: CC1(C)SC(Cc2ccccc2)N[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A 250 mL flask was charged with 20 mL of water and 2.0 g (13.4 mmol) of D-penicillamine. To the resulting colorless solution was added 1.6 g (13.3 mmol) of phenyl acetaldehyde dropwise over 2 minutes. The suspension obtained was stirred vigorously for 30 minutes and allowed to stand at room temperature overnight. The solids were collected by suction filtration to yield the crude title thiazolidine which was carried on without further purification.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[NH:13]1[CH:17]=[CH:16][N:15]=[N:14]1>>[F:1][C:2]1[C:3]([N:14]2[N:15]=[CH:16][CH:17]=[N:13]2)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: c1c[nH]nn1
Reactant: O=C(O)c1cc(F)cc(F)c1I
Product: O=C(O)c1cc(F)cc(F)c1-n1nccn1

Procedure:
The title compound was prepared using the methods described herein, using 3,5-difluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 226 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][CH2:13][C:14]([NH2:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:11])[NH:12][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: NCC(N)=O
Reactant: Cc1cccc(Cl)c1N=C=S
Product: Cc1cccc(Cl)c1NC(=S)NCC(N)=O

Procedure:
2-[3-(2-Chloro-6-methylphenyl)-thioureido]-acetamide was prepared by the procedure described in Example 2 using 18.3 g of 2-chloro-6-methylphenyl-isothiocyanate and 12.0 g of glycinamide. 22.8 Grams of the product was obtained, m.p. 161°-163° C. (dec.). This compound was used without further purification in the next paragraph.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH2:27]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([Cl:1])[CH:11]=2)[C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)cc21
Temperature: 110 °C
Yield: 77.4 %

Procedure:
13.5 g of 7-chloro-3-ethoxycarbonyl-6-fluoro-4-hydroxyquinoline and 13.8 g of potassium carbonate in 160 cm3 of DMF were stirred and heated at 110° C. for 1 hour in a round-bottomed flask equipped with a reflux condenser. After cooling to 60° C., the solution was treated with 24 g of allyl bromide. The mixture was stirred and heated at 100° C. until the medium was neutral (duration: about 6 hours). The solvent was evaporated off in vacuo, the residue was taken up in 300 cm3 of water and the reaction product was extracted with chloroform (3×100 cm3). The combined organic extracts were washed with water, dried (MgSO4) and evaporated to dryness. The residue was recrystallised from 72 cm3 of isopropanol. 12 g of 1-allyl-7-chloro-3-ethoxycarbonyl-6-fluoro-4-oxo-1,4-dihydroquinoline, m.p.=162°-164° C., were obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([NH:47][CH3:48])[N:42]=[C:41]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=4)[S:54][CH:55]=3)[C:40]=2[C:63]#[N:64])=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:65]>ClCCl.C(OCC)C>[ClH:62].[ClH:65].[NH2:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([NH:47][CH3:48])[N:42]=[C:41]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=4)[S:54][CH:55]=3)[C:40]=2[C:63]#[N:64])=[CH:37][CH:38]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN)cc2)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.00 g (1.071 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(methylamino)pyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-L-alaninate (Example 23A) were initially charged in 18.7 ml of dichloromethane. 10.71 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and the reaction solution was stirred at RT for 18 h. Another 10.71 ml of a 1N solution of hydrogen chloride in diethyl ether were then added. After a reaction time of 18 h, the reaction mixture was treated in an ultrasonic bath for 90 min. The mixture was concentrated by evaporation. This gave 867 mg (100% of theory) of the target compound.
Reaction SMILES: C([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]([O:9]C(=O)C)[C@H:6]1[NH2:7])(=O)C.[C:25]1([S:39](Cl)(=[O:41])=[O:40])[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[C:27]([S:35](Cl)(=[O:37])=[O:36])[CH:26]=1>C(#N)C.N1C=CC=CC=1>[C:25]1([S:39]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:41])=[O:40])[CH:30]=[C:29]([S:31]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:33])=[O:32])[CH:28]=[C:27]([S:35]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:37])=[O:36])[CH:26]=1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)S(=O)(=O)c1cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c1

Procedure:
The novel intermediate benzene 1,3,5-trisulfonyl trisglucosamine compound is prepared by reacting tetra-O-acetyl glucosamine (II) with 1,3,5-benzenetrisulfonyl chloride in a weakly basic polar medium such as acetonitrile-pyridine for 24 hours. The solvent is concentrated and the tetraacetyl trisulfonyl derivative (III) is precipitated from ice water and extracted into methylene dichloride. The solvent is evaporated and the material is dissolved in cold methanol saturated with ammonia. Standing in the cold for 24 hours, followed by the addition of nitrogen gas to remove ammonia, produces a thick oil (IV) on evaporation. The oil is purified from water with activated charcoal, filtration and drying to give the intermediate glucopyranose.
Reaction SMILES: Cl[Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3]1.[CH2:9]([OH:11])[CH3:10]>C(N(CC)CC)C>[CH2:9]([O:11][Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3]1)[CH3:10]
Reactant: CCO
Reactant: C[Si]1(Cl)CCC(S)C1
Solvent: CCN(CC)CC
Product: CCO[Si]1(C)CCC(S)C1
Reaction time: 18 h

Procedure:
To a 0.5 liter 3-neck round-bottom glass flask was charged 16.7 grams (0.10 moles) of 1-chloro-1-methyl-3-mercaptosilacyclopentane and 0.225 liters of ethanol and 10 grams of triethylamine. The mixture was stirred and refluxed for 16-20 hours. The solvent was removed at 50-75 C./10-50 mm and nitrogen bubbled through the liquid residue at 25 C. for an additional 16-20 hours. After standing for two more days at about 25° C., the mixture was filtered to give 12.4 grams of a liquid product analyzed by GLC to be about 93% pure. Based on these analysis, a 65.5 mole % yield was obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=O)[NH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:24][C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:30])=O>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([Cl:30])=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:24][C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(-c2cnc(-c3ccccc3)[nH]c2=O)cc1OC(C)=O
Product: CC(=O)Oc1ccc(-c2cnc(-c3ccccc3)nc2Cl)cc1OC(C)=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4-(3,4-Dihydro-4-oxo-2-phenyl-5-pyrimidinyl)-o-phenylene diacetate (6.8 g) (18.7 mmol) are dissolved in 150 ml of phosphorus oxychloride. After stirring at 100° C. for 6 hours the mixture is concentrated in a vacuum at 50° C. and the residue is dried in a vacuum. Now, dichloromethane and ice/water are added thereto and, after good intermixing, the dichloromethane phase is separated. After drying over sodium sulphate and distilling off the solvent the product is crystallized from ethanol. The product is filtered off and washed with ethanol/diethyl ether. There are obtained 6 g of 4-(4-chloro-2-phenyl-5-pyrimidinyl)-o-phenylene diacetate as white crystals of m.p. 152°-153° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14]>[O-]CC.[Na+]>[NH2:14][C:13]1[N:1]([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]=[N:3][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Product: COc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(azidomethyl)-4-methoxybenzene (5 g) and 2-cyanoacetamide (5 g) was added to a solution of sodium ethoxide (made from 1.6 g of sodium in 100 mL of ethanol). The resulting mixture was refluxed for 20 h. It was cooled down to room temperature and solvent was removed under reduced pressure. The remaining solid was dissolved in water (20 mL) and extracted with ethyl acetate (3×50 mL). The extracts were combined, washed with brine and dried over sodium sulfate. Solvent was removed and the residue was crystallized from hot water to give the desired product 5-amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. ESMS calculated for C11H13N5O2 (m/z): 247.1; found (M+H+): 248.1
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[F:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Reactant: NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(Br)c1
Yield: 73.9 %

Procedure:
A solution of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (0.648 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 mL, 5.6 mmol) in dichloromethane (45 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl, and dried over Na2SO4. The organic layer was evaporated to give a pale amber residue. The residue was triturated with a small amount of DCM, then sonicated to give a uniform mixture. A white solid was collected and dried to afford N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.08 g, 73.9%) as a crystalline solid. LC-MS m/z 589.1 (M+H)+, 0.79 min (ret time).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([C:15]([OH:16])([CH3:17])[CH3:14])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)=O
Reactant: Brc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 3,5-dibromopyridine (264 g, 1.12 mol) in toluene (3000 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexanes (2.6 M, 475 mL, 1.24 mol) was then added, giving a solution that was stirred for 2 hours at −78° C. Acetone (108 g, 1.86 mol) was then added. After 1 hour, the reaction mixture was quenched by addition of 350 mL saturated aqueous ammonium chloride solution. The resulting solution was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (ethyl acetate/petroleum ether 1:10-1:5) provided the title compound: 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.56 (s, 1H), 8.01 (s, 1H), 1.61 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:6][CH:7]=1
Reactant: Oc1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Product: CC(C)(C)OC(=O)C(C)(C)COc1cnc(Cl)cn1
Yield: 84.2 %

Procedure:
By using 5-chloropyrazin-2-ol (700 mg) and tert-butyl hydroxypivalate (1402 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain tert-butyl 3-[(5-chloropyrazin-2-yl)oxy]-2,2-dimethylpropanoate (1294.5 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(N)nc(NC2CCCCC2)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 14.5 g (0.1 mol.) of 2,4-diamino-6-chloro-1,3,5-triazine produced in the Referential Example 1 and 280 mL of water was heated to 85° C. and was dropwise added with 29.7 g (0.3 mol.) of cyclohexylamine over two hours and further reacted at the same temperature for one hour. Successively, a solution of 6.0 g of sodium hydroxide in 30 mL of water was dropwise added to the reaction solution over one hour and the reaction was further continued for one hour. 200 mL of toluene was added in the reaction solution and(stirred at 85° C. for one hour. The stirring was continued to cool the termperature of the solution to the room temperature. Product was separated from the reaction solution through filtration and washed twice with each 100 mL of toluene and twice with each 100 mL of water, successively. The filtrated product was dried at 70° C. for six hours under vacuum to obtain 17.5 g of 4,6-diamino-2-cyclohexylamino-1,3,5-triazine (yield: 84%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
7 g (31.5 mmol) of methyl 4-fluoro-3-trifluoromethyl-benzoate are dissolved in 60 ml of dry dimethylsulphoxide (DMSO) and combined with 5.55 g (31.5 mmol) of N-benzylpiperazine and 4.35 g (31.5 mmol) of potassium carbonate. The mixture is stirred for 12 hours at 90° C. After cooling, the reaction mixture is poured into 200 ml of water and extracted three times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and distilled off in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate and n-heptane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=1.Cl.CCOC(C)=O>CC(O)C>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:28][C:29]2[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Nc1cnn(CCO)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of tert-butyl 3-[(2,5-dichloropyrimidin-4-yl)amino]-9-azaspiro[5.5]undecane-9-carboxylate (501.5 mg, 1.21 mmol) and 2-(4-aminopyrazol-1-yl)ethanol (306.5 mg, 2.411 mmol) in propan-2-ol (6 mL) was added a solution of HCl in EtOAc (1 mL, 4 mmol). The mixture stirred in a sealed tube under the microwave radiation at 140° C. for 1 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/20 to 1/7) to give the product as a light yellow solid (500.0 mg, 0.9881 mmol, 81.85%).