Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.O>[OH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][C:4]2[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:12]([CH3:20])([CH3:13])[C:3]=2[CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 14 g (103 mmol) of 3-phenyl-1-propanol and 18.2 g (123 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 15 g (113 mmol) of aluminum chloride. After the addition of aluminum chloride was complete, the reaction was heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature and 100 mL of water was added, followed by 100 mL of 1N HCl. The reaction mixture was stirred for 2 hours, filtered through a Celite pad and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 13.45 g (53%) of 2-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH:12]=[CH:11][CH2:10]2)=[CH:5][N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:9]1([C:6]2[CH:5]=[N:4][C:3]([CH2:2][Cl:27])=[N:8][CH:7]=2)[CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1(c2cnc(CO)nc2)CC=CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(c2cnc(CCl)nc2)CC=CC1
Temperature: 25 °C

Procedure:
To a solution of ethyl 1-(2-hydroxymethylpyrimidin-5-yl)cyclopent-3-ene carboxylate (5.0 g, 20.1 mmol), in chloroform (50 ml) was added pyridine (5.1 ml), followed by thionyl chloride (4.4 ml, 60.3 mmol). The reaction mixture was refluxed for 30 minutes, cooled to room temperature and quenched with water (50 ml). The chloroform layer was collected, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic extract was dried over MgSO4 and then evaporated to an oily residue, which was purified by flashe chromatography with hexanes/ethyl acetate (3:1) as eluent.
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH2:16][CH2:15][NH:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]=[CH:26]C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH2:16][CH2:15][N:14]2[CH:26]=[O:25])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: c1ccc(Oc2ccc(CC3NCCC4=C3CCCC4)cc2)cc1
Solvent: ClC(Cl)Cl
Product: O=CN1CCC2=C(CCCC2)C1Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.6 %

Procedure:
To a solution of 0.78 g (0.002 mol) of (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline in 5 ml of chloroform was added 0.42 g of chloral in 1 ml of chloroform dropwise. After the mixture had been stirred at room temperature for 3 hrs it was diluted with 15 ml of chloroform and washed with 4 N hydrochloric acid (10 ml) and water (10 ml). After drying, the solvent was removed under reduced pressure to give 0.81 g (96%) of crude (±)-1-(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For characterization, a sample of this compound was distilled, bp 225°-227° (0.08 mm Hq).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.O>C(CN)O>[NH2:3][CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN2C(=O)c3ccccc3C2=O)C1
Solvent: O
Solvent: NCCO
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Yield: 72.3 %

Procedure:
A solution of (R)-tert-butyl 2-((1,3-dioxoisoindolin-2-yl)methyl)morpholine-4-carboxylate (37.9 g, 0.11 mol) in ethanolamine (250 mL) was stirred at room temperature for 16 hr. Afterward, the mixture was poured into water (500 mL). The aqueous layer was extracted with EtOAc (3×250 mL), and then the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (100% EtOAc then 0-10% MeOH in CH2Cl2 (with 1% NH4OH)) to provide the title compound (17.2 g, 73%) as an oil. HRMS (ESI) m/z calcd for C10H20N2O3 217.15 [M+H]+. found 217.28. 1H NMR (300 MHz, CDCl3) δ ppm 1.28 (s, 2H), 1.46 (s, 9H), 2.56-2.70 (m, 1H), 2.73-2.76 (m, 2H), 2.85-2.98 (m, 1 H), 3.30-3.39 (m, 1H), 3.52 (td, J=11.61, 2.82 Hz, 1H), 3.78-3.95 (m, 3H).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:24][S:25]([O:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:27])=[O:26]
Reactant: CCCCCCCCCCCCCCCCCCOCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
In dichloromethane (50 ml) is dissolved 3-(octadecyloxy)propanol (8.0 g). To the solution are added, under ice-cooling, methanesulfonyl chloride (4.18 g) and triethylamine (5.1 ml). The mixture is stirred at room temperature for one hour. The reaction mixture is washed with water and an aqueous solution of sodium hydrogencarbonate, successively, and then dried. The solvent is distilled off under reduced pressure to give the above-titled compound (9.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([O:13]CC1C=CC(CC2C=CC=CC=2)=CC=1)=[O:12].BrC(C(C)C)C(OC(C#N)C1C=CC=C(CC2C=CC=CC=2)C=1)=O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:10]([C:11]([OH:13])=[O:12])[CH:28]([CH3:30])[CH3:29])=[CH:4][CH:3]=1
Reactant: CC(C)C(Br)C(=O)OCc1ccc(Cc2ccccc2)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: CC(C)C(Br)C(=O)OC(C#N)c1cccc(Cc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O

Procedure:
Following the procedure of Example 6, 4-chloroaniline is reacted with each of p-benzylbenzyl α-bromoisovalerate and m-benzyl-α-cyanobenzyl α-bromoisovalerate to yield the p-benzylbenzyl ester of N-(4-chlorophenyl)valine, MS m/e 407 (M+), and the m-benzyl-α-cyanobenzyl ester of N-(4-chlorophenyl)valine, MS m/e 432 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
The product was prepared, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophenecarbonitrile according to the procedure outlined in Example 5, as a yellowish solid: mp 230–231° C. (decomposed); 1H-NMR (CDCl3) δ 8.32 (s, 1H, D2O exchangeable), 7.83 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.4 Hz), 7.43 (dd, 1H, J=8.2, 1.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=8.2 Hz), 1.78 (s, 6H); MS (EI) m/z 283 ([M−H]−, 100%); Anal. Calc. For C15H12N2O2S0.2H2O: C, 62.57, H, 4.34, N, 9.73. Found: C, 62.48, H, 4.31, N, 9.64.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (11.2 g, 0.052 mol) in anhydrous DMF (40 mL) and anhydrous dioxane (40 mL) was added, dropwise, bromoacetyl bromide while keeping the internal temperature between 0° C. and 5° C. After the addition was completed (~25 min), the ice-bath was removed and the mixture was stirred for 20 h at rt. The reaction mixture was cooled in an ice-bath, water was added (100 mL), and then the mixture was poured into ice water. The precipitate which formed was filtered, washed with water, and then dried in a vacuum oven for 20 h at 40°-45° C., affording 9.9 g (57%) of the title compound: mp 203°-204° C.; 1H NMR (CDCl3) δ11.67 (s, 1H, NH), 8.64 (d, 1H, J=8.8), 8.55 (d, 1H, J=2.4), 7.71 (dd, 1H, J=2, J=6.8), 3.72 (s, 2H ); 13C NMR (CDCl3): 200.55, 138.06, 134.22, 134.20, 122.06, 107.46. 67.08; MS (EI, m/z) 337 (M+). HRMS (EI) calcd for C9H7NO3Br2 334.8792, found 334.8791.
Reaction SMILES: CC1C=C(C)C=C(C)N=1.[C:10]([C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][C:17]1[N:22]=[C:21](O)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])([CH3:13])([CH3:12])[CH3:11].O.P(Cl)(Cl)([Cl:34])=O>>[C:10]([C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][C:17]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:19][CH:20]=[C:21]([Cl:34])[N:22]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccccc1Oc1nc(O)ccc1[N+](=O)[O-]
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 77 %

Procedure:
2,4,6-Trimethylpyridine (1.6 mL) was added dropwise into 136a (2.32 g, 8.0 mmol) in phosphorus oxychloride (3.2 mL) at 0° C. The reaction mixture was heated at 130° C. for 20 h. The reaction was stopped at ˜70% conversion as determined by HPLC. The dark brown solution was poured into water (40 mL) with stirring, and stirred for 15 min. The brown precipitate was filtered, air dried, and purified by SiO2 chromatography (120 g), loaded with a CH2Cl2 and eluted using a gradient of ethyl acetate in hexanes to afford 136b (1.91 g, 77% yield) as an amber colored oil; HPLC purity 100%, 3.95 min (Method A); 1H NMR (500 MHz, CDCl3) δ ppm 8.36 (d, 1H, J, J=10.0 Hz), 7.47 (d, 1H, J=5.0 Hz), 7.23 (m, 2H), 7.16 (d, 1H, J=10.0 Hz), 6.95 (d, 1H, J=10.0 Hz), 1.36 (s, 9H); 13C (125 MHz, CDCl3) δ (ppm), 155.30, 153.23, 150.87, 141.45, 137.72, 133.22, 127.59, 126.91, 125.79, 123.04, 118.39, 34.60, 30.25.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:26]Cl>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:20]=3[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3ccccc3o2)CC1
Reactant: ClI
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3cc(I)ccc3o2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-benzoxazol-2-yl-piperazine-1-carboxylic acid benzyl ester (0.50 g, 1.48 mmol) and iodine monochloride (0.265 g, 1.63 mmol) in acetic acid (4.94 mL) was stirred at 60° C. overnight, cooled, and concentrated in vacuo to provide the title compound, which was used without further purification, in Example 3.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:13][C:14]1[C:15]([NH:26][NH2:27])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]#[N:25])=[CH:19][CH:18]=2.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[C:15]([NH:26][NH:27][C:10](=[O:11])[CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]#[N:25])=[CH:19][CH:18]=2
Reactant: N#Cc1ccc2nc(NN)c(Cl)nc2c1
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)NNc1nc2ccc(C#N)cc2nc1Cl)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (2.15 g, 10 mmol) in 20 ml of dry tetrahydrofuran was added to a solution of 3-chloro-6-cyano-2-hydrazinoquinoxaline (2.0 g, 9 mmol) and dry triethylamine (1.4 ml, 10 mmol) in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature overnight, and filtered. The filtrate was evaporated, and the title compound was isolated as a semisolid residue, which was used in the next step without further purification; 1H-NMR (DMSO-d6): δ 1.26 (t, 6H), 3.09 (d, 2H), 4.10 (quint, 4H), 7.71 (d, 1H), 7.97 (dd, 1H), 8.39 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:1]([O:8][C:9]1[C:10]([NH:17][NH2:18])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncccc1OCc1ccccc1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NNc1ncccc1OCc1ccccc1
Temperature: 90 °C
Yield: 68.5 %

Procedure:
3-(Benzyloxy)-2-chloropyridine (22.3 g, 101 mmol) was dissolved in EtOH (300 ml) and hydrazine monohydrate (10.2 ml, 203 mmol) added. The reaction was heated to reflux at 90° C. for 90 minutes. Hydrazine monohydrate (50 ml) was added and the reaction was heated at reflux overnight. K2CO3 (10 g) was added and the mixture was heated at refluxed for 4 hours. The mixture was concentrated to a residue and dissolved in n-BuOH (120 ml) and hydrazine monohydrate (40 ml) was added. The mixture was heated at reflux for 6 days. The reaction was cooled, diluted with water and extracted with EtOAc. The organics were concentrated to an oil that was dissolved in CH2Cl2 and decanted away from the solids. The organics were concentrated and dried on high vacuum overnight. The residue solidified on high vacuum. The crude product (24.47 g) was triturated in water and the solids filtered to give 3-(benzyloxy)-2-hydrazinylpyridine (14.9 g, 68% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[CH3:7][C:8](O)([CH2:10][CH:11]([OH:13])[CH3:12])[CH3:9]>OS(O)(=O)=O>[OH:5][C:2]([C:3]1[O:13][CH:11]([CH3:12])[CH2:10][C:8]([CH3:9])([CH3:7])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CC(O)CC(C)(C)O
Reactant: CC(C)(O)C#N
Agent: O=S(=O)(O)O
Product: CC1CC(C)(C)N=C(C(C)(C)O)O1
Reaction time: 1 h
Yield: 26 %

Procedure:
To a 250 ml 3-necked flask with a thermometer, a mechanical stirrer, and a 100 ml addition funnel attached was added 200 ml of concentrated H2SO4. The acid was cooled to 0°-5° C. with a dry-ice/acetone bath while 51 g (0.6 mole) of the acetone cyanohydrin was added at such a rate so as to maintain the temperature in the -10° to 10° C. range (Note--caution must be exercised in the initial stages of the addition since a vigorous exotherm occurs). After the addition of the nitrile, 59.0 g (0.5 moles) of 2-methyl-2,4-pentanediol was added again at a rate that kept the temperature in the -10° to 10° range (see the previous note). The mixture was stirred for an additional one hour then poured onto crushed ice (~5° C.). The acidic aqueous solution was then extracted twice with ether and the ether layers discarded. The acidic aqueous layer was then poured into a large beaker which contained ~400 g of NaHCO3 and ether. The beaker was cooled with an ice-water bath and was not allowed to rise pass 36° (basification with aqueous KOH resulted in more extensive decomposition due to the higher temperature attained). The ether layer was dried over K2CO3 and concentrated. The residue obtained was distilled at 43° C. (0.5 mm) to yield 24 g (0.13 mole, 26%) of product. The structure of this alcohol was confirmed by I.R. and N.M.R.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1ncc(Br)cn1
Product: COc1ccc(CNc2ncc(Br)cn2)cc1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
5-Bromo-2-chloropyrimidine (300 mg, 1.55 mmol) was dissolved by heating at 120° C. in 4-methoxybenzylamine (2.1 g, 15.4 mmol), and the solution was stirred at the same temperature for 2 hours. The reaction mixture was directly subjected to silica gel column chromatography (hexane:ethyl acetate=30:1→5:1) for purification to obtain 5-bromo-N-(4-methoxybenzyl)pyrimidin-2-amine (445.4 mg, 98%) as colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[C:7]([CH3:10])[NH:8][CH:9]=1)=[O:4].[OH-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[C:7]([CH3:10])[N:8]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:9]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1c[nH]c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(C)c1C
Temperature: 7.5 °C
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2,3-dimethyl-1H-pyrrole-4-carboxylic acid methyl ester (Heterocycles 1977, 7, 77) (7.95 g, 51.9 mmol) in THF (160 mL) was added dropwise 50% NaOH (80 mL). The reaction mixture was stirred for 5 minutes and then a solution of p-toluenesulfonyl chloride (11.87 g, 62.3 mmol) in THF (160 mL) was added dropwise to the stirred mixture at room temperature. The mixture was stirred at room temperature for 30 minutes then cooled to 5 to 10° C. and treated dropwise with water (200 mL). The THF was evaporated in vacuo and the aqueous residue was thoroughly extracted with CH2Cl2. The organic extract was washed, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give the required compound (13.6 g, 85%) as a pale yellow solid, m.p. 108°-114° C.
Reaction SMILES: C(OC(=O)[NH:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]([OH:40])([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][C:14]1([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH2:15][CH2:16][N:11]([S:8]([NH2:7])(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(=O)(=O)NC(=O)OC(C)(C)C)CC3)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(N)(=O)=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 82.2 %

Procedure:
To a solution of tert-butyl({4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}sulfonyl)carbamate (45 mg, 0.073 mmol) in DCM (0.7 mL) was added TFA (0.120 mL, 1.5 mmol) and the reaction was stirred at room temperature for 80 min, then more TFA (0.120 mL, 1.5 mmol) was added. After 90 min most volatiles were removed by N2 flow and vacuum. The residue was diluted with saturated aqueous NaHCO3 and ethyl acetate. The combined organic layers were dried and evaporated to give 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-sulfonamide (31 mg, 0.06 mmol, 82% yield). MS ESI: [M+H]+ m/z 515.2. 1H NMR (600 MHz, CDCl3): δ 8.59 (d, J=4.8 Hz, 1H); 7.87 (s, 1H); 7.81 (s, 1H); 7.25 (s, 1H); 7.02 (s, 1H); 7.00 (d, J=4.8 Hz, 1H); 3.59 (d, J=12 Hz, 2H); 3.14 (m, 2H); 2.34 (s, 3H); 2.26 (m, 2H); 1.94 (d, J=12 Hz, 2H). rhSYK activity=+++
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)=O)C.[CH3:38][NH2:39]>CO>[CH3:38][NH:39][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)=[N:10][C:9]=2[N:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Solvent: CO
Product: CNC(=O)c1cn(Cc2ccccc2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
8-Benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (7.6 mg, 0.015 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column; 32 mL/min 5-100% MeCN/H2O gradient over 15 mm) and lyophilized to provide 1.3 mg of 8-benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.54 (br s, 1H), 9.25 (s, 1H), 8.70 (s, 1H), 7.23-7.30 (m, 5H), 7.13-7.15 (m, 2H), 6.83 (d, 2H, J=8.9 Hz), 5.35 (s, 2H), 3.13 (br s, 4H), 2.91 (s, 3H), 2.53 (br s, 4H), 2.30 (br s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H29N7O2: 483.24, Found: 484.3 (M+H).
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]2[CH2:19][O:18][C:17](=[O:20])[CH2:16][C:15]2=[O:21])[CH2:9]1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>O1CCCC1.O>[C:22]([CH:16]1[C:15](=[O:21])[CH:14]([CH:10]2[CH2:11][CH2:12][CH2:13][S:8][CH2:9]2)[CH2:19][O:18][C:17]1=[O:20])(=[O:25])[CH2:23][CH3:24]
Reactant: O=C1CC(=O)C(C2CCCSC2)CO1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)C1C(=O)OCC(C2CCCSC2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
2.4 g of triethylamine is added to 5 g of 5-(tetrahydrothiopyran-3-yl)-tetrahydropyran-2,4-dione in 50 ml of anhydrous tetrahydrofuran. At 0° C., 2.2 g of propionyl chloride is dripped in and the mixture is stirred for 12 hours at room temperature. The mixture is then diluted with 150 ml of water, and the aqueous phase is separated and extracted with 100 ml of ether. The combined organic phases are washed once with ice-cold 5% strength hydrochloric acid and once with water, and dried with magnesium sulfate, and the solvent is removed. The oily residue is dissolved in 50 ml of anhydrous toluene, 0.3 g of 3-dimethylaminopyridine is added, and the mixture is stirred at 80° C. for 2 hours. After cooling, extraction is carried out twice with 25 ml of hydrochloric acid and twice with 25 ml of water. The organic phase is dried over sodium sulfate and concentrated in a rotary evaportor. The residue is chromatographed with methylene chloride on silica gel. There is obtained 1.8 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[OH:10]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]=[O:10]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(Cl)cccc1Cl
Temperature: 5 °C

Procedure:
To a solution of 2,6-dichloroaniline (42.3 g, 0.26 mole) in glacial acetic acid (520 ml) in a 1 litre conical flask at room temperature, was added 100 vol hydrogen peroxide (157 ml, 1.38 mole). The flask was plugged with absorbant cotton, and set aside on a thermostatically controlled water bath at a temperature of 25°-30° C. for 70 hours. The flask was then cooled to 5° C., and the crystalline solid collected on a sintered glass funnel, washed with ethanol-pet. ether (40°-60°) (200 ml, 1:1, v/v), and dried in an oven at 90° C. The buff leaflets weighed 40.25 g (87.6%) m.p. 171°-172° C.