Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[Br-].Cl[CH:4]([CH3:8])[C:5](=O)[CH3:6].[NH2:9][C:10]1[C:11]([NH2:19])=[N:12][CH:13]=[C:14]([CH:18]=1)[C:15]([NH2:17])=[O:16]>C1(=O)CCCCC1>[NH2:9][C:10]1[C:11]2[N:12]([C:4]([CH3:8])=[C:5]([CH3:6])[N:19]=2)[CH:13]=[C:14]([C:15]([NH2:17])=[O:16])[CH:18]=1
Reactant: NC(=O)c1cnc(N)c(N)c1
Reactant: CC(=O)C(C)Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O=C1CCCCC1
Product: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 117.3 %

Procedure:
NaBr (27.0 g; 0.259 mol; 1.33 equiv) was suspended in cyclohexanone (220 mL) and 3-chloro-2-butanone (25.7 mL; 0.242 mol; 1.24 equiv) was added in one portion. The mixture was heated to 80° C. and stirred for 3 h. The mixture was cooled to 50° C., the white solid was filtered off and washed with cyclohexanone (60 mL). 5,6-Diamino-nicotinamide (30 g; 0.1946 mol; 1.0 equiv) was added to the filtrate and the mixture was heated to 100° C. for 4 h, after which 98% conversion was determined by HPLC. The reaction mixture was cooled to 20° C., stirring was continued for 2 h at 20° C. The solid was filtered off, washed with TBME (220 mL) and dried to yield 46.6 g of the title compound. Yield: 73%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([NH:17][C:18]2[CH:22]=[C:21]([CH:23]3[CH2:25][CH2:24]3)[NH:20][N:19]=2)=[N:12][C:13](Cl)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C:10]1[C:11]([NH:17][C:18]2[CH:22]=[C:21]([CH:23]3[CH2:25][CH2:24]3)[NH:20][N:19]=2)=[N:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 22.4 %

Procedure:
A mixture of 5-((tert-butyldimethylsilyloxy)methyl)-2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.53 mmol, 1.0 eq), phenylboronic acid (90.5 mg, 0.742 mmol, 1.4 eq), Pd2(dba)3 (48.5 mg, 0.053 mmol, 0.1 equiv.), tricyclohexylphosphine (35.7 mg, 0.127 mmol, 0.24 equiv.), K3PO4 (450 mg, 2.12 mmol, 4 eq) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 100° C. under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool to room temperature and concentrated to give a residue, which was purified by silica gel chromatography (CH2Cl2/MeOH 500:1 to 100:1 as eluent) to afford 5-((tert-butyldimethylsilyloxy)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (50 mg, 22.5%) as a solid. LC-MS (m/z)=422.2 [M+H]+.
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[CH:5]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[C:6]([F:13])[CH:5]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Methyl iodide (1.49 mL, 24 mmol) was added to a suspension of 4-bromo-2-fluorobenzoic acid (4.38 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) in dimethylformamide (50 mL), and the mixture was stirred overnight at room temperature. After completion of the reaction, ethyl acetate was added, and the mixture was washed with water and a saturated ammonium chloride aqueous solution. After drying over magnesium sulfate, concentration was carried out to obtain 4.50 g of the desired product as a colorless solid (yield 97%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)(C([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[I-].[Li+].CN(C)C=O.O>C(OCC)(=O)C.C1CCCCC1>[C:1]([NH:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(C#N)c1)(NC(C)=O)C(=O)[O-]
Agent: [I-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(Cc1cccc(C#N)c1)NC(C)=O
Temperature: 150 °C
Reaction time: 5 h

Procedure:
The process is performed as in Example 5, starting with 14.9 g of ethyl 2-acetylamino-2-(3-cyanobenzyl)malonate, 30 g of anhydrous lithium iodide and 150 cm3 of dry dimethylformamide. After stirring for 5 hours at a temperature in the region of 150° C., the reaction mass is cooled to room temperature. 1500 cm3 of water are added and the mixture is extracted with 3 times 300 cm of ethyl acetate. The extracts are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 45° C. After drying in an oven at a temperature in the region of 40° C. under reduced pressure (10 Pa), 11.39 g of ethyl (2RS)-2-acetylamino-3-(3-cyanophenyl)propanoate are obtained in the form of a beige-colored paste. (Rf=0.51 in a 90/10 by volume mixture of ethyl acetate/cyclohexane, on a Merck 60F254R silica plate).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[CH:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=O>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[CH2:18][CH2:17]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Agent: Cl
Product: COc1ccc2oc(=O)cc(NC3CCN(Cc4ccc(C(=O)O)cc4)CC3)c2c1

Procedure:
According to Procedure C above, (I) (0.300 g of hydrochloride salt; 1.09 mmol) and 4-formyl-benzoic acid were allowed to react to afford after HPLC purification and precipitation with hydrochloric acid as described before, 0.182 g (35.4%) of the title compound. MS (DCI/NH3)(+)Q1MS m/z 409 (M+H)+; 1H NMR (500 MHz, pyridine-d5) δ ppm 1.78 (m, 2H), 2.13 (m, 4H), 2.89 (m, 2H), 3.42 (s, 3H), 3.56 (m, 1H), 3.57 (s, 2H), 5.72 (s, 1H), 7.15 (dd, J=9.05, 2.81 Hz, 1H), 7.34 (d, J=9.05 Hz, 1H), 7.53 (d, J=8.11 Hz, 2H), 7.62 (br d, J=7.18 Hz, N H), 7.70 (d, J=2.50 Hz, 1H) 8.41 (d, J=8.11 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.Br[CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:15][CH2:14][CH2:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1
Reactant: COC(=O)c1cc(O)nn1C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)n(C)n1
Yield: 94.3 %

Procedure:
Using methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0 mmol), 1-bromo-2-methoxyethane (3.13 g, 22.5 mmol), potassium carbonate (4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL), and in the same manner as in Reference Example 57, the title compound (3.03 g, yield 94%) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]([O:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:5]([O:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:2][CH2:3][OH:4])[CH2:14][CH2:13]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
2-Bromo-ethanol (2.38 mL, 33.5 mmol, 1.0 eq) is added at room temperature to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (7.0 g, 33.5 mmol, 1.0 eq) in N,N-dimethylformamide (300 mL), followed by potassium carbonate (4.64 g, 33.5 mmol, 1.0 eq). After 6 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×40 mL) and water (40 mL). pH of the aqueous layer is neutralized with a 0.1 N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as an off-white oil (7.96 g, 97% yield).
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:1]([S:9][CH2:10][CH:12]1[O:14][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCS
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCSCC1CO1

Procedure:
293 g of n-octylmercaptan and 5 g of tetrabutylammonium chloride are placed into a 1 liter Sovirel reactor (double-walled reaction vessel) fitted with thermometer, stirrer, dropping funnel, dosing dropping-funnel and pH-electrode. To this solution are added dropwise within 80 minutes at a pH value of 11.6-12.0, with stirring and intensive cooling, 184 g of epichlorohydrin. The pH value is maintained constant over the total period of 80 minutes by the corresponding controlled addition of about 10 ml of a 22% aqueous sodium hydroxide solution. The reaction temperature should not exceed 20° C. After completion of the exothermic reaction, 305 ml of 22% sodium hydroxide solution are introduced dropwise within 15 minutes. The reaction mixtue is subsequently stirred at 50° C. for 30 minutes; the aqueous phase is then separated, the organic phase is washed twice with 200 g of water each time, and the organic phase is fractionated in vacuo. The yield is 382 g (94% of theory) with a boiling point of 92°-94° C. at 0.04 mbar and a refractive index of nD20 : 1.4718.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:34](OCCCC)(=O)[CH:35]=[O:36].CC(O)=O>CCO>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:5]3[N:6]=[CH:7][C:2]4[N:1]=[CH:34][C:35](=[O:36])[N:28]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)[C:3]=4[N:4]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)CC1
Reactant: CCCCOC(=O)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)CC1
Yield: 42.9 %

Procedure:
A mixture of 0.82 g (1.8 mmol) of 5-amino-2-[[4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]amino]-4-(cyclopentylamino)pyrimidine (from preparation 14A), 0.52 g (4 mmol) of butyl glyoxylate (F. J. Wolf, J. Weijlard, Org. Synth. Coll., 1963;4:124–125), and 0.5 mL HOAc in 15 mL of EtOH is heated under reflux for 14 hours, and the solvent is removed under vacuum. The residue is diluted with aqueous ammonia solution and extracted into EtOAc. Chromatography on silica, eluting with hexane/EtOAc (3:2) gave 0.38 g (43%) of the title compound (Compound 52): mp (MeOH) 215–217° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:37])[CH:12]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:5]=1.O.[OH-].[Li+]>O.O1CCOCC1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:20]2[N:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][N:6]=3)=[O:37])[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
6-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-nicotinic acid methyl ester (24 mg, 0.04 mmol) was dissolved in water (0.5 ml) and dioxane (0.5 ml). Lithium hydroxide monohydrate (9 eq, 17 mg) was added and the mixture stirred 3 h at room temperature. The dioxane was removed under reduced pressure and the residue acidified to pH2 with 3M aqueous hydrochloric acid. The precipitate was filtered to afford the title compound as a white solid (20 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][C:4]=1/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Ethyl 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoate (4.5 g) obtained in step A was dissolved in 40 mL of methanol, and 16 mL of a 20% aqueous solution of potassium hydroxide was added. The resulting solution was stirred for 2 hours at 80° C., and then cooled to room temperature. The reaction mixture was adjusted to pH of about 3 with the use of 60 mL of 1 M hydrochloric acid. The resulting precipitate was separated by filtration, washed with water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 4.1 g (99%) of 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid.
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13]([B:15]([CH2:18][CH3:19])OC)[CH3:14].C(OCC)(=O)C>CCOCC.[Cl-].[Na+].O>[CH2:13]([B:15]([CH2:18][CH3:19])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCB(CC)OC
Reactant: Brc1ccncc1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCB(CC)c1ccncc1
Temperature: -40 °C

Procedure:
N-Butyllithium (1.6M in hexanes, 20 ml) was added to dry ether (100 ml) and cooled to −40° C. under nitrogen. The solution was stirred and a solution of 4-Bromopyridine (32 mmols) dissolved in dry ether was added drop wise. The ethereal solution was stirred for 30 minutes at −40° C. then cooled to −70° C. Diethyl methoxy borane (4.6 ml) dissolved in dry ether (50 ml) was added drop wise and the mixture was allowed to warm to room temperature over night. Ethyl acetate (100 ml) and brine (70 ml) were added to the resulting brown solution and the organic layer was separated. This was dried over magnesium sulfate, filtered and evaporated to yield a brown tar. The product was purified by column chromatography on silica eluted with toluene to yield (0.94 g, 6.4 mmols) of Diethyl (4-pyridyl borane) (I) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([C:9]([F:10])([F:11])[F:12])=[N:3]1
Reactant: Cn1cc(CO)c(C(F)(F)F)n1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: Cn1cc(C=O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 1-methyl-3-trifluoromethyl-1H-pyrazol-4-methanol (0.51 g, 2.83 mmol), N-methyl morpholine N-oxide (0.37 g, 3.16 mmol), and crushed, dried, and activated 4 Å sieves (1.5 g) in anhydrous dichloromethane (15 ml), is added tetrapropyl ammonium peruthenate (0.09 g, 0.26 mmol). The reaction mixture is stirred for one hour at room temperature, then filtered through a silica gel plug and eluted with ethyl acetate. The filtrate is concentrated in vacuo to give 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxaldehyde (0.44 g, 88%), which is used without further purification. 1H NMR (CDCl3): δ=9.92 (1H, s), 7.99 (1H, s), 4.00 (3H, s).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:8]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:9])[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(O)C>[NH2:2][CH:3]([CH:8]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:9])[CH2:4][OH:5]
Reactant: COC(=O)C(N)C(C)c1c[nH]cn1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(c1c[nH]cn1)C(N)CO
Temperature: 0 °C

Procedure:
7.7 g (30 mmol) methyl 2-amino-3-(1H-imidazol-4-yl)butyrate hydrochloride are added at 0° C. to a stirred suspension of 3.4 g (90 mmol) lithium aluminium hydride in 125 ml tetrahydrofurane. Subsequently, the mixture is refluxed for 3 hours, cooled to 0° C. and and hydrolysed by addition of 6.5 ml water in 15 ml tetrahydrofurane. Stirring with 20 ml 5N sodium hydroxide solution affords a coarse-grained precipitate which is filtered off and extracted by means of 100 ml ethanol in 3 portions. Concentration of the fractions affords an oil which is treated with anhydrous ethanol to separate inorganic material. Filtration and evaporation yield 4 g (85.9%) 2-amino-3-(1H-imidazol-4-yl)butanol wich is converted into the oily dihydrochloride. An analytical sample is converted into dipicrate and recrystallized from ethanol/water. Yellow crystals, melting point 168° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH:5]1[C:10]2=[N:11][S:12][N:13]=[C:9]2[C:8]([NH:14][C:15]2[NH:19][CH2:18][CH2:17][N:16]=2)=[C:7]([Cl:20])[CH:6]=1>CC(C)=O>[CH:5]1[C:10]2=[N:11][S:12][N:13]=[C:9]2[C:8]([NH:14][C:15]2[NH:19][CH2:18][CH2:17][N:16]=2)=[C:7]([Cl:20])[CH:6]=1.[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Agent: Clc1ccc2nsnc2c1NC1=NCCN1
Solvent: CC(C)=O
Product: CC(=O)[O-]
Temperature: 2.5 °C

Procedure:
To 60 ml of acetic acid 40 g of the tizanidine base (99.15% HPLC) are gradually added under stirring and heating until a yellow solution is obtained at 70 to 80° C., to which 200 ml of acetone are added. Shortly thereafter crystallization begins. After cooling to 0 to 5° C. and aspiration 47.25 g of tizanidine acetate (i.e. 95.5% th.) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[N:7](C)[C:8](=O)C(F)(F)F.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[NH:7][CH3:8]
Reactant: CN(C(=O)C(F)(F)F)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
5-Chloro-N-methyl-2-nitro-N-trifluoroacetylaniline (30 g) from Example 9 was dissolved in methanol (300 ml), followed by addition of an aqueous 15% NaOH solution and subsequent addition of methanol (50 ml) under stirring for 3 hours. The reaction mixture solution was poured into water (400 ml), and the precipitate was given by filtration, which was then washed with water. The precipitate was dissolved in methylene chloride (300 ml), and then the methylene chloride layer was washed with water and saturated sodium chloride solution to dry the product over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the title compound was given (19 g; 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]=[CH2:33])=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:42]=[C:43]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH:44]=[CH:45][CH:46]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:45]4[CH:46]=[CH:41][CH:42]=[C:43]([N:47]5[CH2:51][CH2:50][CH2:49][C:48]5=[O:52])[CH:44]=4)=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCCN1c1cccc(I)c1
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2cccc(N4CCCC4=O)c2)nn3C2CCCCO2)CC1
Temperature: 125 °C
Yield: 67 %

Procedure:
To a solution of 4-[6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.56 mmol) in DMF (2.55 mL) were added 1-(3-iodo-phenyl)-pyrrolidin-2-one (0.19 g, 0.67 mmol), tri(o-tolyl)phosphine (34 mg, 0.11 mmol) and triethylamine (2.55 mL). The resulting solution was degassed using argon, palladium acetate (6 mg, 0.03 mmol) was then added and the reaction mixture was heated at 125° C. overnight. The reaction mixture was concentrated under vacuum and the residue taken up in water and then acidified to pH=1. The precipitate was filtered, washed with water and then dried under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc (0-100%) in cyclohexane to yield the title compound as a beige solid (0.26 g, 66%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:23])([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]1=[O:24])[CH2:2][CH2:3]C.[Cl:25]C1C=C2C(=CC=1)N(CCC)C(=O)C2=O.C(C1C=CC=CN=1)(=O)C>>[Cl:25][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH2:2][CH3:3])[C:6](=[O:24])[C:7]2([OH:23])[CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Agent: CC(=O)c1ccccn1
Product: CCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-propylindoline-2,3-dione and 2-acetyl pyridine (purchased from Fisher Scientific). 1H-NMR δ 8.70 (d, 1H), 8.10 (d, 1H), 7.92 (t, 1H), 7.56 (dd, 1H), 7.28 (m, 2H), 6.79 (d, 1H), 3.63 (m, 5H), 1.70 (m, 2H), 0.96 (t, 3H). Calculated mass for C18H17ClN2O3, 344.09. Observed 345.0 (M+1), 367.1 (M+Na).