Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16]([C:25]4[N:29](CC5C=CC(OC)=CC=5)[N:28]=[N:27][N:26]=4)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2-c2c(N3CCOCC3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(CCc2ccn3c(=O)c(-c4nnn[nH]4)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-3-(1-p-methoxybenzyl-1,2,3,4-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (10 mg) obtained in (C) was dissolved in trifluoroacetic acid (1 ml) and added with anisole (50 ml), and then stirred at room temperature for 4 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (7 mg) as yellow powder.
Reaction SMILES: [O:1]=[CH:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.C[Si](C)(C)[C:23]([F:26])([F:25])[F:24].C1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:24][C:23]([F:26])([F:25])[CH:2]([OH:1])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: O=CCOC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(OCC(O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A mixture of benzyl 4-(2-oxoethoxy)piperidine-1-carboxylate (2.00 g), trimethyl(trifluoromethyl)silane (1.23 g), tetrabutylammonium fluoride (1 M THF solution, 1 drop) and THF (20 mL) was stirred at 0° C. for 1 hr, and then at room temperature for 3 days. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in THF (20 mL). Tetrabutylammonium fluoride (1 M THF solution, 8.65 mL) was added thereto at 0° C., and the obtained mixture was stirred at 0° C. for 2 hr. 1M Hydrochloric acid was added, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.60 g).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C(Cl)(Cl)Cl>CN(C)C=O>[N:28]([C@@H:11]1[CH2:10][C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:14]2[CH2:15][O:16][C@@H:12]1[O:13]2)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](OCc3ccccc3)[C@H]3CO[C@@H]2O3)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Temperature: 150 °C
Reaction time: 72 h
Yield: 89.7 %

Procedure:
To a solution of 1,6-anhydro-4-O-benzyl-3-deoxy-2-O-p-toluenesulphonyl-β-D-arabino-hexopyranose (See Preparative Example 3) (0.50 g) in N,N-dimethylformamide (10 ml) was added sodium azide (0.25 g) and the mixture was heated with stirring at 150° C. for 3 days. Chloroform was added and the mixture was washed with water (×4), dried (MgSO4) and concentrated to a syrup. Purification by flash chromatography gave the title compound (0.30 g), [α]D -14.8°; 13C-nmr data: 100.8 (C-1), 55.8 (C-2), 24.6 (C-3), 71.0 and 70.6 (C-4 and PhCH2O), 74.7 (C-5), 65.7 (C-6), 137.8, 128.4, and 127.7 (aromatic).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33]Br)[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][O:15][C:3]2[C:2]([Br:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(O)c(Br)cc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Br)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Yield: 55.1 %

Procedure:
A mixture of 2 g (0.0073 mol) of 1-(5-bromo-2,4-dihydroxy-3-propylphenyl)-ethanone, 2.84 g (0.0073 mol) of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester and 1.52 g (0.011 mol) of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux for 20 hours. An additional 1 g of potassium carbonate was added and reflux was continued for a total of 35 hours. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to a oil which was dissolved in ethyl acetate and washed with 1N sodium hydroxide and sodium chloride solution. The crude product was purified by HPLC, eluting with 25% ethyl acetate in hexane to yield 2.33 g (55% yield) of [4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH2:14][CH2:13]2)[CH3:11])=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](OCCCCBr)CC1

Procedure:
In analogy to example 11.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester and 1,4-dibrombutane were reacted to yield trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester as yellowish oil, MS:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:40][C@H:41]2[N:45]([CH3:46])[C:44](=[O:47])[CH2:43][CH2:42]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][C@H:41]1[N:45]([CH3:46])[C:44](=[O:47])[CH2:43][CH2:42]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H]1CCC(=O)N1C
Temperature: 95 °C
Yield: 33 %

Procedure:
To a solution of 7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (225 mg, 0.7 mmol), (prepared as described in Example 49), in DMF was added powdered potassium carbonate (290 mg, 2.1 mmol) and (5S)-5-(p-toluenesulphonylmethyl)-1-methyl-2-pyrrolidinone (340 mg, 1.2 mmol). The reaction was then heated at 95° C. for 5 hours. The inorganic material was filtered off and the DMF removed by evaporation. The residue was then purified by chromatography eluting from methylene chloride to 12% methanol/88% methylene chloride (+1% ammonium hydroxide). The product was evaporated, triturated with ether and filtered to give (5S)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(1-methyl-2-oxopyrrolidin-5-ylmethoxy)quinazoline (100 mg, 33%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:32]([O-:46])([O:34][CH2:35][C@@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40]O)=[O:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([O:13][CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([O:42][N+:43]([O-:45])=[O:44])[CH2:35][O:34][N+:32]([O-:46])=[O:33])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])OC[C@H](CCCCO)O[N+](=O)[O-]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)OCCCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 12 h

Procedure:
To a dichloromethane (20 mL) solution of 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (1.76 g, 3.72 mmol), (2S)-6-hydroxyhexane-1,2-diyl dinitrate (intermediate 3, 0.83 g, 3.72 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.85 g, 4.46 mmol), and 1-hydroxybenzotriazole (0.68 g, 4.46 mmol) was added N-methylmorpholine (1.84 mL, 16.7 mmol), followed by N,N-dimethylaminopyridine (4.5 mg, 0.04 mmol). After 12 hours, the reaction mixture was washed with saturated sodium bicarbonate solution, brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. Purification of the reaction mixture by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound. 1H NMR (500 MHz, CD3CN) δ 7.69 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 5.63 (s, 2H), 5.34-5.41 (m, 1H), 4.83 (dd, J=2.5, 12.8 Hz, 1H), 4.58 (dd, J=6.2, 13.0 Hz, 1H), 4.25 (t, J=6.2 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 1.79 (q, J=7.5 Hz, 2H), 1.71 (quintet, J=6.8 Hz, 2H), 1.48-1.60 (m, 4H), 1.28 (sextet, J=7.4 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); LC-MS: m/z 643 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OC(C)=O

Procedure:
To a stirred solution of the 2-methoxy-4-nitrophenyl acetate prepared in Part A (99.2 mg, 0.47 mmol) in EtOAc (4.5 mL) was added palladium on carbon (33.0 mg, 5% dry basis, Degussa type: 50% water content). The suspension was hydrogenated (1 atm, balloon) for 3 h, filtered through CELITE® and the filter cake was rinsed with MeOH (5×10 mL). Evaporation of the combined filtrates gave the desired aniline (84.8 mg, quant.) as a brown oil: MS (electrospray, + ions) m/z 182 (M+H).
Reaction SMILES: [C:1]([CH:4]1[CH:9]([CH3:10])[CH:8]=[CH:7][CH2:6][C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1([CH3:11])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)[C@H]1[C@@H](C)CCCC1(C)C

Procedure:
464 g 1-acetyl-2,2,6-trimethyl-4-cyclohexene (V, prepared according to K. S. Ayyar Chem. Comm. 1973, 161) (2.8 moles) in 800 ml of ethanol and 3 g 10% palladium on charcoal are hydrogenated in an autoclave under a pressure of 50 atm and at 50°C. After the uptake ceases, the reaction mixture is filtered and concentrated by distillation under reduced pressure. The product cis-1-acetyl-2,2,6-trimethylcyclohexane (VI, containing about 10% of the trans isomer) is collected at 83°-88°C/12 mm; yield 420 g (90%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=2[CH3:14])[CH3:2].Cl[CH2:17][C:18]([CH3:20])=[CH2:19]>C(Cl)(Cl)Cl.CCCCCC>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([O:13][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:9]=[CH:8][C:7]=2[CH3:14])[CH3:2]
Reactant: CCc1cc2c(O)ccc(C)c2[nH]c1=O
Reactant: C=C(C)CCl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: C=C(C)COc1ccc(C)c2[nH]c(=O)c(CC)cc12
Yield: 75 %

Procedure:
Using 3-ethyl-5-hydroxy-8-methylcarbostyril (0.91 g, 4.87 mmol) and 3-chloro-2-methyl-1-propene (0.485 g, 5.36 mmol), the procedure of Reference Example 31 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane) to obtain 0.94 g of the title compound as pale brown crystals (75.1%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](O)=O.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:7][CH2:8][C:9]([C:14]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:13])[CH3:10]
Reactant: CC(C)(CCl)C(=O)O
Reactant: CNC(=S)NN
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(C(C)(C)CCl)s1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
An 87.2 g. portion of 4-methylthiosemicarbazide and 113.2 g. of 3-chloro-2,2-dimethylpropionic acid were suspended in 300 ml. of dioxane. The mixture was heated to 90°C. and 139.5 g. of phosphorus oxychloride was added dropwise while holding the temperature constant. After the addition was complete, the reaction mixture was stirred at 90°C. for three hours. The mixture was then allowed to cool and stand overnight at room temperature.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Yield: 31 %

Procedure:
10 g of 2,6-diacetylpyridine (0.0613 mol), 9.54 g of 2-chloro-4,6-dimethylaniline (0.0613 mol) and 0.6 g of p-toluenesulfonic acid were heated under reflux on a water separator in 400 ml of toluene for 90 min. The solvent was distilled off completely and the residue was recrystallized from 50 ml of isopropanol. 5.66 g (0.019 mol) of 1-{6-[1-(2-chloro-4,6-dimethyl-phenylimino)ethyl]pyridin-2-yl}ethanone were obtained in a yield of 31%.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([N:23]([CH3:38])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:26]=2)[CH:17]=[N:16]3)[CH:10]=[N:9]1)=O)(C)(C)C.Cl.N>O1CCOCC1.C1COCC1>[CH3:38][N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)[CH:26]=1)[C:18]1[CH:17]=[N:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[CH:14]=2)[N:19]=1
Reactant: CN1CCN(c2cccc(CN(C)c3cnc4cc(-c5cnn(C(=O)OC(C)(C)C)c5)ccc4n3)c2)CC1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN1CCN(c2cccc(CN(C)c3cnc4cc(-c5cn[nH]c5)ccc4n3)c2)CC1
Reaction time: 1 h
Yield: 56501.7 %

Procedure:
To a solution of 4-(2-{Methyl-[3-(4-methyl-piperazin-1-yl)-benzyl]-amino}-quinoxalin-6-yl)-pyrazole-1-carboxylic acid tert-butyl ester (0.110 g, 0.000214 mmol) in 1,4-dioxane (1.5 mL), was added HCl in dioxane (1.0 ml) at room temperature. The mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and washed with diethyl ether (5.0 mL) to afford the crude compound (0.075 g). The compound was basified by ammonia in THF and then further purified by preparative TLC to afford the title compound (0.050 g, 54%). The mobile phase used for the Preparative TLC was DCM:Methanol (9:1).
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@@H:4]([NH2:18])[CH2:3][C@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C[C@H](F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 153 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.61-7.41 (m, 4H), 7.27 (dd, J=14.5, 5.8 Hz, 2H), 4.84-4.56 (m, 1H), 3.67 (d, J=7.4 Hz, 3H), 3.44-3.34 (m, 2H), 3.21-2.86 (m, 3H), 2.22-2.07 (m, 1H), 1.87 (ddt, J=34.3, 21.1, 7.4 Hz, 3H), 1.70-1.53 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[CH2:44]([NH2:47])[CH2:45][NH2:46]>CN(C)C=O.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:46][CH2:45][CH2:44][NH2:47])=[O:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCCNC(=O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
80 mg (0.24 mmol) of N-[3-chloro-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 70.8 mg (0.36 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 42 mg (0.36 mmol) of N-hydroxysuccinimide are dissolved in 3 ml of dimethylformamide and stirred for 2.5 h at RT. The reaction mixture is then added dropwise at 0° within a period of 30 minutes to a solution of 0.77 ml (11.8 mmol) of ethylenediamine in 2 ml of DMF. After stirring for 14 h at RT, the reaction mixture is poured into 50 ml of ethyl acetate and extracted with 30 ml of water. The organic phase is dried (sodium sulfate) and concentrated. Crystallisation from isopropanol/ethanolic hydrochloric acid gives N-[3-chloro-phenyl]-4-[2-(N-{2-amino-ethyl}-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine hydrochloride; m.p. 161°-163°, FAB-MS: 369 (M+ +H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[C:34]2[NH:41][NH2:42]>>[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[C:34]2[N:41]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:42]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Reactant: NNc1ccnc2ccc(Cl)cc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1ccnc2ccc(Cl)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and (6-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=547.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13]C)=[O:6].B(Cl)(Cl)Cl.CCCCCCC.C(=O)(O)[O-].[Na+]>ClCCl>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]([C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1ccccc1C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
This procedure is based on that reported in Tetrahedron Lett., 1966, 4153. To a solution of 2,2′-dimethoxybenzophenone (11) (6.7 g, 0.0277 mol) in anhydrous dichloromethane (95 mL) cooled to −65° C. under nitrogen was added 52 mL of a 1.0 M solution of boron trichloride in heptane (0.052 mol). The mixture was allowed to warm to room temperature and stirred for 75 minutes. The reaction mixture was slowly poured into a cold (0° C.) solution of saturated aqueous sodium bicarbonate, which was then extracted with dichloromethane. The organic extracts were washed with water and saturated with NaCl, followed by drying over anhydrous sodium sulfate. Analytically pure product was obtained after removal of the solvent in quantitative yield.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH:17]([Br:19])[CH3:18].O>CN(C=O)C>[Br:19][CH:17]([CH3:18])[CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: CC(Br)CBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Br)COc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a stirring solution of 4-iodophenol (15 g, 70 mmol) and K2CO3 (12.4 g, 90 mmol) in DMF (30 mL) was added 1,2-dibromopropane (7.8 mL, 90 mmol) over a period of 1 hr. The solution was heated at 50° C. and stirred overnight under Ar. Water (500 mL) was added and the reaction mixture was extracted with dichloromethane, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. Purified on silica gel chromatography, eluted with 10% ethyl acetate in hexanes to give the title compound as a white solid (10 g, 29 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH2:19](O)[CH3:20]>>[NH2:11][C:9]([C:8]1[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=[CH:5][C:4]=1[C:1]([O:3][CH2:19][CH3:20])=[O:2])=[O:10]
Reactant: CCO
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1
Product: CCOC(=O)c1cnn(-c2cccc(Cl)c2)c1C(N)=O

Procedure:
A 2.5 g. portion of 4-carboxy-1-(3-chlorophenyl)-5-pyrazolecarboxamide was suspended in 50 ml. of absolute ethanol, made acid, and esterified and isolated as described in Example 14 above. The product was 1.64 g. of the desired product, m.p. 132°, and its elemental analysis was as follows.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][CH:14]([C:20](=O)[CH3:21])[C:15](OCC)=[O:16]>CC(O)=O>[F:13][C:14]1[C:20]([CH3:21])=[N:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:15]=1[OH:16]
Reactant: CCOC(=O)C(F)C(C)=O
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: CC(=O)O
Product: Cc1nc2cc(-c3ccccc3)nn2c(O)c1F
Temperature: 100 °C
Yield: 64 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5-amine x131 (52 mmol, 1 eq, 8.3 g) in 50 ml of AcOH, is added ethyl 2-fluoro-3-oxobutanoate x132 (57 mmol, 1.2 eq, 8.5 g). The mixture is heated at 100° C. for 0.5 hour. After cooling to room temperature, the resulting product is filtered, washed with EtOH and dried to afford 8.1 g of 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol x133.