Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si:30]([O:37][CH2:38][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:40][OH:41])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CC(C)([O-])C.[K+]>C1COCC1>[Si:30]([O:37][CH2:38][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:40][O:41][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][N:7]\1[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)=[O:23])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cn(C[C@@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCO1)CO[Si](C)(C)C(C)(C)C
Yield: 69.8 %

Procedure:
A mixture of Example 32B (87 mg, 0.2 mmol), (R)-tert-butyl 2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)ethylcarbamate (62 mg, 0.2 mmol) and 1N potassium tert-butoxide in THF (0.2 mL, 0.2 mmol) in THF (10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried with MgSO4 and concentrated under reduced pressure to afford 100 mg of the title compound. MS (DCI/NH3) m/z 716 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH3:25])[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCF
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OCCF
Yield: 20.8 %

Procedure:
4-Chloro-2-[2-(2-fluoroethoxy)-3-formylphenoxy]benzonitrile (0.35 g, 1.1 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration and dried to give 4-chloro-2-[2-(2-fluoroethoxy)-3-(methylaminomethyl)phenoxy]benzonitrile fumarate (I 94 mg, 40%) as a beige solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([C:22]4[CH:26]=[C:25]([CH3:27])[O:24][N:23]=4)[N:11]3[N:10]=2)=[N:5][C:4]([CH2:28]O)=[N:3]1.S(Cl)([Cl:32])=O>ClCCl>[Cl:32][CH2:28][C:4]1[N:5]=[C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([C:22]4[CH:26]=[C:25]([CH3:27])[O:24][N:23]=4)[N:11]3[N:10]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc(CO)nn4C)nn23)no1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc(CCl)nn4C)nn23)no1
Yield: 78 %

Procedure:
A suspension of [1-methyl-5-({[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yl]oxy}methyl]-1H-[1,2,4]triazol-3-yl}methanol (350 mg, 0.9 mmol) in dichloromethane (15 ml) was treated portionwise with thionyl chloride (5 ml) at room temperature for 1 h. The mixture was evaporated in vacuo and the residue partitioned between 5% MeOH/DCM and water. The aqueous layer was basified with saturated K2CO3 solution. The organic layer was separated, dried (MgSO4), and concentrated to give the title compound as a white solid (0.28 g, 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1>N1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:30]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])[CH2:3]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.47 mmol) in pyridine (2 mL) was added pyridine-3-sulfonyl chloride (100 mg) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 462.3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:32](OCC)(=O)C>CN(C)C=O.O>[CH3:32][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=2)=[C:7]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C)ccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Cc2c(-c3ccccc3)n(C)c3cc(C)ccc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (100 mg) in N,N-dimethylformamide (2 mL) was added sodium hydride (min. 55% in oil, 13 mg) under ice-cooling, and this mixture was stirred at room temperature for 30 minutes. Then, methyl iodide (0.026 mL) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (35.3 mg). 1H-NMR (CDCl3) δ ppm: 2.51 (3H, s), 3.62 (3H, s), 4.02 (3H, s), 4.36 (2H, s), 6.88-6.95 (1H, m), 7.12-7.20 (2H, m), 7.29 (1H, d, J=8.0 Hz), 7.33-7.49 (5H, m), 7.58 (1H, t, J=7.8 Hz), 7.88-7.95 (1H, m).
Reaction SMILES: B.[CH2:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6][CH2:5]1)[CH3:3]>C1COCC1>[CH2:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[CH3:3]
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Borane in THF (1M, 64.1 mL, 64.1 mmol) was added dropwise to trans-4-ethylcyclohexanecarboxylic acid (10.0 g, 64.1 mmol) in dry THF (100 mL) at −60° C. under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with saturated ammonium chloride solution at 0° C., diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×200 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain (trans-4-ethylcyclohexyl)methanol. 1H NMR (300 MHz, CDCl3): δ 3.44 (d, J=6.0 Hz, 2H); 1.85-1.70 (dd, J=1.19, 10.5 Hz, 4H); 1.50-1.35 (m, 1H); 1.30-1.10 (m, 4H); 0.95-0.85 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[C:18]1([CH3:31])[CH:23]=[CH:22][C:21]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1>C(OCC)C>[O:16]=[C:14]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([CH3:31])=[CH:19][CH:20]=2)[CH2:26][CH2:27]1)[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=2[CH:11]=1)=[O:17]
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Solvent: CCOCC
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4c(c3)OCC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-p-tolyloxy-piperidine according to the method described in Example 1c. Melting Point: 226-228° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:20][C:15]3[CH2:16][NH:17][CH2:18][CH2:19][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])=[C:4]([F:24])[CH:3]=1.[CH:25]1[CH:26]=[CH:27][C:28]2[N:33](O)[N:32]=[N:31][C:29]=2[CH:30]=1.CCN=C=NCCCN(C)C.CN([CH:49]=[O:50])C>>[NH:31]1[C:29]2[CH:30]=[CH:25][C:26]([C:49]([N:17]3[CH2:18][CH2:19][C:14]4[C:13]([C:21]([NH2:23])=[O:22])=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:24])[S:20][C:15]=4[CH2:16]3)=[O:50])=[CH:27][C:28]=2[N:33]=[N:32]1
Reactant: On1nnc2ccccc21
Reactant: NC(=O)c1c(NC(=O)Cc2ccc(Cl)cc2F)sc2c1CCNC2
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1c(NC(=O)Cc2ccc(Cl)cc2F)sc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 80 °C
Yield: 12 %

Procedure:
Starting material 20 (118 mg, 0.3 mmol) was suspended in 2 ml dry DMF and 1H-1,2,3-benzothiazole-5-carboxyllic acid (63 mg, 0.4 mmol, 1.2 equiv.), dry HOBt (52 mg, 0.4 mmol) and EDCI (74 mg, 0.4 mmol) were added. The brown suspension was stirred at 80° C. over night. Then another 0.5 equiv. 1H-1,2,3-benzothiazole-5-carboxyllic acid were added and the reaction was stirred another 6 h at 80° C. the solvent was reduced under vacuo and the remaining crude product further purified by prep. HPLC (Method 3). The pure fractions were combined and the solvent was reduced. The remaining product was lyophilized yielding the desired products 21 as a light-brown solid (20 mg, 0.04 mmol, 12%).
Reaction SMILES: [Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1I.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(Cl)c(-c2ccccc2)c2c(=O)[nH]ncc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To 206 mg (0.484 mmol) of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 30-(b) were added 71 mg (0.58 mmol) of phenylboronic acid, 54 mg of tetrakistriphenylphosphine palladium, 6 ml of toluene, 4 ml of ethanol and 1 ml of 2M aqueous sodium carbonate solution, the mixture was degassed under reduced pressure and replaced with argon, and the mixture was stirred at 80° C. for 16 hours. After completion of the reaction, a saturated aqueous solution of sodium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 152 mg of the title compound as a pale yellowish solid. (Yield: 84%)
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:31]=3[N:30](COCC[Si](C)(C)C)[N:29]=[CH:28]4)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:31]=3[NH:30][N:29]=[CH:28]4)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cccc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2(COCc3cccc4cn[nH]c34)CCNCC2)cc1

Procedure:
tert-Butyl 4-phenyl-4-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (34 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the compound purified by reverse phase HPLC to afford 11 mg (56%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 8.91 (s, 1H), 8.24 (m, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.40-7.43 (m, 2H), 7.28-7.35 (m, 4H), 7.22-7.25 (m, 1H), 4.81 (s, 2H), 3.48 (s, 2H), 3.38-3.41 (m, 2H), 2.96-2.97 (m, 2H), 2.39-2.41 (m, 4H). Mass spec.: 322.08 (MNa)+. Accurate mass spec.: m/z 322.1909 [MH]+, Δ=3.2 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([O:27][C:18]3[C:17]4[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=4)[N:21]=[CH:20][CH:19]=3)=[C:29]([CH3:36])[C:30]=2[CH3:35])=[S:12])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (55 mg, yield 68%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[I-:17].[K+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16]
Reactant: [I-]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCI
Temperature: 25 °C
Reaction time: 120 h
Yield: 67.5 %

Procedure:
A solution of 5.0 g (0.018 mol) of N-(4-bromobutyl)phthalimide in 116 mL of acetone was treated with 20.7 g (0.125 mol) of potassium iodide and stirred at room temperature for 5 days. The reaction was filtered and the filtrate was diluted with 400 mL of ether, then filtered again through celite. The filtrate was concentrated at reduced pressure. The resulting solid was recrystallized from 300 mL of hexane (filtered hot and boiled down to 150 mL) to yield 4.0 g (68.6%) of 3 as white needles.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17]C(Cl)(Cl)C(O[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O>C1(C)C=CC=CC=1>[ClH:17].[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:1]2[CH2:10][CH2:9][CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH2:2]2)=[CH:24][CH:25]=1
Reactant: COC(=O)C1CCCNC1
Reactant: COc1ccc(COC(=O)C(Cl)(Cl)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Product: Cl
Yield: 63.8 %

Procedure:
A mixture of 23 g of methyl nipecotate, 24.3 g of potassium carbonate, and 52 g of p-methoxybenzyl trichloroacetate in 800 ml of toluene is refluxed under nitrogen for seventy-two hours. The mixture is cooled, the toluene removed in vacuo, the residue dissolved in chloroform, and this solution washed once with 400 ml of aqueous potassium carbonate and then with 400 ml of 10% hydrochloric acid. The chloroform solution is dried and concentrated in vacuo to a viscous brown oil. Trituration of this oil with ethyl acetate affords 30.7 g of methyl N-(p-methoxybenzyl)nipecotate hydrochloride as an off-white crystalline solid. Recrystallization from ethyl acetate yields the analytical sample, m.p. 150°-154°.
Reaction SMILES: [CH2:1]1[CH:5]2[C:6]([N+]([O-])=O)([C:11](O)=O)[CH:7]([C:8]([OH:10])=[O:9])[CH:2]1C=C2.[Cl-].[K+]>>[C:7]1([C:8]([OH:10])=[O:9])[C:6](=[CH2:11])[CH:5]=[CH:1][CH:2]=1
Reactant: O=C(O)C1C2C=CC(C2)C1(C(=O)O)[N+](=O)[O-]
Agent: [Cl-]
Agent: [K+]
Product: C=C1C=CC=C1C(=O)O

Procedure:
The concentrated black liquor, lignin, and humic acid are mixed into slurry, with their mass percentage respectively being 80%, 5% and 15%. KCl is added. Then a solid state fulvic acid fertilizer is obtained, with a content of organic matter of 67%, a total content of N+P2O5+K2O of 4%, and a content of fulvic acid of 40%. The mildly contaminated condensate with an NH4+—N concentration of 85 mg/l is reused in the washing section in Step 4).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[NH2:31]>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:29]=2)[CH:33]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1cccnc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)no2)C1

Procedure:
250 mg (about 0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 98 mg (0.71 mmol) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 35 mg (11% of theory)
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:35][CH2:36][OH:37]>>[CH3:33][N:2]([CH3:1])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:35][CH2:36][OH:37])[C@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C[C@@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1
Reactant: OCCBr
Product: C[C@@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1CCO
Yield: 68.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-((R)-3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (43 mg, 0.095 mmol) and 2-bromo ethanol (13 mg, 0.105 mmol) gave 7-cyclopentyl-2-{5-[(R)-4-(2-hydroxy-ethyl)-3-methyl-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (32 mg, 68%). MS(ESI) m/z 493.3 (M+H)+
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:13]2[N:14]=[CH:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1(=O)O[CH2:20][CH2:19][O:18]1>CN(C=O)C.O.CO>[O:16]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:20][CH2:19][OH:18])[C:13]=2[N:14]=[CH:15]1
Reactant: Oc1cccc2ocnc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: OCCOc1cccc2ocnc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
K2CO3 (254 mg, 1.84 mmol) was added to a stirred solution of 4-hydroxybenzoxazole* (248 mg, 1.84 mmol) in DMF (5 mL) at room temperature. The mixture was heated at 90° C. for 15 min and ethylene carbonate (176 mg, 2.00 mmol) was added. The mixture was stirred at 150° C. for 2 h and allowed to attain room temperature. The mixture was diluted with water (2 mL) and MeOH (2 mL), and concentrated. The residue was partitioned between water and CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL). The organic phases were pooled and washed with water and brine, and dried over MgSO4. The filtrate was concentrated to give the product as a brown oil that slowly solidified: yield 278 mg (84%); mp 47-49° C. Anal. (C9H9NO3) C, H, N.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH2:5]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([C:19]([C:21]4[N:22]=[CH:23][NH:24][CH:25]=4)=[O:20])=[CH:18][C:12]=3[CH:11]=[CH:10][C:9]=2[O:8][CH2:7][CH2:6]1.[Cl-].[NH4+]>C1COCC1>[CH2:5]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([C:19]([C:21]4[N:22]=[CH:23][NH:24][CH:25]=4)([OH:20])[CH2:1][CH3:2])=[CH:18][C:12]=3[CH:11]=[CH:10][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: O=C(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethylmagnesium chloride in THF (3M; 3 mL) was added to a solution of (2,3-dihydro-1H-benzo[f]chromen-8-yl)(1H-imidazol-4-yl)ketone (0.523 g) in THF (20 ml) at 0° C. The mixture was stirred at room temperature for 2 h. Aqueous ammonium chloride solution was added to the mixture and extracted with ethyl acetate. The extract was dried and concentrated. The residue was chromatographed on silica gel (eluent; dichloromethane:methanol=20:1) to give the titled compound (0.512 g) as a colorless solid.