Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[NH2:52][C:53]1[CH:58]=[C:57]([O:59][C@H:60]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH3:61])[C:56]([N+:68]([O-:70])=[O:69])=[CH:55][C:54]=1[C:71]1[CH:87]=[CH:86][C:74]([C:75]([O:77][C:78]2[CH:83]=[CH:82][C:81]([CH2:84]O)=[CH:80][CH:79]=2)=[O:76])=[CH:73][CH:72]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:84][C:81]2[CH:82]=[CH:83][C:78]([O:77][C:75](=[O:76])[C:74]3[CH:73]=[CH:72][C:71]([C:54]4[CH:55]=[C:56]([N+:68]([O-:70])=[O:69])[C:57]([O:59][C@H:60]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH3:61])=[CH:58][C:53]=4[NH2:52])=[CH:87][CH:86]=3)=[CH:79][CH:80]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(CO)cc3)cc2)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCc3ccc(OC(=O)c4ccc(-c5cc([N+](=O)[O-])c(O[C@@H](C)CCCCCC)cc5N)cc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
0.2 g of N,N'-dicyclodicyclohexylcarbodiimide was added at room temperature while stirring to a solution of 0.6 g of 2,5-bis(4-[6-acryloyloxyhexyloxy]phenylcarboxy)benzoic acid, 0.4 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]-phenyl)benzoyloxy]phenylmethanol and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from acetone of the fractions which were pure according to thin-layer chromatography gave 0.4 g of (4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]phenyl)-methyl 2,5-bis(4-[6-acryloyloxyhexyloxy]phenylcarboxy)benzoate; m.p. (C-I) 100° C., Sc* -N*, 96° C., cl.p. (N* -I) 100° C.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-:26].[Na+].O.[CH2:29]([OH:31])C>>[CH2:11]([O:10][C:5]1[CH:4]=[CH:9][C:8]([C:29]([OH:31])=[O:26])=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCO
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCOc1ccccc1C(=O)OC
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
Twenty grams of tetradecyloxy benzoic acid methyl ester and 2.75 g of sodium hydroxide were dissolved in 80 ml of ethanol. After the addition of 50 ml of water was heated for 2.5 hours to boiling temperature. The resulting suspension was concentrated by evaporation and the evaporation residue was dissolved in hot water. The solution then was acidified with dilute hydrochloric acid, filtered, washed with water and dried. 4-tetradecyloxybenzoic acid melting at 95° to 99° C. (clear at 135° C. was obtained in a yield of 18.2 g, corresponding to 95% of the theoretical.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](O)=[O:12])=[N:2]1.[CH3:14][C:15]1[C:16]([CH2:20][C:21](O)=[O:22])=[N:17][O:18][N:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][OH:12])=[N:2]1.[CH3:14][C:15]1[C:16]([CH2:20][CH2:21][OH:22])=[N:17][O:18][N:19]=1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: Cc1nonc1CC(=O)O
Product: Cc1nonc1CCO
Product: OCCc1noc2ccccc12

Procedure:
In analogy to example 356, the starting compounds 2-(benzo[d]isoxazol-3-yl)-ethanol and 2-(4-methyl-furazan-3-yl)-ethanol were prepared from 2-(benzo[d]isoxazol-3-yl)-acetic acid and 2-(4-methyl-furazan-3-yl)-acetic acid, respectively.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH2:21][O:13][C:12]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH:1]=[O:2])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC2)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of methyl 3-formyl-4-hydroxybenzoate (2 g, 11.10 mmol) in DMF (20 ml), K2CO3 (3.07 mg, 22.2 mmol) and (bromomethyl)cyclopropane (2.156 ml, 22.2 mmol) were added. The mixture was stirred at RT for 2 hours. The reaction was quenched with water, and the product was extracted with EtOAc. The organic layer was washed with water (2×) and NaCl sat. sol., dried over Na2SO4 and evaporated under vacuum to give 2.6 g of the desired compound (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:9]=2[CH:10]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8](/[CH:11]=[C:12](/[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)\[CH3:13])[C:9]=2[CH:10]=1
Reactant: CN1CCc2c(c3cc(Cl)c(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cc(Cl)c(Cl)cc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-(7,8-dichloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (500 mg, 1.2 mmol) in thionylchloride (5 mL) and stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (5 mL) and the solution was stirred at RT for 5 min. Powdered KOH (482 mg, 8.5 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, formate salt) δ (ppm): 8.60 (d, 2H), 7.70 (d, 2H), 7.65 (s, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 4.0 (s, 2H), 3.20 (t, 2H), 2.98 (t, 2H), 2.80 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:58]=[CH:57][C:37]3[NH:38][C:39]([C:41]4[C:49]5[C:44](=[CH:45][CH:46]=[C:47]([NH2:50])[CH:48]=5)[N:43]([CH:51]5[CH2:56][CH2:55][CH2:54][CH2:53][O:52]5)[N:42]=4)=[N:40][C:36]=3[CH:35]=2)[CH2:30][CH2:29]1>CN(C=O)C>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:50][C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][O:52]1)[N:42]=[C:41]2[C:39]1[NH:38][C:37]2[CH:57]=[CH:58][C:34]([N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)=[CH:35][C:36]=2[N:40]=1)=[O:6]
Reactant: O=C(O)C1CC1(F)F
Reactant: Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
2,2-Difluorocyclopropanecarboxylic acid (6.42 mg, 0.053 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (9.69 mg, 0.072 mmol), EDC (13.74 mg, 0.072 mmol) and sodium bicarbonate (4.01 mg, 0.048 mmol) was added to a solution of 3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.048 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Upon purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (15 mg). 1H NMR: (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.76-7.72 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.05 (m, 2H), 5.86 (dd, 1H, J=2.4 and 9.6 Hz), 3.99 (m, 1H), 3.86 (m, 4H), 3.81 (m, 1H), 3.16 (m, 4H), 2.77-2.69 (m, 1H), 2.61 (m, 1H), 2.18-2.08 (m, 3H), 1.89-1.80 (m, 2H), 1.74-1.68 (m, 2H); ESI-MS [M+H]+: 523.2.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)([Cl:8])=O.[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][C:12]2=O.P([O-])([O-])(O)=O.[K+].[K+]>ClCCCl.O>[Cl:8][C:12]1[CH:11]2[CH2:17][CH:14]([CH2:15][CH2:16]2)[C:13]=1[CH:4]=[O:5]
Reactant: O=C1CC2CCC1C2
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: O=CC1=C(Cl)C2CCC1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with anhydrous 1,2-dichloroethane (24 mL) and anhydrous DMF (9.12 g, 125 mmol). The reaction mixture was cooled to 0° C., and phosphorus oxychloride (15.3 g, 100 mmol) was added over a period of 5 minutes, while maintaining the reaction temperature between 0 and 10° C. The cooling bath was removed, and the reaction was stirred at room temperature for 30 minutes. A solution of bicyclo[2.2.1]heptan-2-one (5.50 g, 50.0 mmol) in 1,2-dichloroethane (10 mL) was added and the resulting mixture was heated at 80° C. for overnight. After this time, the reaction was poured into a solution of potassium monohydrogenphosphate (43.5 g, 250 mmol) in water (200 mL) and stirred for 15 minutes. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in methylene chloride (300 mL) and washed with water (2×50 mL). The methylene chloride layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 1:100 ethyl acetate/petroleum ether to give 334a as a yellow oil (2.2 g, 28%). MS: [M+H]+ 157. 1H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 3.42 (s, 1H), 3.07 (d, J=1.7 Hz, 1H,), 1.95-1.77 (m, 2H), 1.67 (t, J=8.9 Hz, 1H), 1.41-1.17 (m, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O:32][C:33](=[O:47])[C:34]([O:44][CH2:45][CH3:46])([CH3:43])[CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)C.O>CS(C)=O.O1CCCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:39]2[CH:38]=[CH:37][C:36]([CH2:35][C:34]([O:44][CH2:45][CH3:46])([CH3:43])[C:33]([OH:47])=[O:32])=[CH:41][CH:40]=2)=[CH:15][CH:16]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(C)(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
Sodium hydroxide (0.105 g; 2.63 mmole) was pulverized and dissolved in DMSO (8 ml). To 4 ml of this solution 2-[4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.515 g; 1.316 mmole) and 2-ethoxy-3-(4-hydroxyphenyl)2-methyl propanoic acid ethyl ester (0.331 g; 1.316 mmole) were added and the mixture was stirred at room temperature over night. The remaining volume (4 ml) of the sodium hydroxide solution and water (1 ml) were added. A precipitate was formed which was dissolved by addition of tetrahydrofuran (1 ml). The mixture was allowed to stand over night and was then evaporated. The residue was redissolved in dichloromethane and water and the phases were separated. The water phase was extracted once more with dichloromethane, acidified with hydrochloric acid (1 M), extracted several times with ethyl acetate and diethyl ether. The organic phases were combined, dried with magnesium sulfate and evaporated. Purification of the crude product by flash chromatography and preparative HPLC gave 0.103 g (17.1% yield) of 3-[4-{2-(4[-tert-butoxycarbonylamino]phenyl)ethoxy}phenyl]-2-ethoxy-2-methyl-propanoic acid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN1C(=O)N(C)CC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[CH:12]1([NH:18][C:2]2[C:3]3[CH:11]=[CH:10][NH:9][C:4]=3[N:5]=[CH:6][C:7]=2[F:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: Fc1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 200 °C
Yield: 12.2 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and cyclohexylamine (87 mg) in DMI (0.4 mL) was heated in the microwave reactor (200° C., 4 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave N-cyclohexyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-amine (5 mg) as a yellow solid.
Reaction SMILES: [OH:1][Ge:2][OH:3].[CH:4]1[CH:5]=[CH:6][C:7]2[C:8](=[C:10]3[N:42]=[C:41]4[N:43]=[C:34]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=54)[N:33]=[C:31]4[NH:32][C:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=54)=[N:23][C:21]4=[N:22][C:14]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=54)=[N:13][C:12]=2[NH:11]3)[CH:9]=1.[C:44]1([CH:50]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][SiH2:67]O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCOCC1>[C:48]1([CH:41]([C:40]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][SiH2:67][O:1][Ge:2][O:3][SiH2:67][O:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH:50]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:49]=1.[CH:5]1[CH:4]=[CH:9][C:8]2[C:7](=[C:12]3[N:13]=[C:14]4[N:22]=[C:21]([C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=54)[N:23]=[C:24]4[NH:32][C:31]([C:30]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=54)=[N:33][C:34]4=[N:43][C:41]([C:40]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=54)=[N:42][C:10]=2[NH:11]3)[CH:6]=1
Reactant: O[Ge]O
Reactant: O[SiH2]OCCCCCCCCCCCCCCCC(c1ccccc1)c1ccccc1
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: C1COCCO1
Product: c1ccc(C(CCCCCCCCCCCCCCCO[SiH2]O[Ge]O[SiH2]OCCCCCCCCCCCCCCCC(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
2 g (3.24 mmol) of dihydroxygermanium-phthalocyanine am boiled at reflux with 2 equivalents of diphenylhexadecyloxysilanol in 210 ml of dioxane for 39 hours. After 24 hours, 500 mg of dihydroxygermanium-phthalocyanine are added. The reaction mixture is allowed to cool and the residue is chromatographed on basic aluminium oxide (Alox B ) using pure hexane and hexane/ethyl acetate (4:1) in succession as eluants. The product-containing fractions am combined and concentrated. The residue is recrystallised from pentane at -20° C., yielding blue crystals of bis(diphenylhexadecyloxy-siloxy)-germanium-phthalocyanine.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[Na+]>O.C(OCC)C.C(O)(=O)C>[I:21][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(I)ccc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
4-Iodo-2-nitroaniline (6.60 g, 0.025 mol) was suspended in water (19 mL) and glacial acetic acid (17.5 mL) (Sapountzis et al., 2005, which is incorporated herein by reference). The mixture was cooled to 0° C. Sulfuric acid (17.5 mL, 0.328 mol) was added cautiously. The mixture was cooled to minus 5° C., and a solution of NaNO2 (1.90 g, 0.028 mol) in water (7.5 mL) was added dropwise at a rate that the temperature would not exceed 0° C. Upon completion of the addition the mixture was stirred for 30 minutes and was added in small portions to a boiling solution of sodium iodide (22.33 g, 0.149 mol) in water (7.5 mL) (CAUTION: vigorous nitrogen evolution!). The resulting mixture was kept at 60° C. for one hour, then cooled down to room temperature, followed by addition of diethyl ether (500 mL). The ether solution was separated, washed twice with water (150 mL) and once saturated NaHCO3 (150 mL). The solution was dried over Na2SO4 and concentrated in vacuo to a solid, which was recrystallized from ethanol to yield 1,4-diiodo-2-nitrobenzene (9.30 g, 99%). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 1H, J=2.0 Hz), 7.75 (d, 1H, J=8.3 Hz), 7.56 (dd, 1H, J=8.3 and 2.0 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([OH:18])[CH2:20]1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reactant: O[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCC[C@@H](O)C2)c1S(C)(=O)=O
Yield: 59.6 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), (R)-(+)-3-hydroxypiperidine (119 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, the residue was extracted with dichloromethane and 10% Na2CO3, and then purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate and the resulting white crystals were filtered off. One obtained 209 mg (60%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:34][CH:35]=1.Cl>N1C=CC=CC=1>[F:43][C:29]([F:28])([F:42])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:37][CH2:38][N:39]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[C:3]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:40][CH2:41]2)=[N:34][CH:35]=1
Reactant: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide (0.1 g, 0.242 mmol) in pyridine (2 ml) was treated with 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (0.3 g, 0.68 mmol) and the reaction mixture was stirred for 1 hour at room temperature. Subsequently the reaction mixture was poured onto crushed ice containing two drops of concentrated hydrochloric acid, extracted with ethyl acetate (25 ml) and the organic layer was washed with brine and evaporated. The title compound was obtained by column chromatographic purification of the crude material with 30% ethyl acetate in hexane. 1H-NMR (DMSO-d6) δ: 3.33-3.37 (m, 4H), 3.56 (m, 4H), 6.86-6.88 (d, 1H), 7.10-7.12 (d, 2H), 7.22-7.29 (m, 3H), 7.35-7.37 (m, 1H), 7.44-7.48 (m, 1H), 7.74-7.79 (m, 3H), 8.38 (s, 1H). MS m/z: 608.8 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@@H:54]2[C@@H:58]([OH:59])[CH2:57][CH2:56][NH:55]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([NH:52][CH2:53][C@@H:54]2[C@@H:58]([OH:59])[CH2:57][CH2:56][N:55]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: O[C@H]1CCN[C@@H]1CNC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CC[C@H](O)[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (250 mg, 0.48 mmol), HOBt (78 mg, 1.2 eq.), EDC (110 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (2R,3S)-2-cyclopropylaminomethyl-pyrrolidin-3-ol (300 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH:30]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][N:33]([CH:30]5[CH2:32][CH2:31]5)[CH2:34][CH2:35]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C6CC6)CC5)c34)cc2Cl)cn1
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-cyclopropylpiperazine to give the title compound in 28% yield; NMR Spectrum: 0.23-0.25 (m, 2H), 0.35-0.38 (m, 2H), 1.51-1.55 (m, 1H), 2.45 (s, 3H), 2.50 (hidden by DMSO, 8H), 2.78 (t, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.25 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 521 (MH+).