Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:36]3[CH:37]=[N:38]N[CH:40]=3)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1.[O:41]1C=C(B(O)O)C=N1.CC1(C)C(C)(C)OB(C2C=NN(C(OC(C)(C)C)=O)C=2)O1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:36]3[CH:37]=[N:38][O:41][CH:40]=3)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cn[nH]c1
Reactant: OB(O)c1cnoc1
Agent: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cnoc1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine of using isoxazol-4-ylboronic acid instead tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate. LC-MS: (M+1=557, obsd.=557).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCCC1.O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)CC=CC1C=CC=CC=1)(C)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:13]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Clc1ccnc2[nH]ccc12
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)CC=Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2[nH]ccc12
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (15 g, 98 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (18.38 g, 108 mmol), potassium phosphate (62.6 g, 295 mmol), and {1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene}chloro {3-phenylallyl}palladium(II) (0.637 g, 0.983 mmol) in tetrahydrofuran (400 mL) and water (133 mL) was purged with nitrogen and heated at 65° C. overnight. The mixture was cooled and poured into water. Ethyl acetate was added, the mixture was stirred for 15 minutes and the organic layer was washed with brine. The combined aqueous extracts were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane and placed on a bed of silica gel equilibrated in 30% ethyl acetate/heptanes that was packed in a coarse Buchner funnel. The material was eluted with 30-40% ethyl acetate/heptanes to provide the title compound. MS (ESI+) m/z 243.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([CH:12]=[CH:13][C:14]2[C:15]([CH:32]([CH3:34])[CH3:33])=[N:16][N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9]C(C)(C)[O:7]1)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:16]=[C:15]([CH:32]([CH3:34])[CH3:33])[C:14]=2[CH:13]=[CH:12][CH:10]([OH:9])[CH2:11][CH:6]([OH:7])[CH2:5][C:4]([OH:37])=[O:3])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: CCOC(=O)C[C@H]1C[C@@H](C=Cc2c(C(C)C)nn(-c3ccccn3)c2-c2ccc(F)cc2)OC(C)(C)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1nn(-c2ccccn2)c(-c2ccc(F)cc2)c1C=CC(O)CC(O)CC(=O)O
Reaction time: 96 h

Procedure:
A solution of 1.44 g (2.84 mmol) of cis-(±)-ethyl-6-[2[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H- pyrazol-4-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate in 15 ml of ethyl acetate was catalytically reduced under one atmosphere of hydrogen gas in the presence of 20% Pd/C. at 25° C. for four days.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:2].[CH3:8][OH:9]>F[B-](F)(F)F.C[N+](C)(C)C>[CH:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:8])=[O:2]
Reactant: O=CN1CCCC1
Reactant: CO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCN1C=O
Yield: 86.7 %

Procedure:
In the same manner as indicated in Example 5 there are electrolyzed 17.7 g of N-formylpyrrolidine and 57.2 g of methanol in the presence of 0.29 g of tetramethylammonium tetrafluoroborate as conducting salt. In this case, however, the current is switched off after the throughput of already 2.0 Faraday per mol of N-formylpyrrolidine. The calculated mean cell voltage is 28.8 volts. Work-up of the electrolysis solution gives 20.0 g of 1-formyl-2-methoxypyrrolidine (boiling point 39°-40° C./0.1 mbar; nD25 = 1.4700), which corresponds to a product yield of 86.6% and a current efficiency of 86.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>C(Cl)Cl>[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[C:2]([NH:1][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NCC2CCOCC2)c(NC(=O)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-{3-Amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (25.9 g, 98.6 mmol) and DIPEA (20.6 mL, 15.4 g, 118 mmol) were dissolved in 500 mL of DCM. Trimethylacetyl chloride (12.7 mL, 12.5 g, 103 mmol) was added dropwise at 0° C. and the solution was stirred for 3 h at 0° C. and 1 h at room temperature. The pink solid was collected by filtration, washed with H2O and dried in vacuo. Yield: 33.1 g (97%); MS (ESI) (M+H)+=348.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH:9]([C:12]([CH3:14])=O)([CH3:11])[CH3:10]>>[CH3:14][C:12]1[C:9]([CH3:11])([CH3:10])[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([CH3:8])[CH:6]=2)[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: Cc1ccc(N)cc1
Product: CC1=Nc2ccc(C)cc2C1(C)C
Yield: 87 %

Procedure:
p-Toluidine was reacted with methyl isopropyl ketone in the same way as in Example 3. 2,3,3,5-Tetramethyl-3-H-indole was formed in a yield of 87% of the theoretical yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=3)[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]=2)=[CH:4][CH:3]=1.[CH3:27][N:28](C)C=O.[C-]#N.[Na+].Cl>O>[C:24]([C:19]1[CH:18]=[C:17]([N:9]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([C:27]#[N:28])=[CH:7][CH:6]=2)[CH:22]=[CH:21][C:20]=1[OH:23])([OH:26])=[O:25]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(-n2c(-c3ccc(Br)cc3)cc3c2CCCC3)ccc1O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(-c2cc3c(n2-c2ccc(O)c(C(=O)O)c2)CCCC3)cc1

Procedure:
A mixture of 6.18 g. (0.015 mole) of 2-(4-bromophenyl)-1-(3-carboxy-4-hydroxyphenyl)-4,5,6,7-tetrahydroindole, 1.6 g. (0.018 mole) of cuprous cyanide, and 10 ml. of dimethyl formamide was heated under reflux for 6 hours, poured into a solution of 3 g. of sodium cyanide and 10 ml. of water, and after 5 minutes diluted with 46 ml. of water. The solution was acidified to pH 1-2 with hydrochloric acid and the solid which separated was collected. Recrystallization from acetic acid gave 1.21 g. (23%) of crystals, m.p. 242°-244°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:34](O)=[O:35])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[NH:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N)CCCCC1.[C:44]([O:48][C:49](=[O:56])[NH:50][CH2:51][CH:52]([OH:55])[CH2:53][NH2:54])([CH3:47])([CH3:46])[CH3:45].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:23]([O:22][C:20]([N:19]([C:17](=[NH:18])[NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:34](=[O:35])[NH:54][CH2:53][CH:52]([OH:55])[CH2:51][NH:50][C:49](=[O:56])[O:48][C:44]([CH3:47])([CH3:45])[CH3:46])[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Reactant: CC(C)(C)OC(=O)N(C(=N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCCNC(=N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.30 g (0.49 mmol) of N2-[(benzyloxy)carbonyl]-N5-[[bis(tert-butoxycarbonyl)amino](imino)methyl]-L-ornithine-cyclohexanamine (1:1) and 0.12 g (0.64 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.123 g (0.64 mmol) of EDC and 0.02 g (0.15 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: BrCc1ccccc1
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc2cc(Cl)ccc2n1Cc1ccccc1
Yield: 42 %

Procedure:
4.97 g (30 mmol) 5-chloro-2-methylindole was treated with 6.84 g (40 mmol) benzyl bromide, 1.97 g (30 mmol) potassium hydroxide (85% powdered in mortar) and 0.25 g (1 mmol) 18-crown-6 as described in Synthesis 1979, p. 618 to give 3.22 g (42%) 5-chloro-2-methyl-1-benzyl-1H-indole, mp: 75-76°, MS (Ei 70 eV) m/Z M+255.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:23]3[N:22]=[C:21]([CH3:20])[O:25][N:24]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)no1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2noc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 408.04 g/mol.
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCC[CH2:21]1.O>CCOCC>[CH3:21][C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=1)=[O:16]
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1.5 h

Procedure:
Over a period of 1.5 hours, methyl lithium (531 ml. of a 2 molar solution, 1.06 M) is added under a nitrogen atmosphere to a rapidly stirring solution of 3-benzyloxybenzoic acid (116 g., 0.532 M) in ether (250 ml.)-tetrahydrofuran (1400 ml.) maintained at 15°-20° C. After stirring an additional 0.75 hour at 10°-15° C., water (600 ml.) is slowly added keeping the reaction temperature below 20° C. The aqueous layer is separated and extracted with ether (3×250 ml.). The organic phases are combined, washed with saturated sodium chloride solution (4×300 ml.), dried over sodium sulfate, and concentrated under vacuum to give the product as an oil.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Temperature: 90 °C

Procedure:
To a solution of 6,6-dimethyl-5,7-dioxaspiro[2.5]-octane-4,8-dione (Aldrich, 51 mg, 0.3 mmol) in DMF (0.5 mL) at room temperature was added 4-fluoroaniline (Aldrich, 33 mg, 0.3 mmol). The reaction mixture was heated at 90° C. for 2 h, cooled to room temperature, and used directly in the next step.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:46][CH3:47])[C:38]2[O:43][CH2:42][O:41][CH2:40][C:39]=2[C:44]=1[F:45])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:45][C:44]1[C:39]2[CH2:40][O:41][CH2:42][O:43][C:38]=2[C:37]([O:46][CH3:47])=[CH:36][C:35]=1[CH:21]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)COCO2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
After adding 21 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 105 mg of {2-(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (74 mg) as a light brown solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1N2CC[N:13](CC2)C1.[N:19]1[CH:27]=[C:26]2[C:22]([N:23]=[CH:24][NH:25]2)=[N:21][CH:20]=1.C(O)(=O)C>CS(C)=O>[CH:5]1[CH:4]=[CH:3][C:2]([CH2:1][O:8][C:27]2[C:26]3[N:25]=[CH:24][NH:23][C:22]=3[N:21]=[C:20]([NH2:13])[N:19]=2)=[CH:7][CH:6]=1
Reactant: C1CN2CCN1CC2
Reactant: OCc1ccccc1
Reactant: c1ncc2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Nc1nc(OCc2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzyl alcohol (215 mg, 1.99 mmol) was added to sodium hydride (0.017 g, 0.71 mmol) in anhydrous DMSO (0.4 ml). After 1 h ‘DABCO-purine’ (0.10 g, 0.36 mmol) was added and the reaction stirred for 48 h at room temperature. Acetic acid (0.06 ml) was added and the solvents removed in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 10% methanol in dichloromethane. The title compound was collected as a white solid (69 mg, 81%). λmax (CH3OH)/nm 285; δH (200 MHz, d6-DMSO) 7.96 (1H, s, C(8)H), 7.40 (5H, m, Ph), 6.44 (2H, s, NH2), 5.61 (2H, s, OCH2).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].[BH4-].[Na+]>C(OCC)(=O)C.CO.CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:31][CH:32]([OH:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nc(C)n(CC(O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-bromo-3,3-dimethylbutan-2-one (0.75 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methanol (10 mL), sodium borohydride (0.092 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 16%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[NH:16])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=1>>[ClH:19].[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][C:15]3[N:16]=[C:24]([C:23]4[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=4)[O:18][N:17]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N=C(CCCC1CCN(C2CCCC2)CC1)NO
Product: Cl
Product: Clc1ccc(-c2nc(CCCC3CCN(C4CCCC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 3, starting from 4-(1-cyclopentylpiperidin-4-yl)-N-hydroxybutyramidine and 4-chlorobenzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH2:8].[CH3:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([C:24](Cl)=[O:25])[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=1)(=[O:13])=[O:12]>>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:24]([C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][CH3:9])[CH:15]=1)=[O:25]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: CN1CCCC1CN
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NCC3CCCN3C)c1)OCCO2
Yield: 77 %

Procedure:
In a similar manner to that of the above example, 71 g of levorotatory 1-methyl-2-aminomethyl-pyrrolidine was reacted with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 175 g of levorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 187°-187.5° C.; yield: 77%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[NH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[N:8]=1
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: NCCCN
Product: NCCCNc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (0.3 g.) and 1,3-diaminopropane (1 ml.) was heated to 90° for 3 hours. The mixture was evaporated to dryness and the residue taken up in 2N aqueous acetic acid. The solution was washed with ether, basified with 17N NaOH and the mixture extracted five times with ether. The combined ether extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylamino)pyrimidine (0.27 g.) which was characterised as the tris hydrogen maleate, m.p. 159° after recrystallisation from acetone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]2)=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(N)ccc1O
Reactant: C=C(CC(=O)O)C(=O)O
Product: Cc1cc(N2CC(C(=O)O)CC2=O)ccc1O

Procedure:
In an analogous manner to that described in Example 2a), 4-amino-o-cresol is reacted with itaconic acid at 140° C. during 10 min to yield the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid as a light brown solid; MS: m/e=234 (M−H)+which directly used in the next step.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl.O>C(OCCCC)CCC.ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCCOCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: ClCCl
Solvent: O
Product: c1ccc2c(c1)Sc1ccccc1N2CCOCCOC1CCCCO1
Temperature: 135 °C
Yield: 55.3 %

Procedure:
Phenothiazine (3.8 g, 19 mmol) was added to a suspension of sodium hydride (0.92 g, 23 mmol, 60% oil dispersion) in dry dibutylether (25 ml) under an atmosphere of nitrogen. The mixture was heated at 135° C. for 1 h and then cooled to approximately 100° C. 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (8 g, 38 mmol) was added in one portion and the mixture was heated overnight at 110° C. The reaction mixture was poured into water (250 ml) and extracted with dichloromethane (3×50 ml) and diethyl ether (50 ml). The combined organic extracts were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo leaving an oil, which was submitted to column chromatography using dichloromethane as eluent. Collecting the proper fractions afforded 3.9 g of crude 10-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-10H-phenothiazine. TLC: rf=0.72 (SiO2 ; dichloromethane/methanol=19:1).