Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:17]([O:21][C:22](=[O:23])[NH:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 12 h
Yield: 36.6 %

Procedure:
To a solution of 4-aminomethyl-1-benzyl-piperidin-4-ol (264 mmol, 58 g) in DCM (200 mL) and saturated NaHCO3 (200 mL) was added di-tert-butylcarbonate (396 mmol, 86.4 g). The reaction mixture was stirred for 12 hours. The layers were separated and the organic layer was washed with brine (50 mL) and evaporated. The product was purified on 1 L of SiO2 using a mixtures of ethyl acetate and DCM to give (1-benzyl-4-hydroxy-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (31 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH:33]=[C:32](B(O)O)[CH:31]=[N:30]2)[CH:26]=[CH:27][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH:33]=[C:32]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]5[CH:21]=[CH:20][N:19]=[CH:18][N:17]=5)(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH:31]=[N:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: OB(O)c1cnn(-c2cccc(Cl)c2)c1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3cnn(-c4cccc(Cl)c4)c3)nccc2c1
Temperature: 100 °C

Procedure:
A vial was charged with 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate GG) (53 mg, 0.17 mmol), (1-(3-chlorophenyl)-1H-pyrazol-4-yl)boronic acid (44 mg, 0.200 mmol), Pd(AmPhos)2Cl2 (12 mg, 0.017 mmol), potassium phosphate (106 mg, 0.500 mmol), dioxane (1.042 μl), and water (0.347 μl). The vial was sealed and heated in an oil bath overnight at 100° C. The crude reaction mixture was purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% ammonium hydroxide modifier to yield 1-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide. m/z (ESI) 463.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH2:28])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:26]2[CH2:27][C:22]([CH3:31])([CH3:21])[NH:23][C:24]([CH3:30])([CH3:29])[CH2:25]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC1(C)CC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC(C)(C)N1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 2,2,6,6-tetramethylpiperidin-4-amine (81.0 mg, 0.51 mmol). The title compound was obtained as a solid (35.0 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.81 (1H, m), 8.47 (1H, s), 7.81 (1H, m), 4.18 (1H, m), 1.96 (2H, m), 1.51 (2H, m), 1.39 (12H, m). MS m/z: 487.25, 489.27 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:18][C:19]1[O:20][C:21]([CH3:35])([CH3:34])[CH:22]([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[S:23](=[O:26])(=[O:25])[N:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][CH2:10][C@H:11]([NH:18][C:19]1[O:20][C:21]([CH3:35])([CH3:34])[CH:22]([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[S:23](=[O:25])(=[O:26])[N:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(O)c1
Agent: Cl
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To detach the protecting group, 150 mg of 3-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-5-yl}phenol were dissolved in 3 ml of methanol and, after addition of 0.3 ml of concentrated hydrochloric acid, stirred at room temperature for 16 hours. The reaction solution was concentrated by rotary evaporation and coevaporated twice more with 10 ml of toluene, and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution. Subsequently, this aqueous residue was extracted with dichloromethane, and the combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (64.2 mg) with a molecular weight of 404.5 g/mol (C20H24N2O5S); MS (ESI): m/e=405 (M+H+).
Reaction SMILES: [K].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.[Cu](Cl)Cl>[C:4]1([CH3:9])[CH:5]=[CH:6][C:7]([O:8][C:11]2[CH:16]=[CH:15][C:14]([O:8][C:7]3[CH:2]=[CH:3][C:4]([CH3:9])=[CH:5][CH:6]=3)=[CH:13][CH:12]=2)=[CH:2][CH:3]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Cc1ccc(O)cc1
Agent: Cl[Cu]Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: Cc1ccc(Oc2ccc(Oc3ccc(C)cc3)cc2)cc1

Procedure:
A three-necked flask equipped with a distilling receiver and a magnetic stirrer was charged with 32.4 g (0.30 moles) of p-cresol, and 16.8 g (0.30 moles) of potassium hydroxide was added into the flask while stirring the resultant reaction mixture at a temperature of 150° C. to provide a potassium salt of p-cresol. To the resultant p-cresol potassium salt melt were gradually mixed 100 ml of toluene, and the resultant reaction mixture was subjected to azeotropic distillation to remove water from the reaction mixture. After 50 ml of toluene were distilled away, the remaining reaction mixture was mixed with a solution of 23.6 g (0.10 moles) of p-dibromobenzene dissolved in 10 ml of hot toluene, and then with a catalyst consisting of 2.0 g of anhydrous copper chloride (II), and the resultant reaction mixture was refluxed for 8 hours while stirring.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 87.5 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-methoxyphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example W-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.17 g of the title compound as a solid, mp 186-188° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: COc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
2-(bromomethyl)-1-chloro-3-methoxybenzene (470 mg, 2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (270 mg, 1.9 mmol), and potassium carbonate (263 mg, 1.9 mmol) were mixed in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. To the mixture, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (400 mg, 70% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.82 (s, 3H), 4.50 (s, 2H), 6.00 (s, 1H), 7.05 (m, 2H), 7.31 (t, 1H); M+ 297.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH3:25][NH:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:26]([CH3:25])[CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CNCCC(N)=O
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1N(C)CCC(N)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-methyl-N-(β-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=1.C([O-])(O)=O.[Na+]>C1COCC1.CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:20][C:21]1[N:22]=[N:23][C:24]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH2:36][CH2:35][CH2:34][N:30]3[CH2:31][CH2:32][CH2:33][C@H:29]3[CH3:28])=[CH:39][CH:40]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(Cl)nn2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Pd(OAc)2 trimer (2.02 g, 9.0 mmol) and Ph3P (9.36 g, 35.6 mmol) were suspended in anhydrous THF (300 mL) and stirred vigorously under a nitrogen atmosphere for 10 min. 3,6-dichloropyridazine (26.82 g, 180 mmol) was added as a solid and stirring was continued for 10 min. (R)-2-Methyl-1-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-pyrrolidine (11.76 g, 34 mmol) was dissolved in a mixture of THF (200 mL) and EtOH (100 mL) and added dropwise to the reaction mixture. Saturated NaHCO3 solution (360 mL) was introduced. The reaction mixture was heated at 80° C. for 15 h, cooled and was evaporated to a residue, which was taken up in CH2Cl2 (300 mL) and washed with water and saturated NaHCO3 solution. The CH2Cl2phase was dried (Na2SO4) and evaporated. The product was obtained by ISCO chromatography on silica gel, eluting with EtOAc initially, then with a mixture of EtOAc/CH3OH (9:1) to provide the title compound (10.20 g, 90%) as a cream solid, m.p. 107-108.5° C.; 1H NMR (CDCl3) 1.10 (d, 3H, —CH3), 2.99 (m, 2H, —CH2—), 3.18 (m, 2H, —CH2—), 4.10 (m, 2H, —CH2—), 7.04 (d, 2H, Ar—H), 7.50 (d, 1H, C—H), 7.78 (d, 1H, C—H), 7.99 (d, 2H, Ar—H) (representative signals only); HPLC retention time 6.893 min. (elution solvents CH3CN w/0.1% TFA and H2O w/0.1% TFA; column: Agilent Zorbax RX-C8 4.6 mm×150 mm w/5 μm particle size; method: 10-100% CH3CN over 20 min., 100% CH3CN for an additional 4.5 minutes; flow rate: 1.6 mL/min; System: Agilent 1100 HPLC).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[NH2:8][CH2:9][C@H:10]([CH3:38])[O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:25]([Cl:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2>>[Cl:37][C:25]1[CH:24]=[C:23]([NH:22][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[CH:21][C:12]=3[O:11][C@@H:10]([CH3:38])[CH2:9][NH:8][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[N:17]=[CH:16][N:15]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CN(C)CC(=O)O
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CNC(=O)CN(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 49 %

Procedure:
The procedure described in Example 1 was repeated using N,N-dimethylglycine and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 49% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.07 (s, 6H), 2.80 (s, 2H), 3.41 (m, 1H), 3.73 (m, 1H), 4.93 (m, 1H), 5.29 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 7.35 (t, 1H), 7.59 (m, 2H), 7.70 (t, 1H), 7.86 (td, 1H), 8.12 (m, 2H), 8.47 (s, 1H), 8.58 (d, 1H), 9.96 (s, 1H); Mass Spectrum MH+ 521.
Reaction SMILES: S(O[CH2:6][CH:7]1[O:11][CH2:10][CH2:9][CH2:8]1)(=O)(=O)C.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[O:21][N:20]=2)[C:16]([O:30][CH3:31])=[CH:15][C:14]=1[NH2:32].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:6][CH:7]4[CH2:8][CH2:9][CH2:10][O:11]4)[CH2:28][CH2:29]3)[O:21][N:20]=2)[C:16]([O:30][CH3:31])=[CH:15][C:14]=1[NH2:32]
Reactant: COc1cc(N)c(Cl)cc1-c1noc(C2CCNCC2)n1
Reactant: CS(=O)(=O)OCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(N)c(Cl)cc1-c1noc(C2CCN(CC3CCCO3)CC2)n1
Yield: 39 %

Procedure:
A mixture of tetrahydrofurfuryl mesylate (2.34 g), intermediate 12 (2.7 g) and sodium carbonate (2.8 g) in 4-methyl-2-pentanone (180 ml) was stirred and refluxed for 24 hours. More tetrahydrofurfuryl mesylate (1 g) was added and the reaction mixture was stirred and refluxed for 24 hours. The reaction mixture was cooled, washed with water, dried over MgSO4, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding of 1.34 g (39%) 2-chloro-5-methoxy-4-[5-[1 -[(tetrahydro-2-furanyl)methyl]-4-piperidinyl]- 1,2,4-oxadiazol-3-yl]-benzenamine (compound 7; mp. 148.5° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH:30]=3)=[O:32])[N:5]=2)=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])#[N:14]
Reactant: O=C(O)c1cc(-c2ccccn2)n[nH]1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4ccccn4)n[nH]3)n2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (300 mg) and 3-(pyridine-2-yl)-1H-pyrazole-5-carboxylic acid (161 mg) using the method of Example 34(d). Yield 166 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.75 (q, 2H), 4.43 (t, 2H), 7.09 (d, 1H), 7.31 (br. s, 1H), 7.39 (m, HA), 7.88-7.96 (m, 3H), 8.20 (d, 1H), 8.37 (dd, 1H), 8.47-8.57 (m, 1H), 8.64 (m, 1H), 8.71 (d, 1H), 13.90 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([NH2:14])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reaction time: 2 h

Procedure:
A solution of (cis-4-azido-cyclohexyl)-carbamic acid tert-butyl ester (6.3 g, 26 mmol) in MeOH (100 mL) was charged with 5% Pd/C, Degussa style (0.63 g). The sealed flask was evacuated and back-filled with hydrogen; this was repeated three times. The reaction was stirred under 1 atm of H2 for 2 h before being filtered and concentrated in vacuo. The residue was partitioned between Et2O and 1 N HCl. The aqueous phase was basified and extracted with EtOAc (2×). The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford (cis-4-amino-cyclohexyl)-carbamic acid tert-butyl ester (3.6 g, 64% yield). MS found: (M+H)+=215.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([S:6][CH3:7])=[CH2:5].C(OC(=C)C(O)=O)C.[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:4]1([S:6][CH3:7])[CH2:5][CH2:25][N:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:30]1)=[O:8]
Reactant: C=C(SC)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: C=C(OCC)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(SC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-ethoxyacrylate 2-Methylsulfanyl-acrylic acid methyl ester 6BP (136 g, 1.03 mol) and benzyl-methoxymethyl-trimethylsilanylmethyl-amine 7BP (290 g, 1.22 mol) in dichloromethane (2.7 L ml) was added at 0° C. a solution of trifluoroacetic acid (26 mL, 0.3 mol). The resulting solution was warmed to room temperature and stirred for one overnight. The crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate in hexane (1:4) to give 1-benzyl-3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 8BP (131 g, 47%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[C:12]([NH:19][CH3:20])=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1.C(N(CC)CC)C.ClC([O:31][C:32](Cl)(Cl)Cl)=O>O1CCOCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][C:11]2[C:12](=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)[N:19]([CH3:20])[C:32]1=[O:31]
Reactant: CNc1nc(SC)ncc1CNc1c(C)cccc1C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(C)cccc1C)C2
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A mixture of 195 mg (0.68 mmol) 5-(2,6-dimethylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.19 ml (1.4 mmol) of triethylamine in 10 ml of dioxan was added dropwise to an ice-cooled solution of 0.085 ml (0.7 mmol) of trichloromethyl chloroformate in 10 ml of dioxan. The mixture was then left to warm to room temperature. After a further 10 minutes the mixture was evaporated. To the residue were added 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 15 ml of pyridine and heated at reflux for 1 hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of dichloromethane and 20 ml of 2M hydrochloric acid. The organic phase was washed with 20 ml of water, dried over magnesium sulfate and evaporated to give 100 mg (47%) of 3-(2,6-dimethylphenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid. [Mass spectrum (ESI) MH+ =315].
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:4]([C:8]#[N:9])=[CH:5][N:6]([CH3:7])[C:2]=2[Cl:1])=[CH:11][CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cn1cc(C#N)c(-c2ccc(CO)cc2)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cc(C#N)c(-c2ccc(CBr)cc2)c1Cl
Yield: 39 %

Procedure:
To a stirred solution of 5-chloro-4-(4-hydroxymethylphenyl)-1-methylpyrrole-3-carbonitrile (450 mg) in methylene chloride (20 ml) was added triphenylphosphine (1.44 g) and carbon tetrabromide (1.21 g) successively at 0° C. and the resulting yellow solution was stirred at the same temperature for a while. The mixture was washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and filtered. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography eluted with a mixture of ethyl acetate and n-hexane 1:4 (V/V) then with 1:3 (V/V) to give 4-(4-bromomethylphenyl)-5-chloro-1-methylpyrrole-3-carbonitrile (220 mg) as a white solid.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:46]([O:49]CC)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([OH:49])(=[O:48])/[CH:47]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCC/C=C/C=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To the trans-2-tetradecenal (2.3 g) dissolved in methylene chloride (80 ml ) was added (carbomethoxymethylene) triphenylphosphorane (4.4 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). Potassium hydroxide (2.8 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-hexadecadienoic acid (2.0 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml), and para-nitrophenol (1.1 g) and N,N'-dicyclohexylcarbodiimide (1.6 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-hexadecadienoic acid (0.8 g). To the active ester (340 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK283 in the yield of 270 mg.