Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[CH:3]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([C:13]1[CH:48]=[CH:47][C:16]([CH2:17][O:18][C:19]2[N:27]=[C:26]3[C:22]([N:23]=[CH:24][N:25]3[C@@H:28]3[O:40][C@H:39]([CH2:41][O:42]C(=O)C)[C@@H:34]([O:35]C(=O)C)[C@H:29]3[O:30]C(=O)C)=[C:21](Cl)[N:20]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:48]=[CH:47][C:16]([CH2:17][O:18][C:19]2[N:20]=[C:21]([NH:8][CH:3]3[CH2:7][CH2:6][CH2:5][CH2:4]3)[C:22]3[N:23]=[CH:24][N:25]([C:26]=3[N:27]=2)[C@@H:28]2[O:40][C@H:39]([CH2:41][OH:42])[C@@H:34]([OH:35])[C@H:29]2[OH:30])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: NC1CCCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCc4ccc(C(C)(C)C)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [H][H]
Product: CC(C)(C)c1ccc(COc2nc(NC3CCCC3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)cc1
Yield: 50 %

Procedure:
A compound having a structure of the above formula was prepared where the substituent R1 is cyclopentyl, R2 is hydrogen, and R3 is —CH2(4-(C(CH3)3)C6H4 (4-tert-butylbenzoyl). The compound (C25H35N5O5) was prepared by reaction of cyclopentylamine with 2-[4-(tert-butyl)benzyloxy]-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 8) as described in Example 2, Step E. The final product was isolated in 50% yield as a solid with a melting point of 118-120° C. 1H-NMR (CDCl3): 1.3 (s, 9H); 1.6 (m, 6H); 2.0 (m, 2H); 3.46 (m, 3H); 3.75 (m, 1H); 3.89 (m, 1H); 4.28 (s, 1H); 4.42 (m, 2H); 5.1 (m, 1H); 5.29 (s, 2H); 5.7 (d, 1H); 5.7 (m, 1H); 7.35 (s, 4H); 7.57 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13].[C:28](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 94 %

Procedure:
1,1-dimethylethyl 4-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 22) (2.59 g, 5.47 mmol), potassium carbonate (1.513 g, 10.94 mmol) in 1,4-dioxane (80 ml) were stirred for 5 min then trimethylboroxin (1.523 ml, 10.94 mmol) and Pd(PPh3)4 (0.632 g, 0.547 mmol) were added and the reaction mixture heated at 100° C. for 1.5 h. Further trimethylboroxin (0.5 mL) was added and the mixture heated at 100° C. for 30 min before allowing to cool overnight. The mixture was concentrated under vacuum then EtOAc (150 ml) added, washed with 200 ml of water, dried on a phase separation cartridge and evaporated under vacuum. Crude material (3.1 g) purified via Biotage (40+M silica column) using a gradient EtOAc/i-hex from 10/90 to 30/70. Desired fractions were collected and concentrated under vacuum to give the title compound (2.1 g).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH:14]([O:17][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)([CH3:16])[CH3:15]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of sodium (290 mg, 12.5 mmol) in isopropanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated to yield 540 mg (98%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([OH:14])C.C(O)(=O)C.[Br-:19].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[Br:19][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:14])[NH:8]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: [Br-]
Reactant: CCO
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1Br)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To the suspension of 5-methoxyindole (5.0 g, 34 mmol) in t-BuOH: ethanol: acetic acid (215 mL: 127 mL: 66 mL) was added pyridinium tribromide (32.6 g, 102 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with more acetic acid (165 mL). Zinc dust (11.1 g, 170 mmol) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off, and the solvent was removed under reduced pressure. The residue was diluted with water, extracted with ethyl acetate. The combined extracts were washed with water (5×), sat. NaHCO3 (2×), brine (3×), dried over Na2SO4, concentrated, triturated with ether to give 2.12 g (26%) of 4-bromo-5-methoxy-1,3-dihydro-indol-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([Br:13])=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:13][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([CH3:14])[CH:16]=2)=[N:12][CH:11]=1
Reactant: CCOC(=O)c1cc(Br)ncc1Br
Reactant: Cc1cncc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2cncc(C)c2)ncc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution ethyl 2,5-dibromoisonicotinate (1-2, 1.5 g, 4.86 mmol) in degassed dimethylformamide (24 mL) at 25° C. was added (5-methylpyridin-3-yl)boronic acid (0.665 g, 4.86 mmol), PdCl2dppf (0.355 g, 0.486 mmol), cesium carbonate (4.75 g, 14.6 mmol) and water (0.262 mL, 14.57 mmol). The reaction flask was purged with nitrogen, sealed and stirred at 50° C. overnight. The crude reaction mixture was partitioned between water and EtOAc, separating layers and washing the organic layer with saturated sodium bicarbonate solution and brine. The solvent was removed by rotary evaporation and the crude product was purified by normal phase column chromatography (0 to 50% EtOAc in hexanes) to afford the product (1-3) as a white solid. ESI+MS[M]+C14H13BrN2O2=321.0.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](Cl)=[O:19].O.[NH3:24]>O1CCCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([NH2:24])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Cl)C(C)(C)CCC1
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(N)=O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
10 g (0.031 mole) of retinoic acid chloride as prepared according to the procedure described in Example 2 was added to the mixture of 300 ml of ammonia water (35%) and 100 ml of tetrahydrofuran and then stirred at room temperature for 20 hours. The reaction solution was distilled under reduced pressure and then concentrated. The residue was extracted with methylene chloride. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, filtered and then distilled under reduced pressure to obtain 9.43 g (Yield 99%) of the desired retinamide.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.ClCCl.Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])(=[O:24])=[O:23]>N1C=CC=CC=1>[CH2:9]([O:8][C:6]([C:3]1([NH:2][S:22]([C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])=[O:29])(=[O:23])=[O:24])[CH2:5][CH2:4]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1(N)CC1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of 774 mg of ethyl 1-aminocyclopropane-1-carboxylate hydrochloride, 1.4 mL of triethylamine, and 15 mL of dichloromethane was stirred at room temperature for 30 minutes, and 15 mL of pyridine and 1.50 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate were added thereto in this order, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1.80 g of 2-(trimethylsilyl)ethyl 3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoate as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=[C:13]=[S:14].Cl.[NH2:16][NH:17][C:18](N)=[NH:19].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:19][C:18]1[N:12]([C:3]2[C:4]([CH3:11])=[CH:5][C:6]([CH:8]3[CH2:9][CH2:10]3)=[CH:7][C:2]=2[Cl:1])[C:13]([SH:14])=[N:16][N:17]=1
Reactant: N=C(N)NN
Reactant: Cc1cc(C2CC2)cc(Cl)c1N=C=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2CC2)cc(Cl)c1-n1c(N)nnc1S
Temperature: 50 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
Compound 3 (935 mg, 4.2 mmol) was dissolved in 5 mL of dimethylformamide, aminoguanidine hydrochloride salt (695 mg, 6.3 mmol) and diisopropyl ethylamine (1.1 mL, 6.3 mmol) were added and the mixture stirred at 50° C. for 18 hours. The mixture was then concentrated and to the resulting residue was added 2M aqueous sodium hydroxide solution (20 mL). The mixture was stirred at 50° C. for 18 hours and then cooled to room temperature. The resulting mixture was then neutralized with aqueous 1N HCl and the precipitate (product) collected to give 5-amino-4-(2-chloro-4-cyclopropyl-6-methylphenyl)-4H-1,2,4-triazole-3-thiol (4). (780 mg, 66% yield)
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(C[CH2:56][N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)CC1>>[ClH:1].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119, see example 80) and amine 21 analogously to the method described in example 1.
Reaction SMILES: NC1N(CCN2CCOCC2)C2C=CC=CC=2N=1.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25][Br:26])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH3:25])=[CH:22][CH:21]=1.[Br-:26]
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: Nc1nc2ccccc2n1CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(O)cc1
Product: [Br-]

Procedure:
A mixture of 2-amino-1-(2-morpholinoethyl)benzimidazole (10 mmol, 2.46 g) and 4-hydroxyphenacyl bromide (10 mmol, 2.15 g) (obtained by bromination of parahydroxyacetophenone with cuptic bromide in a mixture of chloroform and ethyl acetate) is heated at reflux for 1 hour in 10 ml of dimethylformamide. After cooling, the mixture is poured into 50 ml of water and rendered alkaline with ammonium hydroxide. The resulting oil is removed and treated with water. The crystallised residue is filtered, dried, and recrystallised from ethanol.
Reaction SMILES: [OH2:1].Cl.O[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[O:11]1[C:15]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@@H:12]1[CH:21]=O>C1COCC1>[O:11]1[C:15]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@@H:12]1[CH:21]=[N:4][OH:1]
Reactant: NO
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To 1000 mL of DI water was added hydroxyl amine hydrochloride (51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodium carbonate (38.1 g, 360 mmol) was added in 3 large portions and the reaction was stirred for 15 minutes. THF (700 mL) was added, followed by (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734 mmol) in 800 mL of THF. The reaction was stirred for 4 hours, then poured into a 4 L separatory funnel. The layers were separated and the aqueous layer was extracted twice with MTBE (about 3000 mL total). The combined organic layers were washed with water (700 mL) and brine (300 mL), dried over MgSO4 and concentrated in vacuo to afford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as a clear viscous oil.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].C=O.N1C=CC(CN[C:15]2[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=CC=1.F[C:35](F)(F)[C:36](O)=O>O1CCCC1>[N:19]1[CH:20]=[CH:21][C:36]([CH2:35][C:15]2[C:33]([NH:2][CH3:1])=[CH:32][CH:31]=[CH:30][C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:16][CH:17]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccncc1
Reactant: O=C(O)C(F)(F)F
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cccc(C(=O)Nc2cccc(C(F)(F)F)c2)c1Cc1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium cyanoborohydride (0.55 g, 14.1 mmol) is added to a stirred mixture of paraformaldehyde (0.82 g, 27.3 mmol) and 2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (Example 14; 1.03 g, 2.78 mmol) in tetrahydrofuran (30 mL) at 20° C. under an argon atmosphere. The resulting mixture is then treated dropwise with trifluoroacetic acid (15 mL) and stirred at room temperature for 20 hours. The mixture diluted with ice-cold aqueous sodium hydroxide (100 mL of 5M) and extracted with dichloromethane (3×100 mL). The organic phase is dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate, to give the title compound as a colourless crystalline solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([N:16]([CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)(=[O:18])=[O:19])[C:10]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1[C@H](N(CCN2CCOCC2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Temperature: 50 °C
Yield: 79.9 %

Procedure:
To a solution of 1.51 g of N-(1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-(4-chloro-phenoxy)-benzenesulfonamide from Example 1 Step E in 20 mL of methylsulfoxide (DMSO) was added 2.9 g of Cs2CO3(s) and 1.2 g of 4-(2-chloroethyl)-morpholine hydrochloride. The mixture was heated to 50° C. for 1 hour. The reaction was cooled, and then dissolved with ethyl acetate. The organic layer was washed with NH4Cl(aq) and NaCl(aq) solutions. The aqueous layers were re-extracted with ethyl acetate, and the organic layers were combined and dried over Na2SO4(s). Filtration and solvent removal was followed by column chromatography on silica gel using a hexanes-ethyl acetate gradient. Obtained 1.48 g of a pale brown oil (80% yield). MS: 612 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11](=O)[CH:12]=[CH2:13].[N:15]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[N:30]([C:27]2[CH:28]=[CH:29][C:24]([S:21]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:23])=[O:22])=[CH:25][CH:26]=2)[C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: O=Cc1ccccc1F
Reactant: C=CC(C)=O
Reactant: Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Product: Cc1ccc(-c2ccccc2F)n1-c1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
2-Fluorobenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-piperidinylsulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 1.50 (6H), 2.21 (3H), 2.85 (4H), 6.15 (1H), 6.25 (1H), 7.03-7.90 (8H); MS (ESI) m/z 399 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:8]=[C:7]([NH:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:6]=1)[CH2:2][CH:3]=C.O=[O+][O-].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O1CCCC1>[N:34]1([CH2:3][CH2:2][CH2:1][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:19])([F:18])[F:20])[N:8]=[C:7]([NH:21][C:22]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)[CH:6]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: C1COCCN1
Reactant: C=CCCc1cc(Nc2n[nH]c3ncccc23)nc(-c2ccccc2C(F)(F)F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1ccccc1-c1nc(CCCN2CCOCC2)cc(Nc2n[nH]c3ncccc23)n1
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution of [6-but-3-enyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl)-amine (0.10 g, 0.25 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) at −78° C. was bubbled through with ozone for 5 minutes. To this mixture was added morpholine (0.05 mL, 0.56 mmol) and sodium triacetoxyborohydride (0.39 g, 1.85 mmol). The reaction was stirred at room temperature for 24 hours when additional morpholine (0.10 mL, 1.28 mmol) and sodium triacetoxyborohydride (0.39 g, 1.85 mmol) were added then the stirring continued another 2 hours. The reaction was quenched with sodium bicarbonate and evaporated. Purification by flash chromatography (SiO2, eluted with 1:9 methanol:dichloromethane), followed by preparative HPLC provided the title compound as a bright yellow lyophilate (0.068 g, 38% yield). 484.3 (M+H). 1H-NMR (500 MHz, DMSO-d6) δ 13.2 (s, 1H), 10.7 (s, 1H), 9.60 (br s, 1H), 8.52 (m, 1H), 8.47 (d, 1H), 7.86 (d, 1H), 7.77 (m, 1H), 7.70 (m, 2H), 7.14 (m, 1H), 3.97 (br m, 2H), 3.61 (br m, 2H), 3.44 (br m, 2H), 3.18 (br m, 2H), 3.05 (br m, 2H), 2.78 (t, 2H), 2.08 (m, 2H) ppm.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.ClCCl.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnccc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1cnccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
4-Phenylamino-3-nitropyridine (1.40 g, 6.51 mmol) was dissolved in the mixed solvent of 15 ml of ethanol and 10 ml of dichloromethane. After the atmosphere was replaced with nitrogen, 0.10 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane: methanol=2:1 (v/v)] to obtain 1.07 g of a light brown solid (yield: 88.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].[Br:11][CH2:12][C:13](Br)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10])=[O:14]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(Cl)cc1CO
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a mixture of (2-amino-5-chlorophenyl)methanol (4.30 g, 27.3 mmol) in dichloromethane (220 ml) was added 2-bromoacetyl bromide (6.06 g, 2.61 ml, 30.0 mmol) at 0-5° C. Stirring for 5 minutes was followed by dropwise addition of aqueous 2 M sodium carbonate solution (130 ml) in approx. 10 minutes. The cooling bath was removed and stirring was continued for 2 h. The solvent was concentrated in vacuo. The aqueous residue was extracted with three 100 ml-portions of ethyl acetate. The combined organic layers were washed with one 50 ml-portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (7.30 g, 96%) as light grey solid which was used in the next step without purification. MS m/e: 276 ([M+1-1]+).
Reaction SMILES: C[C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.C([N:18](CC)CC)C.FC1C=CC=CC=1[N+]([O-])=O>CN(C)C=O>[CH3:8][CH:5]1[NH:6][CH2:7][CH2:2][N:3]([C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH2:18])[CH2:4]1
Reactant: CCN(CC)CC
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Agent: O=[N+]([O-])c1ccccc1F
Solvent: CN(C)C=O
Product: CC1CN(c2ccccc2N)CCN1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2(R),5(S)-Dimethyl-1-N-benzyl-piperazine (6.0 g, 29 mmol) was dissolved in dimethylformamide (100 mL), and triethylamine (6.4 mL, 44 mmol) and the mixture was placed under nitrogen. To the solution was added 2-fluoro-nitrobenzene (3.5 mL, 31 mmol). The reaction was heated at 100° C. for 72 hours The solution was evaporated in vacuo and redissolved in ethyl acetate (100 mL). The solution was then washed with saturated sodium bicarbonate solution (100 mL) and saturated brine solution (100 mL). The separated organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The crude product was then purified by flash chromatography, eluting with ethyl acetate/methanol/triethylamine 85:10:5. The product (8.2 g) was dissolved in ethanol (250 mL). Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the solution and the solution was hydrogenated in a Parr apparatus at 3 bar for 3 hours. The solution was filtered and evaporated to give the aniline product. Yield (5.2 g, 87%)