Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17]CC)=O)=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH3:21][S:20][C:11]1[N:10]=[C:9]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:29][C:15](=[O:17])[C:14]2=[CH:13][N:12]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(=O)[nH]n(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
60 mL of triethylamine was added to tetrahydrofuran (200 mL) solution of 25 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 12.7 mL of phenylhydrazine, and stirred at room temperature for 18 hours. The solvent was concentrated under reduced pressure, water was added to the residue, then washed with ether, and made acidic with aqueous 5 N hydrochloric acid solution added thereto. The precipitated solid was taken out through filtration, and washed with water and 2-propanol to obtain 10.8 g of the entitled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C@@H:5]([NH2:7])[CH3:6].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23](Cl)(=[O:25])=[O:24])([O-:13])=[O:12].C(N(CC)C(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:5]([NH:7][S:23]([C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])(=[O:24])=[O:25])[CH3:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: C[C@H](N)c1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 94.4 %

Procedure:
To a stirred ice-cooled solution of (S)-(−)-3-bromo-α-methylbenzylamine (832 mg, 4.16 mmol, from Chiragene) in 15.6 mL of THF was added 1.33 g (4.99 mmol, 1.20 eq.) of 2,4-dinitrobenzenesulfonyl chloride, followed by 1.08 mL (6.20 mmol, 1.49 eq.) of N,N-diisopropylethylamine. The ice bath was removed, and the mixture was stirred at room temperature for 19 h and then concentrated. The residue was taken up in EtOAc, washed with 2×H2O, dried over Na2SO4, filtered, and concentrated. The residue was sonicated in ca. 5 mL of EtOAc until a precipitate was formed. The mixture was diluted to ca. 25 mL with hexanes. Filtration afforded product as a tan solid (1.69 g, 94.4% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(O)Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 18 %

Procedure:
A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (285 mg, 1.0 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid. (315 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) in 2M sodium carbonate aqueous solution (3 mL, 8 mmol) and 20 mL of DME was stirred at 80° C. for 2 hr. Then the reaction mixture was diluted with 50 mL of ethyl acetate and extracted with 1N NaOH (50 mL, three times)). The combined aqueous layers were neutralized to pH=6. Then the aqueous solution was extracted with ethyl acetate (50 mL, three times). The combined organic layers were washed with saturated sodium carbonate and brine. Then the organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid (68 mg, 18% yield). HPLC: Rt=2.04 min; MS 386 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:9][CH3:10].C(N(CC)CC)C.[H][H]>O1CCCC1.[C].[Pd]>[N:4]1[CH:5]=[CH:6][C:7]([CH:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH3:10])=[CH:2][N:3]=1
Reactant: CCC(c1cc(Cl)nnc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(c1ccnnc1)N1C(=O)c2ccccc2C1=O
Yield: 28 %

Procedure:
2-[1-(3,6-Dichloropyridazin-4-yl)propyl]isoindoline-1,3-dione, triethylamine (1.11 mL, 8 mmol) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in tetrahydrofuran in a hydrogen atmosphere (1 atm) at room temperature for 4 days. The reaction solution was filtered through celite and concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, and the resulting organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to give the desired product (294 mg, 28% yield, two steps).
Reaction SMILES: [I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C=O)C.O>[I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc2[nH]cc(I)c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (0.549 g, 1.906 mmol) in DMF (9.5 mL) at 0° C. was added NaH (60% in mineral oil, 0.191 g, 4.76 mmol). After 30 min at 0° C., p-toluenesulfonyl chloride (0.436 g, 2.287 mmol) was added and the reaction was warmed to RT. After 1 h at RT, the mixture was poured into H2O and the mixture was acidified with 5 M HCl (aq.). The precipitate was collected by filtration, washed with H2O and dried in a vacuum oven overnight to afford 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid. (0.663 g, 1.499 mmol, 79%) as a tan solid. MS (ESI, pos. ion) m/z: 442.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (3H, br s), 7.44 (2H, d, J=8.22 Hz), 7.96-8.01 (2H, m), 8.10 (1H, d, J=8.80 Hz), 8.47 (1H, d, J=8.80 Hz), 8.54 (1H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:11])[CH2:8][CH2:9][OH:10])=[O:6].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:12]=[O:13])[C:5]([N:7]([CH3:11])[CH2:8][CH2:9][OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CN(CCO)C(=O)NCCCl
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(CCO)C(=O)N(CCCl)N=O
Yield: 67 %

Procedure:
0.9 g of 1-(2-chloroethyl)-3-methyl-3-(2-hydroxyethyl)urea is dissolved in 10 ml of acetic acid, and 0.9 g of sodium nitrite is added thereto under stirring. The mixture is stirred at room temperature for one hour. Then, 0.5 g of sodium nitrite is again added to the mixture, and said mixture is further stirred at the same temperature for 4 hours. After the reaction, the mixture is freeze-dried, and the residue obtained is purified by silica gel chromatography (Solvent: chloroform-methanol=10:1). 0.7 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-(2-hydroxyethyl)urea is thereby obtained as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br>CN(C)C=O>[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:8]([CH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH3:13])[OH:9]
Reactant: Cc1ccccc1CBr
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1CN(O)Cc1ccccc1C
Yield: 58.2 %

Procedure:
The procedure of Example 1 is repeated using 21.2 g of sodium carbonate, 3.47 g of hydroxylamine hydrochloride and 18.51 g o-methylbenzyl bromide in 75 ml of dimethylformamide. Recrystallization from ethanol affords 7.01 g of the title hydroxylamine as a white solid, mp 90°-93° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=2)[C@H:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][C@H:10]1[C@@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COc1cc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C)c2occc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([C@H]2CCNC[C@H]2C)c2occc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 0.30 gm cis-1-(tert-butoxycarbonyl)-3-methyl-4-(5-methoxybenzofur-7-yl)piperidine in 10 mL 4N hydrochloric acid in dioxane is stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and the white solid residue is dried under reduced pressure at 60° C. for about 16 hours to provide 0.16 gm (96%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.ClCCCl.N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:36](=[O:37])[O:38][C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a suspension of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (196.8 mg, 0.6201 mmol) in 1,2-dichloroethane (6.0 mL, 76 mmol) was added pyridine (0.15 mL, 1.8 mmol) and p-nitrophenyl chloroformate (0.1406 g, 0.6975 mmol). The reaction mixture was stirred at room temperature for 2 hours and then pyridine (0.15 mL, 1.8 mmol) and p-nitrophenyl chloroformate (131.9 mg, 0.6544 mmol) were added. After an additional hour at room temperature, the reaction mixture was evaporated in vacuo and purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-100% ethyl acetate in heptanes) to yield 114.8 mg (38%) of 4-nitrophenyl 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenylcarbamate. LCMS (ESI): M+H=483.2; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.47 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.90 (d, J=8.9 Hz, 2H), 6.54 (d, J=5.8 Hz, 2H), 2.14-2.02 (m, 4H), 0.85 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].O>C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[S:18]([C:14]1[CH:13]=[C:12]([S:9]([NH:8][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: CNC
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1cccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylamine gas was allowed to bubble for 3 minutes into a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. Water was added and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to a solid which was triturated with hexane/isopropryl ether to give 1.59 grams of the titled compound, m.p. 100-102° C.
Reaction SMILES: [Br:1][C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19]Br)=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C-:21]#[N:22].[Na+].O>CN(C)C=O>[Br:1][C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:21]#[N:22])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [C-]#N
Reactant: O=c1cc(C2(Br)CCCCC2)oc2c(CBr)cccc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Temperature: 10 °C
Yield: 42.1 %

Procedure:
2-(1-Bromocyclohexyl)-8-bromomethyl-4-oxo-4H-[1]-benzopyran (11.2 g, 0.028 mole) was dissolved in dimethylformamide (200 ml) and to the solution was added NaCN (1.5 g, 0.0305 mole) with stirring at 10° C. The mixture was stirred for 30 minutes. Water was added to the reaction mixture and crystals precipitated were filtered off. The crude crystals were purified by silica gel chromatography (eluent: chloroform-hexane (10:1)) to obtain the title compound (4.08 g), yield 44.7 %. The product was recrystallized from ethyl acetate to obtain prisms, m.p. 144°-145° C.
Reaction SMILES: [CH:1]([CH:3]([CH:14]([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[N+](C)([O-])=O>[O:2]1[CH:1]2[CH2:11][CH:10]([CH3:12])[C:9]31[C:5]([CH2:4][CH:3]2[CH:14]([CH3:16])[CH3:15])=[C:6]([CH3:13])[CH2:7][CH2:8]3
Reactant: C=C(C)C1CCC(C)=C1CC(C=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CC1=C2CC(C(C)C)C3CC(C)C2(CC1)O3
Yield: 78.8 %

Procedure:
To a solution, cooled to =40°, of 3.3 g of 2-(2-formyl-3-methylbutyl)-3-isopropenyl-1-methyl-1-cyclopentene in 225 ml of nitromethane were added 45 ml of a 0.5-M solution of tin tetrachloride in nitromethane. The reaction mixture became intensely yellow in colour and an initially resulting precipitate dissolved again. The mixture was treated immediately with excess 2-N sodium carbonate solution and extracted with ether. After washing, the ethereal phase was dried in a conventional manner and the solvent was removed. Distillation under a high vacuum yielded 2.6 g of crude 3a,6-epoxy-7-isopropyl-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene in the form of a colourless oil which could be separated by chromatography on 40 times the amount of Florisil (magnesium silicate gel) with hexane/ether (19:1) into two pairs of epimers (A and B). Epimer A: b.p.0.01 ca 75°; IR(film):νmax =1465/40, 1380, 1345, 1245, 1162, 1125, 1108, 1080, 1050, 995, 965, 945, 910, 880 cm-1. The odour is camphorous, woody. Epimer B: b.p.0.01 ca 80° IR(film):νmax =1465/35, 1380, 1340, 1295, 1245, 1200/1195, 1170, 1145, 1110, 1060, 1030, 1000, 990, 950, 925, 910, 878 cm-1. The odour is camphorous, dull.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH:12]([NH:34][S:35]([C:38]2[C:39]3[CH:40]=[CH:41][N:42]=[CH:43][C:44]=3[CH:45]=[CH:46][CH:47]=2)(=[O:37])=[O:36])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]3[C:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:30]=4[CH:31]=[CH:32][CH:33]=3)(=[O:23])=[O:22])=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)(=O)C.[CH3:48]I>>[OH:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([N:34]([CH3:48])[S:35]([C:38]2[C:39]3[CH:40]=[CH:41][N:42]=[CH:43][C:44]=3[CH:45]=[CH:46][CH:47]=2)(=[O:37])=[O:36])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]3[C:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:30]=4[CH:31]=[CH:32][CH:33]=3)(=[O:22])=[O:23])=[CH:16][CH:15]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)OC1CCN(CC(Cc2ccc(OS(=O)(=O)c3cccc4cnccc34)cc2)NS(=O)(=O)c2cccc3cnccc23)CC1
Reactant: CI
Product: CN(C(Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)CN1CCC(O)CC1)S(=O)(=O)c1cccc2cnccc12

Procedure:
The amorphous compound obtained in Example 103 was treated with methyl iodide according to the procedure in Example 89 and the intermediate product was subjected to alkaline hydrolysis according to the procedure in Example 104, to obtain the same product as in Example 99.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:17]1([N:23]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NNc1ccccc1
Solvent: CCO
Product: C1=C(c2ccccc2)NN(c2ccccc2)C1c1ccccc1

Procedure:
20.8 g benzylideneacetophenone was condensed with 10.8 g phenylhydrazine in 400 ml boiling ethanol over 5 hours, and then allowed to cool. During the cooling process the desired reaction product separates. The sediment was filtered, washed with ethanol and dried.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C([Li])CCC.[Cl:14][SiH2:15]Cl>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[SiH2:15][Cl:14]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: Cl[SiH2]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CCCC(C)N1[SiH2]Cl
Temperature: 25 °C
Yield: 26.7 %

Procedure:
To a solution of 7.55 g (66.68 mmol) cis-2,6-dimethylpiperidine in 50 mL of THF at −78° C. was drop-wise added 28.00 mL (70.02 mmol) of a 2.5M solution of n-butyllithium in hexanes. A precipitate evolved and the reaction mixture was warmed to room temperature while stirring. After one hour this mixture was added drop-wise to a solution of 6.74 g (66.68 mmol) dichlorosilane in 30 mL xylenes and 70 mL hexanes at −40° C. and a light gray precipitate formed. The reaction mixture was stirred for 16 hours after which it was decanted from the evolved solid and subjected to distillation at ambient pressure to remove volatiles. 3.16 g of desired product was isolated with a yield of 27%. The product was confirmed by GC/MS analysis as 2,6-Dimethylpiperidinochlorosilane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A solution of ethyl 3-[4-benzyloxyphenyl)-2-hydroxypropanoate (5.0 g, 16.6 mmol) (prepared in a similar manner as described in Ref: WO95/18125) in dry dimethyl formamide (5 mL) was added to a suspension of sodium hydride (0.1 g, 41.6 mmol) (60% dispersion in oil) in dry dimethyl formamide (3 mL) at 0° C. and stirring was continued for further 1 h. To the above reaction mixture n-butyl bromide (3.4 g, 24.0 mmol) was added at 0° C. and stirring was continued for 10 h at ca. 25° C. Water (30 mL) was added and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with water (50 mL), brine (25 mL), dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and and pet. ether (1:9) as an eluent to afford the title compound (0.7 g, 20%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]#[C:10][Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[N:15]=[C:16]1[S:20][CH2:19][C:18]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[N:17]1[CH2:25][CH:26]([CH3:28])[CH3:27].[OH-].[Na+]>CO.C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]#[CH:10])[CH:5]=[CH:4][C:3]=1[N:15]=[C:16]1[S:20][CH2:19][C:18]2([CH2:21][CH2:22][CH2:23][CH2:24]2)[N:17]1[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: Cc1c(C#C[Si](C)(C)C)ccc(N=C2SCC3(CCCC3)N2CC(C)C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(N=C2SCC3(CCCC3)N2CC(C)C)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 2-(2,3-dimethyl-4-(2-trimethylsilyl-1-ethynyl)phenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane (0.005 g, 0.0125 mmol) and NaOH (0.006 g, 0.15 mmol) in MeOH (2 mL) was stirred overnight at room temp. The reaction mixture was diluted with CH2Cl2 (20 mL), filtered, and the filtrate was concentrated under reduced pressure. Thre residue was purified by preparative TLC (2% EtOAc/Hex) to give 2-(2,3-dimethyl-4-ethynylphenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane (0.003.2 g, 78%): TLC (20% EtOAc/hex) Rf0.70.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:44])[CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])=[O:21])=[CH:4][CH:3]=1.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(O)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:44])[CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])=[O:21])=[CH:4][CH:3]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Reactant: C1CNCCN1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(-c2cccc(CN3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.3 %

Procedure:
N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (37.0 mg, 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing piperazine (0.18 mmol) and acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirring at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and purification was completed using reversed phase HPLC (acidic conditions) via a Gilson. The product after HPLC purification was dissolved in 3 mL of MeOH and was passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 12.1 mg of the title compound (29.3%). LC-MS m/z 687 (M+H)+, 1.88 min (ret time).