Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:33])[CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+].Cl.O>C(O)C>[OH:33][CH:15]([C:13]1[CH:12]=[CH:11][C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([CH3:1])[CH:14]=1)[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32]
Reactant: CCOC(=O)COc1ccc(C(=O)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1ccc(C(O)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
To a suspension of ethyl [2-methyl-4-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}acetyl)phenoxy]acetate (intermediated 15, 0.165 g) in absolute ethanol (5 ml) at 0° C. under nitrogen was added sodium borohydride (0.013 g) after stirring for an hour the reaction was allowed to come to room temperature and stirred for a further two hours. 2M aqueous hydrochloric acid was then added drop-wise and once the effervescence had subsided water was added, the product was extracted twice with ethyl acetate and the combined organic extracts were dried (magnesium sulfate) filtered and evaporated. The product was purified by flash column chromatography using cyclohexane then ethyl acetate:cyclohexane(1:4) as eluents to give title compound as a pale yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[CH:9]=1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:21]O>>[CH:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11]([O:13][CH3:21])=[O:12])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: COc1cc(C)c(CC(=O)O)cc1C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C(C)C)c(OC)cc1C
Reaction time: 2 h

Procedure:
(5-Isopropyl-4-methoxy-2-methylphenyl)acetic acid (CAS No. 81354-65-6, 5.5 g) was dissolved in methanol (50 mL), and thionyl chloride (3.5 mL) was added dropwise under ice-cooling. After dropwise addition of the reagent, the mixture was brought back to room temperature and stirred for two hours. The reaction solution was concentrated under reduced pressure. A saturated sodium bicarbonate solution and tert-butyl methyl ether were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (5.0 g). The property values of the compound are as follows.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][NH:18][C:19]2[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[C:21]3[N:28]([CH2:31][CH3:32])[N:29]=[CH:30][C:20]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][NH:18][C:19]2[C:24]([C:25]([NH:55][CH2:56][C:57]3[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=3)=[O:26])=[CH:23][N:22]=[C:21]3[N:28]([CH2:31][CH3:32])[N:29]=[CH:30][C:20]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)O)cnc21
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)NCc3ccncc3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Using the procedure of method 1A, triethylamine (4.0 ml, 28.0 mmol) was added to a mixture of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.0 g, 5.6 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC.HCl, 1.6 g, 8.4 mmol), and 1-hydroxybenzotriazole (1.1 g, 8.4 mmol) in anhydrous THF (50 ml). The resulting solution was stirred at rt for 10 min. To the resulting reaction solution was then added 4-aminomethylpyridine (0.72 g, 6.7 mmol) and this solution was stirred at rt for 24 h. The resulting reaction solution was concentrated via evaporation under reduced pressure, and the residual solid was resuspended in EtOAc (250 mL). This EtOAc suspension was washed with H2O (200 ml), NaOH (0.1 N, 2×200 ml), potassium phosphate buffer (50 mM, pH 7, 2×200 ml) and H2O (200 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated via evaporation under reduced pressure until a solid began to precipitate. This mixture was allowed to stand at rt, and the precipitated solid was collected and washed thoroughly with Et2O and once with 50% Et2O-EtOAc to afford a white solid (2.2 g, 90%): mp: 209-210.5 C; LRMS (m/z) 450; 13C NMR (CDCl3): δ 171.8, 156.4, 153.7, 153.1, 151.7, 150.8, 150.5, 135.7, 132.0, 130.5, 128.3, 124.5, 124.3, 114.2, 105.6, 104.4, 57.4, 49.8, 43.7, 43.6, 15.9. Anal. Calc'd for C23H23C1N6O2: C, 61.26; H, 5.14; N, 18.64; Cl, 7.86. Found: C, 61.03; H, 5.22; N, 18.66; Cl, 8.02.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:22]=1[C:23]#[N:24].O>CN(C=O)C>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:15][CH2:14][CH:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[O:4][CH3:3])[CH2:13][CH2:12]2)[C:22]=1[C:23]#[N:24]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1ccccc1CC1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1CC1CCC(COc2cccc(F)c2C#N)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (0.043 g; 1.1 mmol) in anhydrous DMF (1.4 mL) is added a solution of [4-(2-methoxybenzyl)cyclohexyl]methanol (0.21 g, 0.9 mmol) in anhydrous DMF (1.4 mL) over 11 minutes. After allowing to room temperature over 2 hours, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (0.14 g; 0.99 mmol) in anhydrous DMF (1.4 mL), and allowed to room temperature over 18 hours. The mixture was poured into a water (40 mL) solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to purify by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain 2-fluoro-6-[4-(2-methoxybenzyl)cyclohexylmethoxy]benzonitrile (0.09 g, 28% yield).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10](=[O:27])[C@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]2[CH2:15][CH2:14]2)=CC=1)([O-])=O.[OH-].[Na+].O>CO>[C:16]([N:12]([CH:13]1[CH2:15][CH2:14]1)[C@H:11]([C:10]([OH:27])=[O:9])[CH2:23][CH:24]([CH3:26])[CH3:25])([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccc([N+](=O)[O-])cc1)N(C(=O)OC(C)(C)C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of Boc-cyclopropyl leucine p-nitrobenzyl ester (8) (300 mg, 7.9 mmol) in MeOH (20 ml) was added 2N NaOH soln. (7 ml) under ice cooling and the mixture was stirred for 3 hr at room temperature, the starting material gradually dissolved and the mixture turned yellow. Water (10 ml) was added and the MeOH was evaporated in vacuo. The aqueous residue was washed with AcOEt, cooled in an ice bath and acidified by the addition of 10% citric acid to pH 3. The resulting white precipitate was extracted with AcOEt (3×20 ml) and the extract was washed with sat. NaCl soln, dried over Na2SO4, and evaporated in vacuo. The resulting of Boc-cyclopropyl-leucine (9) was recrystallized from AcOEt-n-hexane to give 140 mg, (72.5%) as colorless prisms; mp 196°-197° C. (dec.); IR: (KBr) 3230(NH), 1690(C=O), 1645(C=O). NMR (CDCl3 +DMSOd6) δ:5.78 (s, 1H, NH), 1.2-1.8 (m,4H,CH2, CHx2),1.4 (s,9H,Boc), 0.9-1.1 (m,6H,(CH3)2CH).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[CH:7][C:8]=2[CH3:15])[N:3]=1.[NH2:17][NH2:18]>>[NH:17]([C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[CH:7][C:8]=2[CH3:15])[N:3]=1)[NH2:18]
Reactant: NN
Reactant: Cc1ccc(C)c2c(C(C)C)cc(Cl)nc12
Product: Cc1ccc(C)c2c(C(C)C)cc(NN)nc12

Procedure:
A solution of 2-chloro-4-isopropyl-5,8-dimethylquinoline (1.00 g, 4.3 mmol) in NH2NH2 was reacted as outlined in Scheme 1 above to give the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.30 (d, J=6.74 Hz, 6 H) 2.64 (s, 3 H) 2.82 (s, 3 H) 3.95-4.10 (m, 1 H) 6.72 (s, 1 H) 6.98 (d, J=7.33 Hz, 1 H) 7.30 (d, J=7.33 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[NH:13][C:12](=[O:24])[C@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:12](=[O:24])[C@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)NC(=O)[C@H]1CC1CCCCCC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)[C@@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere 59 mg (1.4 mmol) sodium hydride were added at 0° C. to 0.50 g (1.2 mmol) (2R)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-3-oxopiperazine-1-carboxylate (isomer 4.1) in 20 ml DMF. After 20 min at 0° C. 0.13 ml (1.4 mmol) methyl bromoacetate were added and the mixture was stirred for 30 min at 0° C. Then the reaction mixture was stirred for 5 h at RT. The reaction mixture was mixed with water and extracted twice with ethyl acetate. The combined organic phases were dried and evaporated down.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(Br)cc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl 4-(6-bromobenzo[d]thiazol-2-yl)piperazine-1-carboxylate (300 mg, 0.753 mmol) in CH2Cl2 (6 mL) was added TFA (0.87 mL, 11.30 mmol). Upon completion of addition, the reaction mixture was stirred at rt for 3 hrs. After this time, the reaction mixture was diluted with CH2Cl2 and washed with aqueous NaOH (1 N, 5 mL) and brine (5 mL), and then dried (Na2SO4). The reaction mixture was filtered and then concentrated under reduced pressure to obtain Compound 13B as a light yellow solid (223 mg, 0.748 mmol, 99% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.72 (s, 1H), 7.41 (s, 2H), 3.58-3.66 (m, 4H), 2.98-3.07 (m, 4H). LC/MS (m/z)=299 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:23]([CH3:25])=[CH2:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH:9]([C@H:8]1[O:11][C:23]([CH3:25])([CH3:24])[N:12]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH2:10]
Reactant: C=C[C@@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C[C@H]1OC(C)(C)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 38 %

Procedure:
32 mg (0.12 mmol) of (1S,2R)-1-phenyl-1-benzoylamino-2-hydroxy-3-butene, in suspension in 0.64 cm3 of anhydrous toluene, are put, under an argon atmosphere, in a 10 cm3 single-necked, round-bottomed flask equipped with a magnetic stirrer system and a reflux condenser. 226 μl (173 mg, 2.4 mmol) of 2-methoxypropene, 6.0 mg (0.024 mmol) of pyridinium p-toluenesulphonate and 8 grains of 4 Å molecular sieve are then added. The resulting reaction mixture is allowed to react at a temperature in the region of 15° C. for 2.5 hours and is then heated at 100° C. for 2 hours. After cooling to a temperature in the region of 15° C., the reaction mixture is diluted in 40 cm3 of dichloromethane. The organic phase is washed once with 5 cm3 of a saturated sodium bicarbonate solution, 3 times with 5 cm3 of water and once with a saturated aqueous sodium chloride solution and is then dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting a first time with an ethyl ether/dichloromethane (2/98 by volume) mixture and then a second time with an ethyl acetate/hexane (10/90 by volume) mixture. There are thus obtained, with a yield of 38%, 14 mg (0.0456 mmol) of (4S,5R)-5-vinyl-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]1[CH2:32][C:24]2[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=2[C:22](=[O:33])[CH2:21]1>>[C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:21]2[CH:20]([CH3:19])[CH2:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[C:22]2=[O:33])=[O:16])=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C(=O)c1ccc(N(C)C(=O)OC(C)(C)C)nc1)C(C)C2

Procedure:
A-13 is prepared via general procedure A1 starting from (5-chlorocarbonyl-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester (A-10) (7.24 g, 26.8 mmol) and N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06) (5.00 g, 22.3 mmol). After evaporation of the solvent 7.72 g of A-13 is obtained that is used without further purification in the next step.
Reaction SMILES: [C:1](Cl)(=O)C.C([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Br:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])(=O)C>CO>[CH3:1][O:16][C:14](=[O:15])[C:13]1[CH:17]=[C:9]([NH2:8])[CH:10]=[CH:11][C:12]=1[Br:18]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc(N)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (29.2 ml, 32.2 g, 410.7 mmol) was added dropwise to methanol (210 ml) at 0-10° C. under nitrogen atmosphere and the solution was stirred for 30 min at 0° C. After addition of 5-acetamido-2-bromobenzoic acid (21.2 g, 82.1 mmol) in methanol at 0° C. the solution was stirred for 3 h at 55° C. After evaporation of methanol ethyl acetate (160 ml) was added and stirring was continued for 1 h at room temperature. The precipitation was filtered off and it was dissolved in water. pH was adjusted to 8 with NaHCO3. The mixture was extracted with ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:50])[NH:40][CH2:41][CH:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:49][CH:42]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:50])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 1 supra) (600 mg, 2.5 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford (4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 35 mg, 8.5%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33]N)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1>>[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc4c(c3)OCCO4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for example 91. MS: M=403.4 (M+H)+
Reaction SMILES: [CH:1]1([C:7]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:20].[Na]>>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:11][CH2:10][CH:9]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:32][CH2:33]1)[CH3:20]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Agent: [Na]
Product: CCOc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Yield: 60.9 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.02 mmol) and 1-(2-ethoxyphenyl)piperazine (1.13 mmol) with sodium triacetoxyboranehydride (1.33 mmol) gave pure product 1-(2-ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine (270 mg) in 52% yield. To a solution of free base in methanol was added required amount of hydrochloric acid solution in diethyl ether. The solvents were removed by reduced pressure, and the product was dried under vacuum to give dihydrochloric acid salt. m.p.=180-183° C.; MS (m/e): 434 (M+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CS(C)=O.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23](=[O:31])[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)Cc3ccccn3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of sodium hydride (0.21 g, 8.8 mmoL) in 10 mL of DMSO was stirred under N2 as 4-[4-(2-pyridine-2-yl-acetyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (3.50 g, 8.83 mmol) in 15 mL of DMSO was added dropwise. After 30 min, a solution of ethyl bromoacetate (1.47 g, 8.83 mmol) in 8.0 mL of toluene was added dropwise. The reaction was stirred at rt for 2 h and then quenched with saturated NH4Cl solution, and the solvent was evaporated. The residue was extracted with CH2Cl2 (3×20 mL), combined, washed with saturated NaHCO3, saturated NaCl solution and dried over Na2SO4. The crude product was purified by Combiflash chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give the product (4.0 g, 94%): Mp 118-120° C.; MS m/z 483 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C[O:30][C:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:18]3[CH2:38][C:33]4[C:32](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:31]3=[O:30])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: COC(=O)c1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN1Cc2ccccc2C1=O
Reaction time: 16 h
Yield: 65.7 %

Procedure:
To a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (100 mg, 0.38 mmol) and N,N-diisopropylethylamine (72 μL, 0.41 mmol) in acetonitrile (6 ml) at 0° C. was added 2-bromomethyl-benzoic acid methyl ester (43 mg, 0.19 mmol). The reaction mixture was stirred for 16 hours and the solvent evaporated in vacuo. The residue was diluted in ethyl acetate (50 ml), washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo, which afforded 50 mg (68%) of 2-amino-7-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH:10]1[CH2:9][CH:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccccn2)CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 4.23 mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (4 ml), and the reaction mixture was allowed to react with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo to afford 2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine as a crude yellow oil (600 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].O>C(O)CCC>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: CN(C)CCCl
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: Cc1c(OCCN(C)C)cccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 100 %

Procedure:
To a slurry containing 5.0 g (33 mmol) of 2-methyl-3-nitrophenol, 9.4 g (65.2 mmol) of (2-chloroethyl)dimethylamine hydrochloride, 9.0 g (65.3 mmol) of K2CO3, and 100 mL of H2O was added 100 mL of butanol and the reaction mixture was heated at 80° C. for 13 h. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4 and filtered. The solvents were removed under reduced pressure and the residue was subjected to silica gel chromatography to give 7.4 g (100%) of dimethyl{2-[(2-methyl-3-nitrophenyl)oxy]ethyl}amine as a brown oil. 1HNMR (400 MHz, DMSO-d6) δ 7.29-7.42 (m, 3H), 4.11 (t, J=5.6 Hz, 2H), 2.66 (t, J=5.6 Hz, 2H), 2.22 (s, 3H), 2.20 (s, 6H). MS (ESI+) m/z 225 [M+H].