Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][N:18]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[S:54](Cl)([C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)(=[O:56])=[O:55]>C(Cl)Cl>[S:54]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:16][CH2:17][N:18]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH3:23])([C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)(=[O:56])=[O:55]
Reactant: CCN(CCN(CCN(CCCCCCO)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCN(CCN(CCCCCCOS(=O)(=O)c1ccc(C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6.1 g amount of 7,10,13-tri (t-butoxycarbonyl)-7,10,13-triazapentadecanol, 100 mg of dimethylaminopyridine, and 4 ml of triethylamine in 100 ml of CH2Cl2 was stirred at 0° C. Dropwise, 2.64 of tosyl chloride in 20 ml of CH2Cl2 was added at 0° to 5° C. The reaction was then stirred overnight at room temperature and then 100 ml of CH2Cl2 was added. The reaction mixture was washed with 30 ml of 2N HCl, 30 ml of water and 30 ml of brine. The organic layer was dried over MgSO4 and was filtered. The solvent was evaporated and the residue from the filtrate was purified using a silica gel column and eluted with ethyl acetate/hexane (1:2 v/v). About 7.8 g of 7,10,13-tri(t-butoxycarbonyl)-7,10,13-triazapentadecanol tosylate was collected. The reaction is shown below:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18](O)([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:32][CH2:33][C:34]#[N:35].S(=O)(=O)(O)[OH:37]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18]([NH:35][C:34](=[O:37])[CH2:33][Cl:32])([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Reactant: N#CCCl
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ncnc2sc(NC(=O)N3CCC(NC(=O)CCl)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (prepared as in Example 65, 114 mg, 0.25 mmol) in acetic acid (0.24 mL) was treated with chloroacetonitrile (0.20 mL, 3.10 mmol). The resulting mixture was sonicated in a water bath until all the solid dissolved and then was cooled to 0° C. The reaction was then treated with concentrated sulfuric acid (0.24 mL) at 0° C. Upon complete addition, the reaction was warmed to 25° C. and was stirred at 25° C. for 2 h. At this time, the mixture was diluted with water and was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting material was triturated with diethyl ether to afford 4-(2-chloro-acetylamino)-4-(3-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (88 mg, 67%) as an off-white solid. This material was used without further purification.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]#[N:14].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>C1COCC1>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]([C:18]1[CH:19]=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[C:13]#[N:14]
Reactant: N#CCc1nc2ccccc2s1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a stirred suspension of NaH (60% in oil, 9.2 g, 0.23 mol) in dry THF (200 ml) was added drop wise under inert atmosphere a solution of 1,3-benzothiazol-2yl-acetonitrile (20 g, 0.15 mol) in dry THF (200 ml). After 1 h 30 stirring at r.t., a solution of 2,4-dichloropyri-midine (17.1 g, 0.15 mol) in dry THF (200 ml) was added dropwise. The reaction mixture was allowed to stir under inert atmosphere at r.t. until complete disappearance of the starting material. The reaction was quenched by addition of water and the THF was evaporated. Water was added and the suspension was slightly acidified with aqueous HCl 1M. The precipitate obtained was filtered off and washed thoroughly with water until neutral then with hexane to remove the oil. The crude solid was dried under vacuum at 40° C., affording 28 g (84%) of the title compound as a light brown powder: mp 246° C. dec.; MS: 286.8 (M+1); HPLC (Conditions a, 268 nm) 97%, rt. 5.66 min; 1HNMR (DMSO-d6) δ 13.25 (br s, 1H, exchangeable), 8.09 (d, J=4.14 Hz, 1H), 7.90 (d, J=7.53 Hz, 1H), 7.61 (d, J=7.92 Hz, 1H), 7.39-7.34 (m, 1H), 7.20-7.15 (m, 1H), 6.96 (br d, 1H). CHN analysis: C13H7ClN4S: Calculated: C, 54.19%; H, 2.48%; N, 19.45%. Found: C, 53.35%; H, 2.77%; N, 17.62%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:30]N1C2C=CC=CC=2N=N1.Cl.[CH3:41][N:42]([CH3:51])[CH2:43][CH2:44]CN=C=NCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([C:44](=[O:30])[CH2:43][N:42]([CH3:51])[CH3:41])[CH3:21])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CNCc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(CN(C)C(=O)CN(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 68.6 %

Procedure:
(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-methylaminomethyl-benzyl)-amino]-4-methyl-pentanoic acid amide (75 mg, 0.17 mmol), (α-dimethylamino)acetic acid (18 mg, 0.17 mmol), 1-hydroxybenzotriazole (24 mg, 0.17 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) were combined in 3 mL CH2Cl2 and stirred overnight. The reaction mixture was diluted with 5 mL CH2Cl2 and washed with 1 N NaOH and brine. The organic phase was dried by filtering through cotton and the solvent was removed in vacuo. Purification via preparative HPLC afforded the title compound (61 mg) in 68% yield. MS (ESI), 523.4 (M+H)+ 1H NMR (CDCl3) δ8.02 (d, 2H, J=8.0), 7.71 (d, 2H, J=8.0), 7.37 (d, 2H, J=8.0), 7.28 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.51 (br s, 1H), 4.46 (s, 2H), 4.70 (d, 1H, Jab=16), 4.33 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 2.69 (s, 3H), 2.63 (s, 2H), 2.20 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[OH:27])[CH2:16][C:15]2[C:17]3[C:11]([CH:12]=[CH:13][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6]1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[O:27][CH:36]([CH3:38])[CH3:37])[CH2:6][C:7]2[C:17]3[C:11]([CH:10]=[CH:9][CH:8]=2)=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2cccc3cccc(c23)C1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-2,3-dihydro-1H-phenalene-2-carboxylic acid methyl ester (22) (175 mg, 0.47 mmol), anhydrous Cs2CO3 (306 mg, 0.94 mmol), and KI (16 mg, 0.09 mmol) in DMF (8 mL) is added 2-bromo-propane (220 μL, 2.35 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give the pure product (25) as white solid (143 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].[N+]([O-])(O)=O>O.[OH-].[Na+]>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[O:14]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1[nH]c(-c2ccccc2)nc1C=O
Reaction time: 16 h

Procedure:
A 102.1 gm. portion of 5-methyl-2-phenyl-4-imidazolemethanol is dissolved in 765 ml. of concentrated HNO3. The solution is cooled in an ice bath and allowed to stand for 16 hours. The solution is heated on a steam bath for 30 minutes, diluted with 2.3 liters of water and neutralized with 50% NaOH while cooling in an ice bath. The solid is collected, dried, recrystallized from 200 ml. of ethanol and then from one liter of 1:2 ethanol:water giving the desired product, m.p. 102°-115° C.
Reaction SMILES: C([C@H]1COC(=O)N1C(=O)[C@@H:15]([O:41][CH3:42])[CH2:16][C:17]1[C:22]2[S:23][CH:24]=[CH:25][C:21]=2[C:20]([O:26][CH2:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH-:44].[Na+].C1[CH2:50][O:49]CC1>>[CH3:42][O:41][C@@H:15]([CH2:16][C:17]1[C:22]2[S:23][CH:24]=[CH:25][C:21]=2[C:20]([O:26][CH2:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[CH:19][CH:18]=1)[C:50]([OH:49])=[O:44]
Reactant: [OH-]
Reactant: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: [Na+]
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
0.195 g of the above prepared (S)-4-benzyl-3-((2S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionyl)-oxazolidin-2-one (0.32 mmol) was dissolved in 2.25 ml of THF and treated with 0.81 ml of 1N NaOH (2.5 eq.). The reaction mixture was kept at 0° and progress of the hydrolysis followed by TLC. After 1 h the reaction mixture was quenched by pouring onto crashed ice/HCl. Twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents left a crude product, which was purified by twofold crystallisation from AcOEt/hexane to remove the chiral auxiliary. Thereby, 0.102 g of the title compound was obtained as white solid, mp.118-120°. The enantiomeric excess was judged according to 1H-NMR in the presence of a large excess of optically pure trifluoromethyl-anthryl-ethanol to be >95%. According to chiral HPLC (Chiralpak-AD) it amounts to 99.3%.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[CH3:29][C:30](C)=[O:31].C(Cl)(=O)C.N.O>O>[C:30]([O:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:31])[CH3:29]
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1
Reactant: CC(C)=O
Agent: N
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)OC(COc1cccc2c1CCC(=O)N2)CN1CCN(c2ccccc2)CC1

Procedure:
2 grams of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril are mixed with 30 ml of acetone and further 12 ml of acetyl chloride are added, followed by heating for 10 hours under refluxing conditions. After cooling the reaction mixture, the product precipitated is collected by filtration and washed with acetone. The crude crystals thus obtained are dissolved in 80 ml of water and made basic with ammonia-water, then extracted with chloroform, dried and chloroform is removed by distillation. The residue is purified by silica gel chromatography to obtain 0.5 g of 5-[2-acetyloxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 159°-161° C.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[CH3:32][N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCNCC2)cc1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
A solution of Compound 140 (0.100 g, 0.28 mmol) in dichloroethane was added with acetic acid (0.48 mL, 0.84 mmol) and 1-methyl-4-piperidone (0.84 mL, 0.68 mmol). After 20 minutes, the mixture was added with sodium triacetoxyborohydride (0.0827 g, 0.39 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-ethanol to obtain Compound 141 (0.0767 g, 0.17 mmol, 59%).
Reaction SMILES: [OH:1][C@H:2]([CH3:19])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:4].[Cl:20][C:21]1[C:26](O)=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O.O1CCCC1>[Cl:20][C:21]1[C:26]([O:1][C@@H:2]([CH3:19])[C:3]([NH:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[O:4])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1
Reactant: C[C@@H](O)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1cc(Cl)cnc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Oc1cc(Cl)cnc1Cl)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a tetrahydrofuran solution (148 ml) of tert-butyl 4-{[(2R)-2-hydroxypropanoyl]amino}piperidine-1-carboxylate (5.13 g), 2,5-dichloropyridin-3-ol (3.40 g) and triphenylphosphine (6.41 g) was added dropwise at room temperature a tetrahydrofuran solution (40 ml) of di-tert-butyl azodicarboxylate (5.63 g) over 10 minutes. The reaction solution was stirred at room temperature for 1 hour, then poured into water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-({(2S)-2-[(2,5-dichloropyridin-3-yl)oxy]propanoyl}amino)piperidine-1-carboxylate (6.40 g).
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)[C:16]([Cl:18])=O.[N+:21](=[CH2:23])=[N-:22]>ClCCl.CN(C)C=O>[Cl:18][CH2:16][C:10]([C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=1)=[O:12].[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:11])[CH:23]=[N+:21]=[N-:22])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCc1ccc(C(=O)C=[N+]=[N-])cc1
Product: CCCCCc1ccc(C(=O)CCl)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 44 %
Yield: 1.3 %

Procedure:
A solution of 4-pentyl-benzoic acid (1.178 g, 6.13 mmol) and oxalyl chloride (630 uL, 855 mg, 6.74 mmol, 1.1 eq) in dichloromethane (15 mL) was stirred at 22° C. for 10 min, then treated with one drop of N,N-dimethylformamide at 22° C. {Caution, gas evolution may become brisk}. After gas evolution was no longer observed, the flask was fitted with a condenser and warmed to reflux for 30 min. The solution was cooled to -5° C., and cannulated into a cold (-5° C.), ethereal solution of diazomethane (40 mL). After the solution was stirred at -5° C. for 30 min, the flask was removed from the cold bath and the yellow solution was allowed to stir at 22° C. for 2 hrs (preferably in the dark). The solution was concentrated in vacuo, and purified by flash chromatography (5% ethyl acetate in hexane) to provide 33 mg (1.3%) of 2-chloro-4'-(n-pentyl) acetophenone and 586 mg (44%) of 4'-(n-pentyl) diazoacetophenone as a bright yellow oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)([O-:4])=[O:3].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)Cl>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH:12]=1)([O-:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1C1=CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC=C(c2ccccc2[N+](=O)[O-])CC1
Reaction time: 0.5 h

Procedure:
4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (0.44 g, 1.8 mmol) was dissolved in a solution of pyridine (0.4 mL) and DCM (20 mL). Acetyl chloride (0.142 mL) was added and the mixture was stirred for 0.5 hours. The mixture was diluted with DCM (20 mL) and the organic solution washed with water then 1 N hydrochloric acid. The solution was dried with magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as an orange oil (0.4 g). LCMS m/z 247.4 [M+H]+. R.T.=3.70 min (Analytical Method 4).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:13]=[CH:17][CH:16]=[CH:15]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)c1ccc(N)cc1
Solvent: CC(=O)O
Product: CC(C)c1ccc(-n2cccc2)cc1
Yield: 99 %

Procedure:
Glacial acetic acid (100 ml) was added to a mixture of 4-isopropylaniline (10 ml, 72.4 mmol) and 2,5-dimethoxytetrahydrofuran (9.6 ml, 72.4 mmol) and the resulting mixture was refluxed for 1.5 h. The reaction mixture was allowed to cool and acetic acid was removed under reduced pressure. The resulting brown syrup was dissolved in ethyl acetate (200 ml) and ,washed with water (2×200 ml). The organic layer was dried over magnesium sulfate and filtered. Removal of the solvent gave 1-(4'-isopropylphenyl)pyrrole (13.28 g, 99% yield) as a brown syrup.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a solution of trans-4-aminocyclohexane carboxylic acid hydrochloride (5.0 g, 34.92 mmol) in aqueous 2.0N NaOH (35 mL) is added benzyl chloroformate (5.0 mL, 34.92 mmol). The mixture stirs for 1.5 h. Then the suspension is acidified with 12N HCl (aq) to pH=1. H2O is added (100 mL) and the precipitate is filtered off. The filter cake is dried to afford 8.2 g of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid. LC/MS: [M+H]30 =278, Rt=0.85 min (method 6)
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C(C)C)=N2)C=CC=1C#N.[O:75]1CCN(C2C=CC(N)=CC=2)CC1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:75])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccc(N4CCOCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccc(N4CCOCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 11 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(4-morpholinophenylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 4-morpholinoaniline instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (33) (the second stage yield: 11%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(4-morpholinophenylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][Br:9])=[CH:5][CH:4]=1.[CH:13](=[N:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][CH3:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)CCl>[Br-:9].[CH:13](=[N:20][N+:21]1[CH:25]=[CH:24][N:23]([CH2:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:10])[C:22]=1[CH2:26][CH3:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1nccn1N=Cc1ccccc1
Solvent: ClCCCl
Product: CCc1n(CC(=O)c2ccc(OC)cc2)cc[n+]1N=Cc1ccccc1
Product: [Br-]
Reaction time: 3 h

Procedure:
2.23 g (10 mmol) of 4-methoxyphenacyl bromide are added to a solution of 1.99 g (10 mmol) of 1-benzylideneamino-2-ethylimidazole in 80 ml of ethylene chloride. The mixture is stirred at 60° for 3 hours, the crystallized-out product is filtered off and washed with ether. There is obtained 1-(benzylideneamino)-2-ethyl-3-(p-methoxyphenacyl)imidazolium bromide of melting point 221°-222°.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:3].S(=O)(=O)(O)O>C(OCC)C>[CH3:1][C:2]1([CH3:3])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(CCCC(C)(C)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(C)(C)CCC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
A solution of 2-methyl-5-(p-tolyl)-pentan-2-ol (10.4 g, 54.1 mmol) in ethyl ether (100 mL) at 0° C. was treated with concentrated sulfuric acid (64 mL). The mixture was stirred at 0° C. for 1.5 hours, and then poured into a mixture of ice/water. The mixture was diluted with ethyl ether, the organic phase was separated, washed with water (2×), saturated sodium bicarbonate and brine. The aqueous phase was extracted with ethyl ether and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (9.6 g, 100% crude) as a yellowish oil which was used for the next reaction.