Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOCC.[CH:87]1([NH2:92])[CH2:91][CH2:90][CH2:89][CH2:88]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:87]1([NH:92][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:91][CH2:90][CH2:89][CH2:88]1
Reactant: NC1CCCC1
Reactant: Cc1cccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Product: Cc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (500 mg, 1.24 mmol) in cyclopentylamine (50 mL) was added successively racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (308 mg, 0.49 mmol), cesium carbonate (0.81 g, 2.47 mmol) and palladium (II) acetate (70 mg, 0.31 mmol). The resultant mixture was heated to 95° C. for 18 hours at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ether was added. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (4:1 hexanes:ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine (360 mg, 64%) as a yellow foam. 1H NMR (CDCl3) δ 7.94 (d, 1H), 7.79 (d, 1H), 7.46 (s, 1H), 7.40 (d, 1H), 7.34–7.29 (m, 2H), 7.24 (d, 1H), 6.27 (d, 1H), 6.03 (m, 2H), 5.12 (broad s, 1H), 4.35 (m, 1H), 3.99 (m, 1H), 2.40 (s, 3H), 2.14–2.04 (m, 4H), 1.81–1.52 (m, 12H); MS m/z 453 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[I:9]N1C(=O)CCC1=O.O>CS(C)=O>[I:9][C:7]1[C:2]([NH2:1])=[N:3][C:4]([NH2:8])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cccc(N)n1
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(I)c(N)n1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
2,6-Diaminopyridine (100 g, 916 mmol) was dissolved in dimethyl sulfoxide (400 mL), and N-iodosuccinimide (100 g, 445 mmol) was added in one portion while stirring at room temperature. The reaction solution was stirring for 10 minutes at room temperature. Water (3.5 L) was added to the reaction solution, and the precipitated solids were filtered out. The resulting aqueous layer was extracted with ethyl acetate (1.3 L) 3 times. The ethyl acetate layers were combined and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=2:3) to obtain the title compound (23.8 g, 22.8%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C(O)CCC>CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 140 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A suspension of 6-chloro-3-nitroimidazo[1,2-b]pyridazine (1.0 g, 5.0 mmol) and (R)-2-(2,5-difluorophenyl)pyrrolidine (Prepared as described in Preparation A; 1.9 g, 11 mmol) in n-butanol (4.6 mL, 50 mmol) was sealed in a pressure reaction tube and stirred in a 140° C. oil bath overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (250 mL), then washed with water (2×150 mL) and brine (150 mL), filtered through a Biotage Phase Separator filter paper and concentrated. The crude material was purified by silica gel chromatography, eluting with 2:1 EtOAc/hexanes to yield the product as a foamy yellow powder (1.3 g, 75% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CN(C=O)C.Cl.CN(C)CCCN=C=NCC>CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottomed flask containing 4-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.92 mmol) was treated with N-hydroxysuccinimide (0.680 g, 5.90 mmol), treated with DMF (8 ml), cooled to 0° C., treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.226 g, 6.40 mmol), stirred at ambient temperature for 2 hours, diluted with Et2O (100 mL), washed with H2O (2×25 mL), dried (MgSO4), filtered and concentrated to provide the title compound. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.90-2.00 (m, 2H), 2.66 (t, J=7.54 Hz, 2H), 2.84 (s, 4H), 3.15-3.28 (m, 2H), 4.73 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.[Cl-].[NH4+].N>CCOCC>[OH:1][CH2:2][CH2:3][N:4]([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16][C:17]1[CH:18]=[C:19]([CH3:20])[CH:22]=[CH:23][CH:24]=1)[CH2:8][CH2:7][OH:6]
Reactant: OCCN1CCOC1c1ccccc1
Reactant: Cc1cccc(CBr)c1
Agent: N
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc(CC(c2ccccc2)N(CCO)CCO)c1
Yield: 82.7 %

Procedure:
A solution of 3-(2-hydroxyethyl)-2-phenyloxazolidine (78 g) in anhydrous ether (300 ml) is added dropwise with stirring to Grignard reagent which is prepared from magnesium turnings (22 g) and m-methylbenzylbromide (150 g) in anhydrous ether (1200 ml), and the mixture is refluxed for 3 hours. After the reaction, the reaction mixture is decomposed with an ammonium chloride aqueous solution, and made alkaline with ammonia. The ether layer is separated and extracted with an excess amount of 10% hydrochloric acid. The aqueous layer is separated and made alkaline with sodium hydroxide and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and the solvent is distilled off to give crude dl-N,N-bis(2-hydroxyethyl)-1-phenyl-2-(3-tolyl)ethylamine (100 g) as an oily substance.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl.O>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][CH2:29][C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][CH:27]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1
Yield: 74.5 %

Procedure:
A solution of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (intermediate 81) (170 mg, 0.344 mmol) and trifluoroacetic acid (14.9 g, 130.7 mmol) in 10 ml of dichloromethane and 100 μl of water is stirred for 2 hours at room temperature. The reaction medium is evaporated to dryness, taken up in ethyl acetate and washed with water, and then with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated to dryness to give 130 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester; compound with trifluoroacetic acid in a yield of 96%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[CH:20]([OH:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[C:20](=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C(=O)C1
Reaction time: 0.25 h
Yield: 102 %

Procedure:
To a solution of oxalyl chloride (42.35 ml, 0.480 mol) in dichloromethane (910 ml) was added a solution of dimethylsulfoxide (68.24 ml, 0.961 mol) in dichloromethane (910 ml) at −70° C. within 45 min. The solution was stirred for 15 min and a solution of 4-hydroxy-6-aza-spiro[2,5]octane-6-carboxylic acid tert-butyl ester (91.00 g, 0.400 mol) in dichloromethane (910 ml) was added within 40 min keeping the internal temperature at below −60°. The mixture was stirred for 35 min and triethylamine (280.4 ml, 2.00 mol) was added at below −60° C. within 10 min. The cooling bath was removed and the yellow suspension was stirred for 1 h then quenched with water (1.4 l). The organic phase was separated, washed with water (3×1 l) and sat. aq. sodium chloride solution (3 l) and evaporated. The residual orange powder was dissolved in tert-butyl methyl ether (1.40 l), the turbid solution filtered (Hyflo Speedex) to remove some insoluble material and the clear filtrate evaporated to provide crude 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester as yellow powder (91.9 g). The material was re-dissolved in tert-butyl methyl ether (300 ml) and purified by filtration over silica gel (700 g) using a 3:1 heptane/tert-butyl methyl ether mixture (6.5 l). Evaporation and drying (10 mbar, 40° C.) afforded 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester as whitish powder (80.58 g, 89%), CC purity 100a %.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:20])[N:14]([CH2:17][O:18][CH3:19])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:38].[Cl:39][CH2:40][C:41]1[N:42]=[C:43]([CH3:46])[S:44][CH:45]=1.Cl>CN(C=O)C.C(OCC)(=O)C.CCOCC>[ClH:39].[ClH:38].[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:40][C:41]3[N:42]=[C:43]([CH3:46])[S:44][CH:45]=3)[C:13](=[O:20])[N:14]([CH2:17][O:18][CH3:19])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(COC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2/C(=O)N(COC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 48 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[[1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene) methyl]-1H-imidazol-1-yl]methyl]benzoate (0.307 g, 0.721 mmol) in DMF (4 mL) is added K2CO3 (0.500 g, 3.62 mmol). After stirring for 5 minutes 4-chloromethyl-2-methylthiazole hydrochloride (0.265 g, 1.44 mmol) is added. The mixture is stirred for 48 hours. A pale brown slurry results which was diluted with ethyl acetate and washed with water and brine and then dried over MgSO4. Chromatography eluting with 1-% methanol in chloroform and evaporation in vacuo affords a viscous oil. This oil is dissolved in ether and treated with ethereal HCl to afford a foamy solid upon evaporation in vacuo. This solid is crystallized from 2-propanol/ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:29](Br)[CH:30]=[CH2:31].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:31]([C:5]1([C:14]([O:16][CH3:17])=[O:15])[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
10 g of 3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate were dissolved in 270 ml of THF. After cooling to −78° C., 100 ml of a 0.5 M solution of KHMDS in toluene were added dropwise. After stirring at −78° C. for 30 min, 5.4 ml of allyl bromide were added dropwise. The mixture was allowed slowly to reach room temperature and was stirred for 14 h. The reaction was then stopped by adding 400 ml of saturated ammonium chloride solution. The THF was removed in vacuo and the aqueous phase was extracted 3 times with 150 ml of ethyl acetate each time. The combined organic phases were washed once with 300 ml of saturated sodium chloride solution and dried with MgSO4. The solvents were removed in vacuo and the residue was chromatographed on silica gel.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[N:38]=[C:37]2[C:32]([CH2:33][CH2:34][C:35](=[O:39])[NH:36]2)=[CH:31][C:30]=1[CH3:40].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].Cl.[C:54]1([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=[CH:56][CH:55]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:40][C:30]1[CH:31]=[C:32]2[C:37](=[N:38][C:29]=1[O:28][CH2:27][CH2:26][CH2:25][CH2:24][N:67]1[CH2:66][CH2:65][N:64]([C:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:57]=[CH:56][CH:55]=3)[CH2:69][CH2:68]1)[NH:36][C:35](=[O:39])[CH2:34][CH2:33]2
Reactant: Cc1cc2c(nc1OCCCCO)NC(=O)CC2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(nc1OCCCCN1CCN(c3cccc4ccccc34)CC1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
To a clear solution of Dess-Martin reagent (1.40 g, 3.3 mmol, 1.3 equiv) in CH2Cl2 (200 mL) was added 7-(4-hydroxy-butoxy)-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.55 g, 2.2 mmol, 1.0 equiv) and the mixture was stirred at room temperature for 4 hours. TLC confirmed the completion of the reaction. The reaction mixture was diluted with CH2Cl2 and poured into a saturated solution of NaHCO3 containing Na2S2O3 (3.0 g). The mixture was stirred and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×30 mL) and the combined organic layer was dried over Na2SO4 and concentrated. The crude aldehyde was dissolved in DCE and 1-naphthalen-1-yl-piperazine monohydrochloride (0.76 g, 3.08 mmol, 1.4 equiv), Et3N (0.5 mL, 1.7 equiv) and NaBH(OAc)3 (0.65 g, 3.08 mmol, 1.4 equiv) were added. The reaction mixture was stirred for 1 hour, diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated. Purification of the residue by column chromatography (5% MeOH/EtOAc) gave the title compound as a white solid (0.40 g, 41%). mp: 76–78° C.; 1H NMR: (400 MHz, CDCl3) δ 8.22 (d, 1H), 7.85 (d, 1H), 7.58–7.38 (m, 5H), 7.25 (s, 1H), 7.05 (d, 1H), 4.25 (t, 2H), 3.30–3.10 (br s, 4H), 2.82–2.65 (m, 4H), 2.65–2.45 (m, 4H), 2.15 (s, 3H), 1.88–1.35 (m, 6H). MS: ES+ 445.41 (M+H)+, exact mass: 444.25.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7](Cl)[N:8]=[N:9][C:4]=2[CH:3]=1.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: Clc1nnc2cc(Br)ccc2n1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2nnc3cc(Br)ccc3n2)cc1
Yield: 35.1 %

Procedure:
A mixture of 7-bromo-3-chloro-1,2,4-benzotriazine (1.93 g), ethyl 2-(4-hydroxyphenoxy)propionate (1.69 g), anhydrous potassium carbonate (1.20 g) and methyl ethyl ketone (50 ml) was heated under reflux overnight. The solvent was removed by distillation under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was separated, dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give an oil. The crude product was purified by chromatography over silica gel (eluent dichloromethane) and the product was recrystallised from aqueous ethanol to give the title compound (1.16 g) as yellow crystals, mp 104° C.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:25][C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[C:9]([NH:11][CH:12]([CH:16]([C:18]2[O:19][C:20]([CH2:23][CH3:24])=[N:21][N:22]=2)[OH:17])[CH2:13][CH2:14][CH3:15])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[CH:1]1([CH2:7][CH:8]([CH2:25][C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[C:9]([NH:11][CH:12]([C:16]([C:18]2[O:19][C:20]([CH2:23][CH3:24])=[N:21][N:22]=2)=[O:17])[CH2:13][CH2:14][CH3:15])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1nnc(CC)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Product: CCCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1nnc(CC)o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (239 mg, 0.48 mmol) at room temperature. After stiffing for 1 hour, 5 mls of saturated Na2SO3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 65 mg of 2-cyclohexylmethyl-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide; H1 NMR (DMSO-d): 8.6, 8.51(11H, dd, J=6.8 Hz, J=5.6 Hz, NH, diastereomeric), 4.98(−4.88 (1H, m), 3.6–3.25(8H, m), 3–2.9(2H, q, J=7.6 Hz), 2.9–2.75(1H, m), 2.5–2.4(1H, m), 2.3–2.1(1H, m), 1.9–1.7(2H, m), 1.7–1.4(7H, m), 1.4–1.2(2H, m), 1.28(3H, t), 1.2–1(6H, m), 0.88(3H, t); MS: 461.4(M−1), 463.4(M+1), 485.4(M+Na).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:25][C:26]([CH3:28])=[O:27].C(Cl)Cl>O1CCCC1.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([C:26]([OH:27])([CH3:28])[CH3:25])[S:8][C:6]=2[N:7]=1
Reactant: CC(C)=O
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-(5-Chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 was slurried in tetrahydrofuran and cooled to −78° C. under nitrogen. Two equivalents of 2M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene was added slowly and the solution was stirred for 30 minutes. Acetone (6 eq) was added and the solution was stirred at −78° C. for an additional one hour. Ice was added and the solution was warmed to room temperature before extraction with methylene chloride. The organic layer was dried with sodium sulfate and concentrated. The resulting residue was purified on silica gel to give the light yellow solid of 2-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol 68.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: CS(=O)(=O)c1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, white solid (13 mg, 15%), MS (ISP) m/z=449.4 [(M+H)+], mp 280° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methylsulfonyl-phenyl)-1H-benzo[d]imidazole (intermediate O) (70 mg, 199 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (53.2 mg, 239 μmol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([NH:9][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
3-Chloropropylsulfonyl chloride 1 (1.456 g,8.23 mmol) was added dropwise to a solution of aniline (0.5 ml, 8.23 mmol) in pyridine (5 ml) with cooling at -20° to -30° C. over about 5 minutes. After the completion of the addition, the reaction mixture was stirred for another 45 minutes at room temperature. The reaction mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:2), 1.683 g (88%) of N-phenyl-3-chloropropylsulfonamide (intermediate 3j) was obtained as a yellow oil, which, when treated in a manner similar to that described in Preparation 1, gave the objective compound 4j as a pale yellow solid (yield 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.C(O)(=O)C.Cl>CO>[CH3:21][C:20]([OH:22])([CH3:23])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([N:1]2[CH:26]=[CH:30][CH:29]=[CH:28]2)=[CH:10][CH:9]=3)=[O:12])[CH2:14][CH2:15]1
Reactant: CC(C)(O)CC1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(O)CC1CCN(C(=O)c2cc3cc(-n4cccc4)ccc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 127 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol in 3 mL of methanol were added 90 μl, of 2,5-dimethoxytetrahydrofuran and 1 mL of acetic acid, followed by stirring at 60° C. for 1 day. 1M hydrochloric acid was added to the reaction liquid which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified from ethyl acetate-hexane to obtain 30 mg of 2-methyl-1-(1-{[5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}piperidin-4-yl)propan-2-ol as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][CH:10]=1)=[O:19]
Reactant: CC(C)c1ccc(CO)cc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CC(C)c1ccc(COC(=O)CCC(=O)CN)cc1
Reaction time: 48 h

Procedure:
From 4-isopropylbenzyl alcohol (5.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 days. The yield was 1.0 g (56%).