Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21](Cl)=[N:20][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1>>[O:29]1[CH2:30][CH2:31][N:26]([C:23]2[C:24]3[S:25][C:17]([CH2:16][N:13]4[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]4)=[CH:18][C:19]=3[N:20]=[C:21]([C:37]3[CH:38]=[CH:39][C:34]([NH2:33])=[N:35][CH:36]=3)[N:22]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
6-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine following General Procedure B-3 was reacted with 2-aminopyridine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 121. (400 MHz, CDCl3): 2.65-2.67 (4H, m, CH2), 3.13 (4H, m, CH2), 3.82 (2H, s, CH2), 3.85-3.88 (4H, m, CH2), 3.99-4.02 (4H, m, CH2), 4.63 (2H, b, NH2), 6.57 (1H, dd (J=8.62, 0.62), ar), 7.27 (1H, s, ar), 7.58-7.60 (2H, m, ar), 7.63-7.67 (1H, m, ar), 7.80 (2H, d (J=7.07), ar), 8.46 (1H, dd (J=8.59-2.26), ar), 9.16 (1H, d (J=1.66), ar). (M+H)+552.34
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][CH3:18])=[CH:9][CH:8]=1)[CH3:2].Cl[CH:21]([C:23]1[C:24]([CH3:39])=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[CH3:22].[Na+].[I-].C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([CH3:18])[CH:21]([C:23]2[C:24]([CH3:39])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Reactant: CCOC(=O)COc1ccc(NC)c2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)COc1ccc(N(C)C(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12
Temperature: 40 °C
Reaction time: 20 h

Procedure:
0.095 g (0.37 mmol) of the above prepared (4-methylamino-naphthalen-1-yloxy)-acetic acid ethyl ester and 0.220 g of [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see below 1G], 2.0 eq.) were treated in 2.8 ml of DMSO with 0.110 g (1 eq.) of NaI and 0.168 g (1.5 eq.) of DBU. After stirring for 20 h at 40° C., the reaction mixture was poured onto crashed ice/KHSO4, extracted twice with AcOEt, washed with water and brine, and dried over sodium sulfate. Evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15), afforded 0.055 g of the title compound as light brown oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH3:21])[S:17](=[O:23])(=[O:22])[N:16]([CH2:24][CH3:25])[CH2:15]2)=[CH:10][C:9]=1Br)(C)(C)C.[CH3:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:24]([N:16]1[CH2:15][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N:32]3[CH2:33][CH2:34][CH:29]([CH3:28])[CH2:30][CH2:31]3)[CH:10]=2)[CH2:19][N:18]([CH2:20][CH3:21])[S:17]1(=[O:23])=[O:22])[CH3:25]
Reactant: CC1CCNCC1
Reactant: CCN1CC(c2ccc(NC(=O)OC(C)(C)C)c(Br)c2)CN(CC)S1(=O)=O
Product: CCN1CC(c2ccc(N)c(N3CCC(C)CC3)c2)CN(CC)S1(=O)=O
Temperature: 25 °C

Procedure:
The title compound is prepared from [2-bromo-4-(2,6-diethyl-1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step) and 4-methylpiperidine following the literature procedure of Buchwald (Org. Lett., 4, 2885-8 (2002)). The residue obtained is purified by silica gel chromatography with an appropriate solvent mixture. After isolation, removal of the BOC protecting group from the resulting intermediate is carried out by stirring at RT in TFA-DCM (1:2), monitoring by TLC for completion, and then concentration in vacuo.
Reaction SMILES: C([O-])=O.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:16].[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25]O)=[CH:20][N:19]=1.Cl>C(O)(=O)C>[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([OH:16])=[C:6]([O:5][CH3:4])[CH:15]=2)=[CH:20][N:19]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: COc1ccc2ccccc2c1O
Agent: Cl
Agent: O=C[O-]
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)c2ccccc2c1O
Yield: 31.5 %

Procedure:
The formate of 2-methoxy-1-naphthol (J. E. Oatis, Jr., M. P. Russell, D. R. Knapp and T. Walle, J. Med. Chem. 1981, 24, 309) (7.23 g, 30.3 mmol), 2,4-diamino-5-hydroxymethylpyrimidine (4.35 g, 30.3 mmol), concentrated hydrochloric acid (4.2 mL) and glacial acetic acid (60 mL) were refluxed 2 hr. The resulting dark solution was evaporated to dryness and the residue dissolved in water and neutralized with ammonia. The resulting tan precipitate (5.2 g) was recrystallized from aqueous ethanol containing a slight excess of hydrochloric acid to give title compound as tan powder (2.83 g, 28%); mp ca. 290°-300° dec. Anal. Calcd for C16H16N4O2.HCl: C, 57.75; H, 5.15; N, 16.84; Cl, 10.65. Found: C, 57.62; N, 5.21; N, 16.79; Cl, 10.61.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([NH:39][CH:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccc(F)cc5c4)c3n2)CC1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (531.3 mg, 0.93 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (556.6 mg, 2.78 mmol), NaHCO3 (467.2 mg, 5.56 mmol) in NMP (10 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate: LCMS tR=3.24 Min (5 min run, UV254nm), Mass calculated for M+737.4, observed m/z 738.3 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(C(=O)NCCCN(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)S(C)(=O)=O)cc1

Procedure:
Compound 2 was coupled with 4-methylbenzoic acid following procedure K. LC-MS showed the product had the expected M+H+ of 574. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.0 (d, 2H) 7.65 (d, 2H) 7.50 (d, 2H) 7.2 (m, 3H) 7.0 (m, 3H), 6.7 (d, 2H), 4.4 (s, 2H), 3.45 (t, 2H), 3.2 (d, 4H), 3.0 (s, 3H) 2.7 (t, 2H), 2.45 (s, 3H), 1.8 (m, 2H).
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:33]>[Pd]>[OH:18][C@@H:17]1[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C@H:12]1[C:10]([OH:33])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Reactant: CO
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above compound (6) (316 mg) was dissolved in methanol (25 mL) and 10% Pd—C (40 mg) was added, and then the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the titled compound (242 mg) as a colorless powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9]1)=O)(C)(C)C.[BH-](O[C:29]([CH3:31])=[O:30])(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:12]1([CH3:13])[CH:11]=[CH:10][CH:9]=[CH:31][C:29]=1[O:30][C:14]1[CH:15]=[C:16]2[C:11]([CH2:17][CH2:10][CH2:9][NH:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1Oc1ccc2c(c1)NCCC2
Reaction time: 48 h

Procedure:
A mixture of 3-formyl-indole-1-carboxylic acid t-butyl ester, Compound 9, where R1 is 4-tolyl, R2 is H, R3 is 2-methylprop-1-yl, and R4 is CH3 (9 mg (0.0609 mmol) and NaBH(OAc)3 (17 mg, 0.0812 mmol) in 1 mL of anhydrous CH2Cl2 was vigorously stirred for 2 days, during which the the initially cloudy solution turned clear. The mixture was partitioned between 5 mL of EtOAc and 3 mL of saturated-NH4Cl solution and extracted three times. The combined EtOAc layer was washed with brine, dried over Na2SO4 and evaporated to dryness under vacuum. The product was purified by a silica gel column with Hexane/EtOAc (4/1-2/1) to afford 15 mg of 7-tolyloxy-3,4-dihydro-2H-quinoline-1-(3-methyl-indole-3-yl-1-carboxylic acid t-butyl ester)-4-spiro-5′-3′-1(2-methylpropy-1-yl)-1′ methyl-imidazolidine-2′,4′-dione as a light brown oil (71% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1([C:15]([OH:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.[CH2:18](O)[CH3:19]>>[NH2:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: NC1(C(=O)O)CCc2ccccc21
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(N)CCc2ccccc21
Yield: 84 %

Procedure:
Thionyl chloride (0.617 mL, 8.465 mmol) was added dropwise to anhydrous ethanol (6 mL) cooled to −30° followed by 1-amino-2,3-dihydro-1H-indene-1-carboxylic acid (0.300 g, 1.693 mmol) the reaction was then refluxed for 4 hours. The reaction was concentrated by rotary evaporation and diluted with water (5 mL) and the pH was adjusted to 9 with 6N aqueous sodium hydroxide. The solution was extracted with ethyl acetate (2×25 mL) and the organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.293 g, 1.43 mmol, 84%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.12 (t, J=7.17 Hz, 3 H) 1.85-2.07 (m, 1 H) 2.31 (s, 2 H) 2.51-2.66 (m, 1 H) 2.93 (t, J=6.99 Hz, 2 H) 3.90-4.21 (m, 2 H) 7.13-7.34 (m, 4 H). MS (DCI) m/z 206 (M+H)+, 223 (M+NH4)+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[OH:9])=[N+:2]=[N-:3].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:9][C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[N:1]=[N+:2]=[N-:3])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1Oc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Trans-1-azidocyclopentan-2-ol 1.27 g was dissolved in DMF and treated with sodium hydride (400 mg. 60%) at room temperature for 1 h. 4-Fluoronitrobenzene (1.41 g) was added and the mixture stirred at 50° C. for 4 h and then left at room temperature overnight. The reaction was quenched with water and extracted with ether. The organic solution was washed with water, dried (MgSO4) and evaporated. Purification by flash chromatography (SiO2-20% DCM/hexane) gave trans-2-(4-nitrophenoxy)cyclopentylazide. 1H nmr (CDCl3) 8.22 (2H, d); 6.98 (2H, d); 5.63 (1H, m); 4.07 (1H, m); 2.20 (2H, m); 1.87 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc3c(c2)OCO3)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccc3c(c2)OCO3)cc1

Procedure:
A mixture of 4.6 g (21.67 m moles) of 4-methyl-3', 4'-methylenedioxy-1,1-biphenyl and 5.0 g (28 m mole) of N-bromosuccinimide in 70 ml of carbon tetrachloride containing 0.1 g of benzoyl perioxide is heated under reflux for 2.5 hours. The mixture is filtered and the filtrate evaporated. The residue is recrystallized from hexane to afford (m.p. 78°-81°).
Reaction SMILES: O.O.O.[Br:4]([O-])=O.[Na+].[Cl:8][C:9]1[C:21]([Cl:22])=[C:20]([C:23]([C:25]2[N:29]([CH2:30][CH3:31])[N:28]=[CH:27][CH:26]=2)=[O:24])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>O>[Cl:8][C:9]1[C:21]([Cl:22])=[C:20]([C:23]([C:25]2[N:29]([CH2:30][CH3:31])[N:28]=[CH:27][C:26]=2[Br:4])=[O:24])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [O-][Br+][O-]
Reactant: CCOC(=O)COc1ccc(C(=O)c2ccnn2CC)c(Cl)c1Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)c2c(Br)cnn2CC)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.3 %

Procedure:
A solution of 1.88 g of sodium bromite trihydrate in 5 ml of water is added dropwise at room temperature to a solution of 1.85 g of ethyl [2,3-dichloro-4-(1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetate and the mixture is stirred at room temperature for 15 hours. The reaction mixture is evaporated to remove solvent and the residue is dissolved in 20 ml of water. The aqueous solution is made alkaline with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is crystallized with a mixture of isopropyl ether and hexane to give 1.98 g of ethyl [2,3-dichloro-4-(4-bromo-1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:46]5[CH:47]=[CH:42][CH:43]=[C:44]([S:48]([N:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)(=[O:50])=[O:49])[CH:45]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(S(=O)(=O)N4CCOCC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (44 mg) and 4-(3-bromo-benzenesulfonyl)-morpholine (prepared from 3-bromobenzenesulfonyl chloride, morpholine and pyridine in acetonitrile, 51 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[3-(morpholine-4-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-86) as a yellow powder (59 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>C(#N)C>[CH3:24][C:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][NH:17][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (1.0 g, 4.4 mmol, 1 equiv.) in acetonitrile (10 mL) at 0° C. was added triethylamine (0.672 mL, 4.8 mmol, 1.1 equiv.) and H-beta-Ala-OtBu HCl (0.8 g, 4.4 mmol, 1 equiv.). After removing the cooling bath the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and to the residue water (20 mL) was added. The precipitate was collected, washed with water and ether to afford N-(5-bromo-2-chloro-4-pyrimidinyl)-β-alanine 1,1-dimethylethyl ester (0.52 g).
Reaction SMILES: CC([Mg]Cl)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.CN(C)[CH:16]=[CH:17][CH:18]=[O:19].Cl>C1COCC1>[Br:6][C:7]1[N:8]=[CH:9][C:10](/[CH:16]=[CH:17]/[CH:18]=[O:19])=[CH:11][CH:12]=1
Reactant: CN(C)C=CC=O
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C/C=C/c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
2-Propylmagnesium chloride (2.0 M in THF, 5.00 mL 10.00 mmol) was added to a solution of 2,5-dibromopyridine (2.37 g, 10.00 mmol) in THF (5.0 mL) at RT. The resulting brown suspension was stirred for 1 h and then cooled to 0° C. 3-Dimethylaminoacrolein (95%, 1.30 mL, 12.36 mmol) was added and the mixture was warmed to RT and stirred for 2 h. 2 N HCl was added and after 5 min the mixture was cooled to 0° C. The precipitated solids were removed by filtration and partitioned between ethyl acetate (75 mL) and 10% NaOH (25 mL). The ethyl acetate layer was washed with brine (25 mL), dried (MgSO4), and concentrated. Recrystallization from ethyl acetate provided 550 mg (26%) of the title compound as shiny brown flakes. MS 211 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:8]([O:10]CC)=[O:9])[N:6]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(N)n1
Solvent: CC#N
Product: Nc1nc(/C(=N/OCCn2ccnc2)C(=O)O)cs1
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
16.1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-bromoethoxy)imino]-acetate and 17 g of imidazole are boiled under reflux for 4 hours in 160 ml of acetonitrile. The mixture is evaporated to dryness under reduced pressure, the residue is taken up in 150 ml of water, 25 ml of aqueous 3N sodium hydroxide solution and 100 ml of ethyl acetate and the aqueous phase is extracted twice with 100 ml of ethyl acetate each time. The organic phase are combined, washed with a small amount of water and evaporated. The residue is saponified at 50° C. for 1.5 hours with 100 ml of aqueous 1N sodium hydroxide solution and 100 ml of methanol. After the addition of 100 ml of 1N aqueous hydrochloric acid, the mixture is evaporated. The evaporation residue is crystallized using 250 ml of methanol and the crystallizate is suction filtered. There are obtained 13.2 g of crude 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-imidazol-1-yl-ethoxy)imino]-acetic acid. For purification, a solution of 11 g of crude product in 100 ml of water is adsorbed on 200 ml of DOWEX 50 W (ion exchange resin; H+ form). The product is recovered by elution with 2.5% aqueous ammonia solution. After evaporation of the solvent, the product is crystallized using methanol. There are obtained 5.6 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-imidazol-1-yl-ethoxy)imino]-acetic acid of melting point 166° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:10]([NH2:16])=[N:11][C:12]([NH2:15])=[CH:13][CH:14]=1.N1C(C)=CC=CC=1C.[O:25]1[N:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1>>[NH2:16][C:10]1[N:11]=[C:12]([NH:15][C:30]([C:27]2[CH:28]=[N:29][O:25][N:26]=2)=[O:31])[CH:13]=[CH:14][C:9]=1[C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Nc1ccc(-c2cc(Cl)ccc2Cl)c(N)n1
Reactant: O=C(O)c1cnon1
Solvent: Cc1cccc(C)n1
Product: Nc1nc(NC(=O)c2cnon2)ccc1-c1cc(Cl)ccc1Cl

Procedure:
N-[6-Amino-5-(2,5-dichlorophenyl)pyridin-2-yl]-1,2,5-oxadiazole-3-carboxamide was prepared by a method analogous to Method A, as described for Example 1 above, using 3-(2,5-dichlorophenyl)pyridine-2,6-diamine (Preparation 7), 1 equivalent lutidine and 1 equivalent acid chloride prepared from 1,2,5-oxadiazole-3-carboxylic acid.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH3:14][C:15]([CH:22]1[CH2:26][CH:25]=[C:24]([CH3:27])[C:23]1([CH3:29])[CH3:28])([CH2:18][C:19]([CH3:21])=[CH2:20])[CH:16]=[O:17]>C(O)(C)C>[CH3:28][C:23]1([CH3:29])[C:24]([CH3:27])=[CH:25][CH2:26][CH:22]1[C:15]([CH3:14])([CH2:18][C:19]([CH3:21])=[CH2:20])[CH2:16][OH:17]
Reactant: C=C(C)CC(C)(C=O)C1CC=C(C)C1(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: C=C(C)CC(C)(CO)C1CC=C(C)C1(C)C
Yield: 95.9 %

Procedure:
A 4 neck 1 liter round bottomed flask was charged with 400 g of dry isopropanol and 100 g of aluminum isopropoxide (0.48 mole). The contents of the flask were refluxed (80° C.) and 200 g of 2,4-dimethyl-2-(2,2,3-trimethylcyclopent-3-en-1-yl)-4-pentenal at 95.2% (0.865 mole) were added dropwise under nitrogen over 80 minutes. The reaction was refluxed for 2 hours. Then the lights were distilled off to a pot temperature of 110° C. After cooling the batch was extracted with 150 ml of 10% sulfuric acid and 300 ml of hexane. The hexane extract was washed with 150 ml of water, 100 ml of 5% sodium carbonate, and 100 ml of brine. After drying with magnesium sulfate, the batch was filtered, concentrated in vacuo and the crude alcohol, 201.1 g, was distilled from 1 g of soda ash to afford 193.6 g of purified product (88% yield). BP 94° C./0.10 mmHg; 1H-NMR (300 MHz), δ 1.007 (3H, s), 1.02 (3H, s), 1.42 (3H, s), 1.54 (3H, s), 1.83 (4H, br s), 2.0-2.4 (5H, br m), 3.60 (2H, AB quartet, JAB =11.1 Hz), 4.75 (1H, s), 4.88 (1H, s), 5.27 (1H, s); 13C-NMR (75 MHz), δ 12.35, 20.07, 22.31, 25.48, 28.38, 30.96, 42.11, 45.10, 48.27, 54.77, 68.48, 114.81, 121.38, 144.22, 148.28; IR (Neat), 3400 br, 2980, 1040 cm-1 ; MS (m/e), 207 (M+ -15), 191, 109 (Base).