Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=O)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13](/[CH:14]=[N:32]/[CH:29]4[CH2:31][CH2:30]4)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1/C=N/C1CC1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 61.9 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde (Example 73, 0.10 g, 0.26 mmol) in THF (5 ml) was added cyclopropanamine (0.03 g, 0.52 mmol) and NaBH(OAc)3 (0.55 g, 0.26 mmol). The reaction was stirred for 3 hours, quenched with aqueous Na2CO3 (10 ml), and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse phase column chromatography (5-35% ACN) to give the title compound (0.068 g, 62%). 1H NMR (400 MHz) δ 11.92 (s, 1H), 9.62 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.31-7.27 (m, 2H), 7.16-7.11 (m, 2H), 6.10 (s, 1H), 5.13-5.10 (m, 1H), 2.96-2.94 (m, 1H), 1.89-1.80 (m, 1H), 1.42 (d, J=6.9 Hz, 3H), 0.98-0.88 (m, 2H), 0.76-0.63 (m, 2H). MS: Calcd.: 422. Found: [M+H]+ 423.
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH2:10]O.[NH2:12][C:13](N)=[O:14]>O>[OH:14][C:13]1[N:12]=[CH:10][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:1]=1
Reactant: Nc1c(Cl)cc(Br)cc1CO
Reactant: NC(N)=O
Solvent: O
Product: Oc1ncc2ccccc2n1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
A mixture of (2-amino-5-bromo-3-chlorophenyl)methanol (3.3 g, obtained from step 3) and urea (10.5 g, 15 equiv.) was heated to 180° C. with vigorous stirring for 1 hr. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 2-hydroxyquinazoline as a yellow powder (2.18 g, crude). ES/MS m/z 259/261 (MH+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>CS(C)=O>[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]#[N:2])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCC#N
Temperature: 90 °C

Procedure:
Sodium cyanide (1.2 g) dissolved in dimethylsulphoxide was heated at 90° C. for 30 min. Solid 1-t-butyldimethylsilyloxy-6-bromohexane (5.8 g, compound X1) prepared according to the method previously described (ref. 37), then was added into the sodium cyanide solution. After heating at 120-130° C. for 20-180 min, the reaction mixture was poured into ice-cold water and the aqueous layer was extracted with ether, washed with brine, dried and concentrated. The product was distilled at 0.5 Torr and 107° C. to give a colourless oil. High resolution mass spectrometer for C12 H24 O N Si: calculated 226.1627, found 226.1624.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[C:11]([Cl:14])=[CH:12][S:13][C:8]=2[CH:7]=1)=[O:5])C.O[Li].O>>[Cl:14][C:11]1[C:9]2[NH:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[S:13][CH:12]=1
Reactant: CCOC(=O)c1cc2scc(Cl)c2[nH]1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1cc2scc(Cl)c2[nH]1

Procedure:
3-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to Procedure F (7 equiv LiOH—H2O; room temperature overnight, then at 50° C. overnight again; acidified aqueous phase extracted with ethyl acetate; combined organic phases dried over MgSO4, concentrated).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[NH:19][C:20]([NH2:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:30][CH:31]([CH3:43])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(#N)C>CCOCC>[CH2:23]([N:30]([CH:31]([CH3:43])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:38]=1)[CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:19][C:20]([NH2:22])=[O:21])[CH:11]=1)=[O:18])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(CC(C)NCc2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1ccc(CC(C)N(CC(=O)c2ccc(OCc3ccccc3)c(NC(N)=O)c2)Cc2ccccc2)cc1

Procedure:
1-(4-Benzyloxy-3-ureidophenyl)-2-bromoethanone (3.1 g) and N-benzyl-(2-[4-carbomethoxyphenyl]-1-methylethanamine) (4.85 g) were heated in refluxing acetonitrile (50 ml) for 2 hours. The solution was diluted with an equal volume of ether, filtered and the filtrate diluted further with ether (200 ml). The solution was washed with water, dried and evaporated to give the title compound, mp 140°-145° (ethyl acetate). τ (CDCl3) 9.00 (3H, d, J=6 Hz), 6.70-7.60 (3H, m), 6.0-6.4 (4H, m), 6.20 (3H, s), 4.90 (2H, s), 6.32 (2H, b), 2.1-3.3 (17H, m), 1.20 (1H, d, J=2 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.Cl.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17]N.B(F)(F)F.CCOCC>C(O)(=O)C>[F:9][C:10]([F:19])([F:20])[C:11]1[C:12]2[NH:17][C:4]3[CH2:3][CH2:2][NH:1][CH2:6][C:5]=3[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: NNc1ccccc1C(F)(F)F
Agent: Cl
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: FC(F)(F)c1cccc2c3c([nH]c12)CCNC3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 4-piperidone.HCl (1.36 g, 10.0 mmol) and 2-trifluoromethylphenylhydrazine.HCl (2.13 g, 10.0 mmol) in acetic acid (50 mL) was added the 1.0 M borontrifluoride etherate (2.46 mL, 20.0 mmol) and the reaction stirred at 90° C. for 8 hours and then allowed to cool. The mixture was concentrated in vacuo and ethanol (ca 20 mL) added and then cooled to 0° C., the solid was filtered off and the mother liquor was concentrated in vacuo and water (adjusted to pH 14 with 2M NaOH) added to the residue. The solid was filtered off and washed with water and dried under high vacuum.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:10])[CH3:9]>CCOCC>[C:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: [O-]c1ccccc1
Solvent: CCOCC
Product: CC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vigorously stirred suspension of thallous phenoxide (5 g., 0.017 m.) in anhydrous ether (15 ml.) is treated dropwise with freshly distilled acetyl chloride (1.33 g., 0.017 m.) in anhydrous ether (3 ml.) over 5 mins. at such a rate that the exothermic reaction is controlled. The mixture is then stirred for 1 hour at room temperature, the precipitated thallous chloride removed by filtration through Celite and the solvent evaporated under vacuum. The residual colorless oil is distilled to give phenyl acetate, 2.27 g., 98%, b.p. 110°/58 mm.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1.[I:26]I>O1CCCC1>[Br:16][C:17]1[CH:25]=[C:24]([I:26])[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1
Reactant: II
Reactant: O=C(O)c1ccc(Br)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Br)cc1I
Temperature: -25 °C
Reaction time: 16 h
Yield: 64775.4 %

Procedure:
n-Butyllithium (2.5M in hexanes, 297 mL, 0.743 mol) was added over 1 h to a cooled (−25° C.) solution of 2,2,6,6,-tetramethylpiperidine (131 mL, 0.77 mol) in tetrahydrofuran (1 L). The mixture was left to stir for 16 h at −25° C. then cooled to −55° C. before addition of solid 6-bromonicotinic acid (50.0 g, 0.25 mmol). The mixture was allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was cooled to −70° C. then poured onto a pre-cooled (−70° C.) solution of iodine (188.5 g, 0.74 mol) in tetrahydrofuran (500 mL). The mixture was then poured into the original reaction vessel and the contents allowed to warm to ambient temperature and stirred for 1 hour. The solvent was evaporated and the resultant residue dissolved in water (500 mL) and washed with dichloromethane (3×300 mL). The aqueous phase was separated and the pH adjusted to 2 by the addition of concentrated hydrochloric acid. Aqueous sodium metabisulfite solution (20% w/w, 30 mL) was added and the solid which deposited was collected by filtration. The resultant solid was washed with water (75 mL) and pentane (75 mL) and dried at 75° C. under vacuum to furnish the title compound as a tan solid (53.1 g, 65%). 1H NMR (DMSO-D6, 300 MHz) 8.62 (s, 1H); 8.35 (s, 1H). LCMS (Method B): RT=2.16 min, M+H+=328/330.
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]#[C:4][Si](C(C)C)(C(C)C)C(C)C.[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]([F:15])([F:16])[C:3]#[C:4][CH:19]([OH:20])[C:18]([CH3:22])([CH3:21])[CH3:17]
Reactant: CC(C)(C)C=O
Reactant: CC(C)[Si](C#CC(F)(F)Br)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)C(O)C#CC(F)(F)Br
Reaction time: 0.5 h

Procedure:
To a solution of (3-bromo-3,3-difluoro-prop-1-ynyl)-triisopropyl-silane (156 mg, 0.5 mmol) and 2,2-dimethyl-propionaldehyde (52 mg, 0.6 mmol) in THF (5 mL), TBAF (1M, 0.75 mL) was added dropwise at −90° C. After the addition was completed, the reaction mixture was stirred for 0.5 hour and quenched saturated aq. NH4Cl. The mixture was extracted with ether (20 mL×3) and washed with water (20 mL×2). After drying over Na2SO4 the solvent was removed and the product was purified by silica gel chromatography (AcOEt:hexane=1:20) to afford the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 4.08-4.09 (m, 1H), 1.83 (d, J=6.0 Hz, 1H), 0.965 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]1[O:13][C:14]([CH3:17])=[N:15][N:16]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[C:18]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]3[C:8](=[C:7]([C:12]4[O:13][C:14]([CH3:17])=[N:15][N:16]=4)[CH:6]=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)=[CH:23][CH:22]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2cccc3c(Br)cccc23)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nnc(-c2cccc3c(-c4ccc(C(=O)O)cc4)cccc23)o1

Procedure:
2-(5-Bromo-1-naphthyl)-5-methyl-1,3,4-oxadiazole (D3) (1.50 g, 5.2 mmol) and 4-carboxyphenylboronic acid (0.86 g, 5.2 mmol) were stirred in dimethoxyethane (DME) (40 ml), and sodium carbonate (2.5 g, 23 mmol) in water (40 ml) was added. The mixture was purged by a stream of Ar for 15 min, when tetrakis (triphenylphosphine)palladium (0) (0.1 g, 0.008 mmol) was added. The mixture was stirred at reflux under Ar for 20 h, and then evaporated to remove DME. The grey suspension was acidified (5M HCl), and the solid was filtered off and dried in vacuo at 60° C. This material was heated at reflux in ethanol (30 ml), and filtered hot. The white solid so collected was dried in vacuo at 60° C. giving 1.32 (77%) of the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.CCOC(C)=O>[CH2:1]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([Cl:9])[S:11][C:12]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2nc(Cl)sc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1nc2ccc(OCc3ccccc3)cc2s1
Temperature: 70 °C
Yield: 93.9 %

Procedure:
Benzyl bromide (0.921 g, 5.39 mmol) was added to a mixture of 2-chlorobenzo[d]thiazol-6-ol (1.00 g, 5.39 mmol) and cesium carbonate (1.76 g, 5.39 mmol) in CH3CN (15 mL). After 2 h at rt the reaction mixture was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×75 mL) and brine (75 mL). The EtOAc layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 8% EtOAc in Hexanes gradient), yielding 1.396 g (94%) of the title compound as a reddish, waxy solid. LC-MS: RT=10.51 min., [M+H]+=275.9. Rf=0.41 in 10% EtOAc/Hexanes.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:3]([CH:2]([CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
Ethyl acetoacetate (1 g, 7.68 mmol) was added dropwise to a suspension of NaH (60% in mineral oil, 338 mg, 8.45 mmol) in toluene (20 mL). The resulting suspension was stirred at rt for 10 min, then treated with 1-bromopinacolone (1.3 g, 7.32 mmol). The mixture was immersed in a 75° C. oil bath, and stirred under Ar for 1 h. The reaction was cooled to rt, diluted with toluene and washed with H2O (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford crude ethyl 2-acetyl-5,5-dimethyl-4-oxo-hexanoate (1.46 g) which was not purified: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.166 (s, 9H), 1.277 (t, 3H, J=7.1 Hz), 2.368 (s, 3H), 3.000 (dd, 1H, J=5.8 Hz, J=18.4 Hz), 3.231 (dd, 1H, J=8.2 Hz, J=18.4 Hz), 4.010 (dd, 1H, J=5.8 Hz, J=8.2 Hz), 4.191 (q, 2H, J=7.1 Hz); Field Desorption Mass Spectrometry: m/z 229 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:32]2[C:27]([Cl:26])=[N:28][CH:29]=[CH:30][CH:31]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-chloropyridin-3-yl)boronic acid (237 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 280 mg, 60%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)C.Cl>CO.C1COCC1>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:21])=[O:5])=[CH:8][CH:9]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Temperature: 35 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A 1N sodium hydroxide solution (20 mL) is added to a mixture of 4-(6-methoxy-pyridin-3-yl)-benzoic acid ethyl ester (2.43 g, 9.44 mmol) in MeOH (20 mL) and THF (20 mL) and stirred at 35° C. for 1 hour. The reaction is cooled and 1N HCl added until the pH is˜4. The precipitate is isolated by filtration and dried in a vacuum desiccator to give a the product as a white solid (2.03 g, 8.86 mmol). 1H NMR (DMSO-d6, 300 MHz) δ8.57 (d, 1H), 8.08 (dd, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 6.95 (d, 1H), 3.89 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)Nc1cccc(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)Nc1cccc(OCCCCl)c1
Reaction time: 20 h
Yield: 83.1 %

Procedure:
A mixture of 45.6 g (0.3 mole) of 1-(3-hydroxyphenyl)urea, 94.5 g (0.6 mole) of 1-bromo-3-chloropropane, 124.4 g (0.9 mole) of anhydrous potassium carbonate and 1 liter of acetone was heated at reflux with mechanical stirring for 20 hr. The mixture was concentrated and the residue was slurried with 1.5 liters of water. The mixture was filtered and the filter cake was recrystallized from isopropanol to yield 57.0 g (83%) of off-white solid, m.p. 141°-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.Br.[CH:15]([C:18]1[S:19][C:20]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:21]=2[N:27]=1)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:25][CH2:26][C:20]4[S:19][C:18]([CH:15]([CH3:17])[CH3:16])=[N:27][C:21]=4[CH2:22][CH2:23]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(C)c1nc2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: Br
Product: CC(C)c1nc2c(s1)CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 2-isopropyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrobromide. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 15 mg (17% of theory). ESI-MS: m/z=420 (M+H)+; Rt(HPLC): 1.34 min. (Method J).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:45])[CH:15]([N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:23]2=[O:44])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:45])[CH:15]([N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)(=[O:34])=[O:35])[C:23]2=[O:44])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC(=O)OC(C)(C)C)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(N)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A solution of (1-{2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-2-phenyl-acetyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (254 mg, 0.39 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×). The residue was dissolved in CH2Cl2 (30 mL) and treated with solid K2CO3. The reaction mixture was stirred at room temperature for 1 hour, filtered and concentrated in vacuo to afford 3-[2-(4-amino-piperidin-1-yl)-2-oxo-1-phenyl-ethyl]-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (179 mg, 83%) as a white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH:11](Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: CC(Br)Br
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(C)=O)CC1
Yield: 64.9 %

Procedure:
Ethyl acetoacetate (100 g, 0.77 mol) was dissolved in acetone (500 ml). To the thus obtained solution was added dibromoethane (361 g, 1.92 mol) and potassium carbonate (266 g, 1.92 mol) and the mixture was heated under reflux for 4 days. After filtering off insoluble matter, the filtrate was distilled under reduced pressure (80° C./8 mmHg) to obtain 78.1 g (65.1%) of the title compound as a colorless oily substance.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:18]=[CH:17][C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][Cl:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[ClH:29].[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][C:8]4[CH:17]=[CH:18][C:5]([O:4][CH2:28][CH2:27][CH2:26][N:20]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]5)=[CH:6][C:7]=4[C:11]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Oc1ccc2oc3ccc(O)cc3c2c1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2oc3ccc(OCCCN4CCCCC4)cc3c2cc1OCCCN1CCCCC1
Reaction time: 24 h

Procedure:
To 200 ml of water containing 13.0 g (0.33 mole) of sodium hydroxide and 12.0 g (0.06 mole) of 2,8-dihydroxydibenzofuran are added 250 ml of toluene and 29.7 g (0.15 mole) of 3-piperidinopropyl chloride hydrochloride, and the heterogeneous reaction mixture is heated to reflux with stirring for 24 hours. When cool, the organic layer is washed with water, dried over magnesium sulfate then concentrated in vacuo. The remaining oily residue is dissolved in ether and treated with ethereal HCl to give the desired product which is recrystallized twice from methanol-ethyl acetate yielding 2,8-bis(3-piperidonopropoxy)dibenzofuran dihydrochloride, M.P. 245°-246.5°C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[N:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1C=CC=CC=1>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[N:8]=1
Reactant: OCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(CBr)nc2n1
Temperature: 25 °C

Procedure:
To a solution of (5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methanol 56 (100 mg, 0.4 mmol) in benzene (3.0 mL) at 0° C. was added PBr3(30 μL, 0.4 mmol). The reaction was heated at reflux for 1 hour. After cooling to room temperature the reaction was quenched by the addition of water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude 4-(2-(bromomethyl)-5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 57 did not require further purification (x mg, x %). MS (Q1)×(M)+