Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(-c2nncn2-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2nc(COc3ccc(-c4nncn4-c4ccncc4)cc3)ccc2c1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of 4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenol (44 mg) in dimethyl formamide (1 ml) in a 7 ml Teflon capped vial was added cesium carbonate (185 mg) and 2-Chloromethyl-quinoline (37 mg) and the reaction mixture heated on a shaker plate at 60° C. for 18 h. The reaction mixture was poured into water and extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated to provide the title compound (45 mg). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.65 (d, J=6.0 Hz, 2H), 8.37 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.78 (m, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.61 (t, J=5.8 Hz, 1H), 7.40 (m, 4H), 7.14 (d, J=9.1 Hz, 2H), 5.38 (s, 2H); MS: (M+H m/z=380.2).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH3:27])[CH:18]=[CH:17][C:16]([S:19]([O:22][CH2:23][CH:24]([OH:26])[CH3:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:47][C:48]1[CH:53]=[C:52]([O:54][C:55]([F:58])([F:57])[F:56])[CH:51]=[CH:50][C:49]=1O>>[I:47][C:48]1[CH:53]=[C:52]([O:54][C:55]([F:56])([F:57])[F:58])[CH:51]=[CH:50][C:49]=1[O:26][CH:24]([CH3:25])[CH2:23][O:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([CH3:27])=[CH:18][CH:17]=1)(=[O:20])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)O)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)OCC(C)Oc2ccc(OC(F)(F)F)cc2I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
Diethyl azodicarboxylate (5 ml, 31.8 mmol) was added dropwise to a stirred solution of (p-toluenesulphonyloxy)propan-2-ol (Description 19; 7.6 g, 33 mmol), triphenylphosphine (9.0 g, 34 mmol) and 2-iodo-4-trifluoromethoxyphenol (10 ml, 33 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (18.7 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[N:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:28][NH:27][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:25])([F:24])[F:1])=[CH:4][C:5]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)=[N:6][C:7]=12)=[NH:13]
Reactant: NO
Reactant: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 69.1 %

Procedure:
A stirred mixture of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile [CAS-No. 851262-50-5] (2.0 g, 5.61 mmol), hydroxylamine hydrochloride (0.78 g, 11.2 mmol) and potassium carbonate (2.33 g, 16.8 mmol) in ethanol (100 ml) was heated under reflux conditions for 3 h. After the reaction mixture reached room temperature the precipitate was collected by filtration and washed with ethanol and ethyl acetate. The combined filtrates were evaporated and the crude product purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield the title compound (1.51 g, 69%) as an orange solid. MS (ISP) 389.9 [(M+H)+]; mp 252° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][CH3:30])[O:17][C@H:16]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][OH:48])=[CH:41][CH:40]=2)[CH:32]=1)(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][CH3:30])[O:17][C@H:16]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]=[O:48])=[CH:41][CH:40]=2)[CH:32]=1)(=[O:13])[CH3:12]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (0.068 mL, 0.80 mmol) was added to a solution of DMSO (0.113 mL, 1.60 mmol) in dry DCM (1 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 5 min. at the same temperature and then a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-(2-hydroxyethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (220 mg, 0.403 mmol), in dry DCM (3 mL) was added. The reaction mixture was stirred at the same temperature for 1 h. NEt3 (0.334 mL, 2.40 mmol) was added and the reaction mixture was allowed to come to r.t. The crude compound was extracted with DCM (30 mL). The organic layer was separated, washed with water (15 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the title compound, which was used as such in next step.
Reaction SMILES: C([O:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C1C=CC=CC=1.C[Si](I)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+].ClCCl>C(#N)C>[CH2:15]([NH:14][C:13]([S:12][CH2:11][CH:10]([O:34][CH3:35])[CH2:9][OH:8])=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(COCc1ccccc1)OC
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CO)OC
Reaction time: 15 h
Yield: 57.2 %

Procedure:
To a solution of 1.02 g (2 mM) of 3-benzyloxy-2-methoxy-1-octadcylcarbamoylthiopropane VI a6 in 80 ml of acetonitrile is added 0.4 ml (2.81 mM) of trimethylsilyl iodide with ice-cooling and the mixture is allowed to stand at room temperature for 15 hours. To the reaction mixture is added 50 ml of 10% aqueous solution of sodium thiosulfate and the product is isolated with dichloromethane extraction. The dichloromethane layer is washed with water, dried, and evaporated. The residue is purified by column chromatography on silica gel using a n-hexane-ethyl acetate (2:1) mixture as an eluent to give 480 mg (1.15 mM) of the titled compound, 3-octadecylcarbamoylthio-2-methoxypropylalcohol V a6 as a solid in 57% yield.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[CH:21]1([C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)[CH2:23][CH2:22]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(C=O)cc21
Temperature: 97.5 °C
Reaction time: 24 h
Yield: 105.3 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (51 mg, 0.12 mmol), cyclopropylboronic acid (21 mg, 0.24 mmol), powdered K3PO4 (103 mg, 0.48 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in PhMe (2 mL) and H2O (0.1 mL) was heated with stirring in a sealed tube under Ar at 95-100° C. for 1 d. The crude mixture was concentrated and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound as a clear oil (40 mg, quant): 1H NMR (400 MHz, CDCl3) δ ppm 10.13 (s, 1H), 8.02 (s, 1H), 7.87 (d, J=8.28 Hz, 1H), 7.70 (d, J=8.28 Hz, 1H), 5.71 (s, 2H), 3.54 (d, J=8.53 Hz, 2H), 2.19-2.28 (m, 1H), 1.06-1.12 (m, 4H), 0.89 (d, J=8.28 Hz, 2H), −0.07 (s, 9H); MS ESI 317.1 [M+H]+, calcd for [C17H24N2O2Si+H]+ 317.5.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
The 2-aminonicotinic acid (5.0 g, 0.0362 mol) and K2CO3 (5.0 g, 0.0362 mol) were suspended in 50 ml of DMF and heated to reflux. Almost complete solution occurred. The mixture was cooled to 25° C. and the CH3I (5.1 g/2.2 ml, 0.0362 mol) was added and the mixture was stirred 18 hours. The mixture was filtered and concentrated. The residue was placed on a bed of silica and eluted with 5%/EtOH/CH2Cl2 /1/10% NH4OH. The fractions containing the product were combined and concentrated. The residue was suspended in Et2O, filtered and washed with Et2O to yield 3.2 g (58%) the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[Cl:11].[CH:12]([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:14])[CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]([CH3:14])[CH3:13])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(Cl)c1ccc(Br)c(Cl)c1
Reactant: CC(C)NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)c(Cl)c1)C1CCCCC1
Reaction time: 1 h

Procedure:
To a stirred, cold (0° C.) solution of 4-bromo-3-chlorobenzoyl chloride (6.14 g, 24.2 mmol) in tetrahydrofuran (20 ml) is added dropwise a solution of isopropyl cyclohexyl amine (6.841g, 48.4 mmol) in THF (7 mL). After stirring for 1 hr. at 0° C., the reaction is stirred at room temperature for 3 hr. and refluxed for 3 hr. The reaction is concentrated in vacuo and the residual mass is dissolved in ethyl ether and water. The layers are separated and the organic layer washed once with water, twice with 0.5N HCl, once more with water, twice with 5% aqueous NaHO3 solution, and once with water. After drying over sodium sulfate, the organic layer is filtered, and the filtrate concentrated in vacuo to give the crude product. This material is purified by chromatography on silica gel using mixtures of EtOAc, and hexane as eluents to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][C:50]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][C:50]4[CH:51]=[C:52]([C:55]([F:57])([F:58])[F:56])[CH:53]=[CH:54][C:49]=4[Cl:48])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCOc4cc(C(F)(F)F)ccc4Cl)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C

Procedure:
This compound is prepared from compound E4 and 2-chloro-5-trifluoromethylphenol, according to the above-described procedure A.
Reaction SMILES: [Cl: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.[N:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][NH:24][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:25]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1cc2c(c(N3CCOCC3)c1)CCNC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(cccc2N2CCOCC2)C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C[O-].[Na+].[CH:18](OCC)=O.CCOC(C)=O>COCCOC.O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[NH:1][CH:18]=[CH:13][C:12]2=[O:14]
Reactant: CCOC=O
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2[nH]ccc(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 1-(2-amino-4,5-dimethoxyphenyl)ethanone (9.80 g, 50 mmol, Lancaster Synthesis LTD) in DME (300 mL) at rt was added NaOMe (15.0 g, 278 mmol), and the mixture was stirred for 30 minutes at rt. To this mixture was added ethyl formate (25 mL) dropwise with stirring at rt. After an hour the reaction was quenched by adding aq HCl (50 mL of 2N HCl), stirred for 10 minutes and the precipitate was filtered, washed with a small amount of H2O and EtOAc to obtain the 1st crop of product. To the filtrate solution was added EtOAc (200 mL), the EtOAc layer was separated, the aqueous layer was washed with EtOAc (200 mL), and the combined EtOAc solution was dried over MgSO4, concentrated in vacuo and the residue was triturated with a small amount of CH3OH/EtOAc to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined, mixed with water (100 mL), stirred for 10 minutes, the solid was filtered and dried to obtain the product (9.75 g, 95%) as a white solid. 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 7.75 (d, 1H, J=4.2 Hz), 7.42 (s, 1H), 7.08 (s, 1H), 5.91 (d, 1H, J=4.2 Hz), 3.83 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[C@H:10]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[NH:5]1.Cl[CH2:27][C:28](=[O:30])[CH3:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:27]([N:5]1[C:6]2[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=2[CH2:8][CH2:9][C@@H:10]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]1=[O:3])[C:28]([CH3:29])=[O:30]
Reactant: CC(=O)CCl
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)CN1C(=O)[C@H](NC(=O)OCc2ccccc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Add powdered potassium hydroxide (KOH) (0.72 g, 12.89 mmol) to a solution of benzyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (2.0 g, 6.44 mmol), chloroacetone (1.19 g, 12.89 mmol), and tetrabutylammonium fluoride (1.29 mL, 1.29 mmol, 1M solution in THF) in tetrahydrofuran (65 mL). Stir the mixture for approximately 16 hours at ambient temperature. Add additional potassium hydroxide (0.361 g, 6.44 mmol), chloroacetone (0.59 g, 6.44 mmol), tetrabutylammonium fluoride (0.65 mL, 0.65 mmol, 1M solution in THF) and THF (20 mL) to the reaction and stir for approximately 48 hours at ambient temperature. Filter the reaction mixture through diatomaceous earth and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (10% ethyl acetate/hexane to 100% ethyl acetate) to give the title compound (1.64 g, 65%): MS (m/z): 389 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:33]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2/[CH:33]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(OCc4ccccc4)cc23)cc(OC)c1OC
Yield: 2.4 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-benzyloxyindole-3-carboxaldehyde (2.51 g) except that the obtained crude crystals were recrystallized twice from acetone, to give Compound 28 (107 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([NH:38][CH2:37][CH2:36][C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)O)CC3)nc3scnc23)cc1OC
Reactant: NCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(C(=O)NCCc4ccncc4)CC3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
The mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylic acid (50 mg, 0.12 mmol), 2-(pyridin-4-yl)ethanamine (22 mg, 0.18 mmol), EDCI (69 mg, 0.36 mmol) and 1-methyl-1H-imidazole (50 mg, 0.60 mmol) in 25 mL of DCM was stirred at room temperature for 16 hours. Excess of DCM was removed under reduced pressure and the residue was washed with H2O (30 mL) and EtOAc (20 mL) dried under reduced pressure to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(pyridin-4-yl)ethyl)piperidine-4-carboxamide (30 mg, 48%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.62 (s, 1H), 8.44-8.42 (m, 2H), 7.61 (d, 1H, J=2.4 Hz), 7.31-7.18 (m, 3H), 6.95 (d, 1H, J=8.7 Hz), 4.82-4.77 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.47 (t, 2H, J=6.9 Hz), 2.95-2.92 (m, 2H), 2.86 (t, 2H, J=6.9 Hz), 2.44 (brs, 1H), 1.74-1.62 (m, 4H). LC-MS: 520 [M+H]+, 260 [M/2+H]+, 518 [M−H]−, tR=1.29 min. HPLC: 97.06% at 214 nm, 97.32% at 254 nm, tR=3.47 min.
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(C#Cc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(C#Cc2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 M aqueous HCl (10 ml) was added slowly to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-(2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (107 mg, 0.226 mmol) in 1,4-dioxane (20 mL) at room temperature. The reaction mixture was allowed to stir at room temperature overnight. After 18 hours the reaction was concentrated to low volume then redissolved in methanol (20 ml) and concentrated in vacuo to afford a light-yellow solid. Yield 71 mg, 81%. MS (APCI) m/z 389.4 (M+H), 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (none, 3H) 1.53 (s, 3H) 2.03-2.17 (m, 1H) 2.33-2.45 (m, 1H) 3.07 (s, 3H) 3.71 (td, J=11.90, 4.88 Hz, 1H) 3.96-4.14 (m, 1H) 6.35 (dd, J=6.93, 1.85 Hz, 1H) 6.56 (d, J=1.76 Hz, 1H) 7.36-7.48 (m, 3H) 7.51-7.61 (m, 2H) 7.69 (d, J=7.02 Hz, 1H) 11.05 (br. s., 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CCOc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 8-ethoxy-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-155° C.) and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C(N(CC)CC)C>CN(C)C=O.C(=O)(O)[O-]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH:13][O:14][Si:16]([CH3:19])([CH3:18])[CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCC=O)cc1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC=CO[Si](C)(C)C)cc1

Procedure:
9.61 g (50 mmol) 3-(4-Methoxycarbonylphenyl)propanal are dissolved, together with 8.3 ml (68 mmol) of trimethylchlorosilane and 18.1 ml (0.13 mol) of triethylamine, in 15 ml of absolute dimethyl formamide and the solution is heated under reflux for 2 hours under nitrogen. After cooling, the reaction mixture is diluted with a saturated bicarbonate solution and extracted with petroleum ether. The organic phase is washed 3 times with a saturated bicarbonate solution, dried with sodium sulphate and concentrated by evaporation. The residue is distilled under a high vacuum (distillation apparatus silylated). 11.06 g of a pale yellow, oily product are thus obtained in the form of a mixture of the cis- and trans-isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[C:24]4[C:19](=[C:20]([F:26])[CH:21]=[CH:22][C:23]=4[F:25])[O:18][CH2:17][CH:16]2[NH:15][CH2:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:34]CCl>>[Cl:34][C:22]1[C:23]([F:25])=[C:24]2[C:19](=[C:20]([F:26])[CH:21]=1)[O:18][CH2:17][CH:16]1[C:11]2([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: ClCCl
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCCNC1COc1c(F)ccc(F)c12
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCCNC1COc1c(F)cc(Cl)c(F)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4a-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2,3,4,4a,10,10a-hexahydro-1H-9-oxa-1-aza-phenanthrene (1.0190 g, 2.5475 mmol) was dissolved in 75 ml dichloromethane and cooled to 0° C. then triethylamine (1.1 mL) was added. The solution was stirred at 0° C. for 10 minutes then II was added slowly and the solution was stirred at 0° C. for 3 h. Then the reaction was warmed to room temperature and stirred for 1 h. The reaction was quenched with 50 ml of ice water. The organic layer washed with 50 ml of 1 N HCl solution and dried over sodium sulfate. The product was purified by column using EtOAc/Hex. as the eluent (gradient from 0/100 to 50/50 in 45 minutes). Yield: 124.0 mg, 11%. 1H NMR (CDCl3 400 MHz) δ 7.57 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.23 (dd, J=9.5, 6.6 Hz, 1H), 5.19 (dd, J=8.8, 6.6 Hz, 1H), 4.32 (d, J=11.7 Hz, 1H), 3.69 (s, 1H), 2.99 (d, J=13.1 Hz, 1H), 2.74 (td, J=13.1, 2.9 Hz, 1H), 2.64 (d, J=13.1 Hz, 1H), 2.20-2.11 (m, 1H), 1.62 (d, J=13.1 Hz, 2H), 1.19-1.06 (m, 1H).