Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:38]2[CH:39]=[C:40]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[CH:49][N:48]=3)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:34])([CH3:35])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCOCC3)cn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCOCC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Yield: 53 %

Procedure:
Following Example 148b, starting with 400 mg of (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b and 284 mg 5-bromo-1-methyl-3-(5-morpholinopyridin-2-ylamino)pyridin-2(1H)-one 255c, 277 mg of 256a was obtained as a yellow solid (53%). MS: [M+H]+ 672
Reaction SMILES: C(N(CC)CC)C.[CH:8](Br)=[CH2:9].[CH2:11]([CH:16]1[CH2:20][CH2:19][C:18](=[CH:21][N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]1=[O:30])[CH2:12][CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>[CH2:11]([C:16]1([CH:8]=[CH2:9])[CH2:20][CH2:19][C:18](=[CH:21][N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]1=[O:30])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: C=CBr
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccc2ccccc2c1-c1c(P(C2CCCCC2)C2CCCCC2)ccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC1(CCCCC)CCC(=CN(C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 90.1 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was purged with argon. The septum was removed, and the tube was charged with tris(dibenzylideneacetone) dipalladium (0) (11.4 mg, 0.013 mmol, 5 mol % Pd) and (+)-2-(dicyclohexylphosphino)2′-(dimethylamino)-1,1′-binaphthyl (13.6 mg, 0.028 mmol 6 mol %). The tube was capped with the septum, purged with argon, and toluene (2 mL) and triethylamine (5 mg, 0.05 mmol) were added through the septum. The mixture was stirred at room temperature for 3 min, then vinyl bromide (1.0 mL 1.0 mmol) was added through septum. The septum was removed and 2-pentyl-5-(N-methyl-anilinomethylene)cyclopentanone (136 mg, 0.5 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added. The tube was capped with the septum and purged with argon. Additional toluene (4 mL) was added and the mixture was stirred at room temperature for 18 h. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), diluted with ether (20 mL) and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 134 mg (90%) of the title compound. The ee was determined to be 80% by chiral HPLC analysis.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][C:7]12[CH2:14][CH2:13][C:10]([C:15]3[NH:23][C:22]4[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=4[N:16]=3)([CH2:11][CH2:12]1)[CH2:9][CH2:8]2.[Li+].[OH-]>C1COCC1>[O:28]=[C:19]1[N:18]([CH2:29][CH2:30][CH3:31])[C:17]2[N:16]=[C:15]([C:10]34[CH2:13][CH2:14][C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])([CH2:12][CH2:11]3)[CH2:8][CH2:9]4)[NH:23][C:22]=2[C:21](=[O:24])[N:20]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCCC(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A solution of 4-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-butyric acid methyl ester (45 mg, 100 μmol) in THF (4 ml) was treated with 1 M LiOH (2 ml) and the resulting turbid solution was stirred at rt overnight. The solution was concentrated in vacuo diluted with water (2 ml) and acidified by the dropwise addition of concentrated HCl. The resulting precipitate was collected, washed with water and dried to afford a white powder (35 mg, 81%). MS: 431 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:37])([F:36])[CH2:16][O:17][C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1>>[F:37][C:15]([F:14])([F:36])[CH2:16][O:17][C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1
Reactant: O=C([O-])c1ccc(-c2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1

Procedure:
Compound 463 was prepared from 4-morpholinoaniline and 4-(5-(2,2,2-trifluoroethoxy)-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C26H23F3N4O3: 497.17; found: 496.97.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:9]([CH3:22])[N:8]=1.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([C:14]2[CH:19]=[C:18]([N+:1]([O-:4])=[O:2])[C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:9]([CH3:22])[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.9 %

Procedure:
Finely ground potassium nitrate (6.5 g 64 mmol) was added to a solution of 2,4-diamino-5-(2,4-dichlorophenyl)-6-methyl pyrimidine (17.23 g, 64 mmol) in concentrated sulphuric acid (150 ml). This mixture was stirred at room temperature for 90 minutes. The reaction mixture was then added to sodium bicarbonate and ice. The product was extracted with ethyl acetate. After the ethyl acetate was removed, a yellow solid was obtained (30.86 g). A portion of this crude product (7.0 g) was passed through a silica flash chromatography column and eluted with ethyl acetate to give the pure product (4.81 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[C:4](Cl)[N:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)c2ncn(OCC(O)CO)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ncc2ncn(OCC(O)CO)c2n1

Procedure:
A mixture of 2-amino-6-chloro-9-(2,3-dihydroxyprop-1-oxy)purine (150 mg, 0.58 mmol), ammonium formate (146 mg, 2.32 mmol) and 10% palladium-on-charcoal (15 mg) in methanol (5 ml) was stirred under reflux for 4 hours. The reaction was evaporated under reduced pressure and the residue was dissolved in water and passed through a SEP-PAK C18 cartridge for decolourisation. After elution with water, the water was evaporated under reduced pressure and the residue recrystallised from ethanol affording the title compound (58 mg, 45%), m.p. 183°-185° C. UV: λmax (H2O) 221 (ε25,600), 305 (ε7,000) nm; IR: υmax (KBr) 3670, 3420, 3310, 3200, 1650, 1620, 1570, 1520, 1480, 1425 cm-1 ; 1H NMR: δH (CD3)2SO] 3.41 (2H, m, CH2OH), 3.76 (1H, m, CHOH), 4.18 (1H, dd, J=7.6, 10.7 Hz, CH2ON), 4.39 (1H, dd, J=3.2, 10.7 Hz, CH2ON), 4.72 (1H, t, J=5.6 Hz, OH), 5.15 (1H, d, J=5.2 Hz, OH), 6.72 (2H, br.s, NH2), 8.27 (1H, s, H-8), 8.59 (1H, s, H-6). Found: C, 42.17; H, 4.91; N, 31.07%, M+ 225.0865. C8H11N5O3 requires C, 42.67; H, 4.92; N, 31.10%, M+ 225.0862.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:36](O)=[O:37])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:36]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[CH:35]=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:37])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: N[C@@H](CCO)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Br)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
(S)-3-Amino-3-(4-bromophenyl)propan-1-ol (Intermediate 51) (191 mg, 0.83 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (300 mg, 0.83 mmol) and DIPEA (0.435 mL, 2.49 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (347 mg, 0.91 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(1-(4-bromophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (212 mg, 44.5%) as a white solid. The product (212 mg, 0.36 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.577 mL, 16.6 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-bromophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (51.0 mg, 13.0%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[O:25][C:26]=1[CH3:27].S1C=CC=C1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Agent: O=C([O-])[O-]
Agent: O=Cc1cccs1
Agent: [I-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(Cc1ccc(OCc2nc(-c3cccs3)oc2C)c2ccoc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 120 f], 2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (example 120 e]) was reacted with 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole (prepared from thiophen-2-carbaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid as white solid.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].Cl.[C:30](=[NH:35])(OCC)[CH3:31].C(N(CC)CC)C.Cl>C1COCC1.CN(C=O)C.O>[NH:35]=[C:30]([NH:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([C:18]2[CH:17]=[N:16][N:13]3[CH:14]=[CH:15][C:10]([N:5]4[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]4=[O:9])=[N:11][C:12]=23)=[CH:20][CH:21]=1)[CH3:31]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NN)cc3)c2n1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=N)NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4C(C)C)nc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a stirred suspension of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (Example 9, Step 2; 95 mg, 0.25 mmol) in a mixture of THF (2 mL) and DMF (1 mL) at ambient temperature was added ethyl acetimidate HCl salt (37 mg, 0.30 mmol) and triethylamine (45 μL, 0.32 mmol). The reaction mixture was stirred at 0° C. for 2 hours followed by stirring at ambient temperature for 17 hours. The mixture was poured into water, neutralized with dilute aqueous HCl, extracted with EtOAc, dried over MgSO4, and concentrated to afford 40 mg (38%) of (S)—N′-(1-imino ethyl)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide which was triturated with dichloromethane. LCMS (APCI+) m/z 422.1 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C(O)C.N1CCCCC1>[C:15]([C:14]([C:13]#[N:17])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)#[N:16]
Reactant: N#CCC#N
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc(C=C(C#N)C#N)cc1

Procedure:
32.6 g (0.2 mol) of 4-acetaminobenzaldehyde and 13.74 g (0.208 mol) of malononitrile are initially charged in 140 ml of ethanol, and 24 drops of piperidine are added. The mixture is stirred at reflux for 30 min. After cooling, the crystals are filtered off with suction and dried.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[NH:57][C:56]([NH2:59])=[N:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49].C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(C(C)C)C(C)C.O>[NH:44]1[CH:45]=[CH:46][N:42]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH:59][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:14]=3)=[O:17])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]
Reactant: O=C(O)c1cccc(C#Cc2ccccc2)n1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cccc(C#Cc2ccccc2)n1
Temperature: 25 °C
Yield: 43 %

Procedure:
0.05 (0.23 mmol) of the above synthesized 6-Phenylethynyl-pyridine-2-carboxylic acid, 0.095 g (0.25 mmol) of HBTU in a mixture of 2.0 ml of DMF and 0.20 mL of DIEA was reacted with 0.05 g (0.20 mmol) of 2-Amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) as described in general procedure A. The reaction mixture was cooled to r.t. 5.0 mL of water and 5.0 mL of saturated NaHCO3 was added, and the resulting solid was filtered. The solid was washed with water and ether and dried to provide 0.04 g (43%) of 2-[(6-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. 1H-NMR (400 MHz, DMSO): 8.3 (d, 1H), 8.21 (t, 1H), 8.12 (bs, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.72 (m, 2H), 7.50 (m, 4H), 7.40 (s, 2H) ppm; LCMS: 448 (M+1)+.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[N+:9]([C:12]1[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH3:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23].O.Cl>O1CCCC1>[N+:9]([C:12]1[O:16][C:15]([CH:17]=[C:21]([C:20](=[O:25])[CH3:19])[C:22](=[O:24])[CH3:23])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])o1)C(C)=O
Reaction time: 1 h

Procedure:
A solution containing 2.43 g of 5-nitro-2-furanecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione and 0.1 g of water in 5 ml of tetrahydrofurane was saturated with hydrogen chloride gas at 20° C. The mixture was stirred for 1 h and evaporated to dryness in vacuo. The product was recrystallized from acetic acid. Yield 0.1 g, mp 117°-120° C.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:3]=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)[CH3:4]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(C)(C)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 4-(2-(2-hydroxypropan-2-yl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 0.543 mmol) in DCM (5 mL) was added TFA (0.4 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material (47% by LCMS) that was purified by prep HPLC to obtain 4-(2-(prop-1-en-2-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a white solid (45 mg, 20.0%). MS (ESI, positive ion) m/z; 414.1 (M+1). 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.50-7.26 (m, 4H), 7.21 (d, J=4.6 Hz, 1H), 7.16-6.94 (m, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.23 (d, J=8.4 Hz, 1H), 5.10 (s, 1H), 4.96 (s, 1H), 4.41-4.08 (m, 2H), 3.52 (d, J=11.7 Hz, 2H), 1.96 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=1
Reactant: Cc1ccccc1-c1nsc(S)n1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1-c1nsc(SN)n1

Procedure:
A solution of 56 g of 5-mercapto-3-(2-methylphenyl)-1,2,4-thiadiazole in 870 ml of 5% sodium hydroxide and 130 ml of water and a solution of 280 ml of 10% NaOCl diluted to 1000 ml with water were added dropwise to 2260 ml of an ammonium hydroxide solution while the mixture was stirred and maintained at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 more minutes and the solids were collected, washed with water and dried under high vacuum (P2O5) to give 43 g of solid, m.p. 110°-112° C.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[S:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]=[C:19]=[O:20].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH3:17][NH:18][C:19]([N:14]1[C:15](=[S:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:20]
Reactant: CN=C=O
Reactant: S=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CNC(=O)N1C(=S)C2(CCCCC2)NC12CCCCC2

Procedure:
4.8 Parts of 7,14-diazadispiro[5.1.5.2]pentadecane-15-thione, 2.28 parts of methyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 4 days. A further 2.28 parts of methyl isocyanate were added and the solution again heated at reflux for 16 hours. The solvent was then evaporated in vacuo and the residue was crystallised twice from ethyl acetate to give 14-methylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecane-15-thione as a colourless solid of melting point 127° to 129°C. This material gave the following elemental analysis by weight:
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH2:17]>>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[CH3:6]
Reactant: NCc1ccccn1
Reactant: CCOC(CBr)OCC
Product: CCOC(CNCc1ccccn1)OCC
Yield: 65.9 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2-bromo-1,1-diethoxyethane (34.6 ml, 230 mmol) was reacted with 2-picolylamine (50 g, 460 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:ethanol=10:1) to obtain the title compound (34.0 g, 65%)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C.ClCCl>[Si:16]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)C1CC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Yield: 50 %

Procedure:
Into a solution of 3-hydroxy-N-methoxy-N-methylcyclobutanecarboxamide (0.6 g, 0.004 mol in DMF (10 mL) was added tert-butylchlorodiphenylsilane (3 mL, 0.01 mol), followed by 1H-imidazole (1 g, 0.02 mol). The mixture was stirred at rt over night. The reaction was diluted with dichloromethane and washed with sat. NaHCO3, water and brine. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-30% EtOAc/Hex) to give the desired product (0.7 g, 50%) as cis- and trans-isomer mixtures. LCMS calculated for C23H32NO3Si(M+H)+: 398.2. Found: 398.1.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Reactant: C1CCNC1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CN4CCCC4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with pyrrolidine. 1H-NMR (DMSO-D6) δ: d 1.74 (m, 4H, CH2), 2.58 (m, 4H, CH2), 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.20 (s, 2H, CH2), 7.04 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.55 (d, 2H, J=8.8 Hz, Ph-H), 7.66 (d, 2H, J=8.8 Hz, Ph-H), 8.48 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.55 (s, 1H, NH), 9.58 (s, 1H, NH). MS (ESI+) m/z 406.97 [M+H]+ (C21H24N6OS requires 408.52).