Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:10]2=[N:11][CH:12]=1.[NH3:40]>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]4[C:23]([CH3:29])([CH3:28])[C:24](=[O:26])[NH:40][C:20]=4[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:10]2=[N:11][CH:12]=1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3c(F)ccc(F)c3F)c3ncc(F)cc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4c(F)ccc(F)c4F)c4ncc(F)cc34)nnc21
Reaction time: 8 h
Yield: 70 %

Procedure:
15 ml of phosphoryl chloride were added to 1.50 g (3.149 mmol) of the compound from Example 82A, and the mixture was stirred overnight. The reaction mixture was then taken up in 222 ml of acetonitrile and, with ice cooling, stirred into 133 ml of concentrated ammonia solution (33% in water). The reaction mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. Ethanol and water were added to the residue. A precipitate formed, which was filtered off and then washed with diethyl ether. Drying under high vacuum gave 982 mg of the title compound (70% of theory).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:15])([F:14])/[C:10](/Br)=[N:11]/[OH:12].[CH2:16]([OH:19])[C:17]#[CH:18]>C1(C)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[C:10]1[CH:18]=[C:17]([CH2:16][OH:19])[O:12][N:11]=1
Reactant: C#CCO
Reactant: O/N=C(\Br)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.3 %

Procedure:
A solution of triethylamine (5.35 ml, 38.6 mmol) in toluene (15 ml) was added dropwise over 10 minutes to a solution of (Z)-2,2,2-trifluoro-N-hydroxyacetimidoyl bromide (71) (5.35 g, 19.3 mmol) and prop-2-yn-1-ol (72) (3.25 g, 57.9 mmol, TCI_JP) in toluene (37.5 ml) and stirred for 10 hours at room temperature. The reaction was quenched with H2O (30 ml), extracted with ethyl acetate (50 ml), washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude product of (3-(trifluoromethyl)isoxazol-5-yl)methanol (73) (1.88 g, yield 47%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1I.[C:14]([Cu])#[N:15]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:14]#[N:15]
Reactant: FC(F)(F)c1cc(Cl)c(I)c(Br)c1
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cc(C(F)(F)F)cc1Br
Temperature: 100 °C

Procedure:
1-bromo-3-chloro-2-iodo-5-(trifluoromethyl)benzene (8.0 g, 20.6 mmol) and CuCN (1.9 g, 20.6 mmol) were dissolved in DMF (20 mL) and heated 100° C. After 2 h the temperature was increased to 110° C. After 3 h the reaction was cooled to room temperature, diluted with DCM, filtered, concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]4[N:27]=[C:28]([NH2:30])[S:29][C:25]=4[CH:24]=[CH:23][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]4[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=4[CH:24]=[CH:23][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Oc3cccc4sc(N)nc34)ncn2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)ncn3)cccc2s1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4-[6-(2-Amino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, (Example 200), (110 mg, 0.26 mmol) was dissolved in toluene (1.0 mL) and treated with acetic anhydride (100 μL, 1.0 mmol, Aldrich) at room temperature. The reaction mixture was stirred at 90° C. for 30 min. The resulting mixture was allowed to cool to room temperature and the solvents were removed in vacuum. The residue was purified by silica gel chromatography (gradient: 0% to 4.0% MeOH/CH2Cl2) to provide the title compound as a light-yellow foam. MS (ESI, pos. ion) m/z: 468 (M+1), 466 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:33]([CH2:34][OH:35])[CH2:32][CH2:31][C@:22]32[O:26][CH2:25][C:24]([Sn](C)(C)C)=[CH:23]3)=[CH:17][CH:16]=1.N>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:33]([CH2:34][OH:35])[CH2:32][CH2:31][C@@:22]32[O:26][CH2:25][C:24]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH:11]([CH3:13])[CH3:12])=[CH:23]3)=[CH:17][CH:16]=1
Reactant: CC(C)Oc1ccc(C#N)cc1Br
Reactant: C[Sn](C)(C)C1=C[C@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)OC1
Agent: N
Product: CC(C)Oc1ccc(C#N)cc1C1=C[C@@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)OC1

Procedure:
The title compound was prepared following the procedure described in Example 6, Step F(d) using 3-bromo-4-isopropoxybenzonitrile and (5R,6S,7S)-6-(4-fluorophenyl)-3-(trimethylstannyl)-1-oxaspiro[4.4]non-3-ene-7-methanol as substrates for the cross-coupling reaction. 400 MHz 1H NMR (CD3OD): δ 1.28 (s, 3H), 1.31 (s, 3H), 1.70 (m, 1H), 2.18 (m, 2H), 2.72 (m, 1H), 2.82 (d, 1H), 3.37 (dd, 1H), 3.55 (dd, 1H), 4.05 (dd, 1H), 4.67 (dd, 1H), 4.70 (m, 1H), 6.35 (m, 1H), 6.92 (t, 2H), 7.07 (d, 1H), 7.30 (m, 2H), 7.38 (d, 1H), 7.52 (dd, 1H); Mass spec (NH3 /CI): 408 (M+1); 425 (M+NH3).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>C(#N)C.CCOC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:8]=1)=[O:24])[CH3:21]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1cccc(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-morpholinylphenol (0.34 g; 1.9 mmol) and powdered K2CO3 (0.576 g; 4.2 mmol) in dry acetonitrile (10 mL) was added diethyl carbamylchloride (0.26 mL; 2.0 mmol) via syringe at room temperature under nitrogen atmosphere. The resulting mixture was heated to reflux for 24 hours, then allowed to cool to room temperature. The reaction was diluted with EtOAc (60 mL), washed with water (2×20 mL) and brine, then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via radial chromatography (4 mm chromatotron plate with 2:1 hexanes/EtOAc) to provide the carbamate as a clear, colorless oil (0.39 g; 74%).
Reaction SMILES: ClC1C=C2C(C)(C)C(/C=C/C(/C3C=CC=C(CCCCC([NH:59][CH2:60][CH2:61][N:62]4[C:66](=[O:67])[CH:65]=[CH:64][C:63]4=[O:68])=O)C=3)=C/C=C3/N(CCCS([O-])(=O)=O)C4C(C/3(C)C)=CC(S([O-])(=O)=O)=CC=4)=NC2=[N+](CCCS([O-])(=O)=O)C=1.[Na+:69].[Na+].[Cl:71][C:72]1[CH:73]=[C:74]2[C:88]([CH3:90])([CH3:89])/[C:87](=[CH:91]\[CH:92]=[C:93](/[C:127]3[CH:132]=[CH:131][CH:130]=[C:129]([CH2:133][CH2:134][CH2:135][CH2:136][C:137](ON4C(=O)CCC4=O)=[O:138])[CH:128]=3)\[CH:94]=[CH:95]\[C:96]3[C:104]([CH3:106])([CH3:105])[C:103]4[C:102]5[CH:107]=[C:108]([S:115]([O-:118])(=[O:117])=[O:116])[CH:109]=[C:110]([S:111]([O-:114])(=[O:113])=[O:112])[C:101]=5[CH:100]=[CH:99][C:98]=4[N+:97]=3[CH2:119][CH2:120][CH2:121][CH2:122][S:123]([O-:126])(=[O:125])=[O:124])/[N:86]=[C:75]2[N:76]([CH2:78][CH2:79][CH2:80][CH2:81][S:82]([O-:85])(=[O:84])=[O:83])[CH:77]=1.[Na+].[Na+].[Na+]>>[Cl:71][C:72]1[CH:73]=[C:74]2[C:88]([CH3:89])([CH3:90])/[C:87](=[CH:91]\[CH:92]=[C:93](/[C:127]3[CH:132]=[CH:131][CH:130]=[C:129]([CH2:133][CH2:134][CH2:135][CH2:136][C:137]([NH:59][CH2:60][CH2:61][N:62]4[C:66](=[O:67])[CH:65]=[CH:64][C:63]4=[O:68])=[O:138])[CH:128]=3)\[CH:94]=[CH:95]\[C:96]3[C:104]([CH3:105])([CH3:106])[C:103]4[C:102]5[CH:101]=[C:110]([S:111]([O-:114])(=[O:113])=[O:112])[CH:109]=[C:108]([S:115]([O-:118])(=[O:116])=[O:117])[C:107]=5[CH:100]=[CH:99][C:98]=4[N+:97]=3[CH2:119][CH2:120][CH2:121][CH2:122][S:123]([O-:126])(=[O:124])=[O:125])/[N:86]=[C:75]2[N:76]([CH2:78][CH2:79][CH2:80][CH2:81][S:82]([O-:85])(=[O:83])=[O:84])[CH:77]=1.[Na+:69].[Na+:69].[Na+:69]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)C=CC3=O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)NCCN2C(=O)C=CC2=O)c1

Procedure:
Compound 35 is prepared analogously to compound 34 (Example 45), except that compound 29 is used as a starting material.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[H-].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCN(CC)C(=O)C(C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCN(CC)C(=O)C(C)(C)Oc1ccc(-c2ccc(N3CCCCC3)cc2)cc1

Procedure:
A mixture of 39 g. of 2-methyl-2-[4-(4-bromophenyl)-phenoxy]-propionic acid diethylamide [obtainable by bromination of 2-methyl-2-(4-phenylphenoxy)-propionic acid diethylamide], 8.5 g. of piperidine, 2.4 g. of NaH, and 60 ml. of HMPA is agitated overnight at 150°. After cooling and the usual working-up operation, 2-methyl-2-[4-(4-piperidinophenyl)-phenoxy]-propionic acid diethylamide is obtained, m.p. 100°-102°.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:20]=[CH:19]2.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=[CH:35][CH:34]=1>CC(O)C.C1COCC1>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:8]3[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:4]#[C:3][CH2:2][NH:1][C:40](=[N:41][C:42]#[N:43])[O:39][C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:6]=4)[N:11]=[CH:10][N:9]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N#CN=C(NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)Oc1ccccc1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
[6-(3-Amino-prop-1-ynyl)-quinazolin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (280 mg, 0.663 mmol) is treated with diphenyl cyanocarbonimidate (163 mg, 1.031 equiv.) in a mixture of i-PrOH (12 ml) and THF (4 ml). Stir mixture overnight, then concentrate to dryness and chromatograph on silica (EtOAc/hexanes) to obtain 186.3 mg (49.6%) of pure desired product.
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1
Reactant: C[O-]
Reactant: Brc1nsc2nc3ccccc3n12
Agent: [Na+]
Solvent: CO
Product: COc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a cooled mixture of 3-bromo-1,2,4-thiadiazolo [4,5-a]benzimidazole (4.55 g, 17.9 mmole) in 50 mL of methanol, sodium methoxide (0.967 g, 17.9 mmole) was added in one portion and stirred for 4 h at room temperature. The reaction mixture was evaporated to dryness under vacuum and the residue was taken-up in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and evaporated to yield 3.64 g (94%) of 3-methoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: mp 172-175° C.; 1H NMR (CDCl3)δ 7.83 (d, 1H), 7.75 (d, 1H), 7.42 (t, 1H), 7.27 (t, 1H), 4.32 (s, 3H) ppm; 13C NMR (CDCl3)δ 163.2, 150.3, 148.1, 128.2, 124.9, 121.8, 119.2, 111.7, 57.5 ppm; IR (KBr)ν 3418, 2942, 1595, 1492, 1404, 1275, 1255, 1206, 1083, 755 cm-1. Anal. Calcd for C9H7N3OS: C, 52.67;H, 3.44; N, 20.49. Found: C, 52.28; H, 3.36; N, 20.45.
Reaction SMILES: [I:1]I.O[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[I:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(I)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Iodine (17.6 g, 69.2 mmol) was added dropwise as a solution in THF (40 mL) over 1 hour to an ice cold solution of benzyl 4-hydroxypiperidine-1-carboxylate (15.5 g, 65.9 mmol), imidazole (4.71 g, 69.2 mmol), and triphenylphosphine (18.2 g, 69.2 mmol) in THF (40 mL). This resulting red solution was stirred overnight with warming to room temperature, then cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane) to give benzyl 4-iodopiperidine-1-carboxylate as a colorless oil (9.50 g, 42% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of 0.50 g (1.32 mmol) of [1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (the preparation of which has been described in example 31) in CH2Cl2 (10 ml), were added 2 ml of TFA. The mixture was stirred 2 hours, then poured onto an aqueous solution of sat. NaHCO3 and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo, to afford 0.25 g (68%) of (4-amino-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone as a light brown solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:59])([CH3:58])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([F:35])=[CH:30][CH:29]=4)=[C:20]2[N:19]=[C:18]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[CH:17]=1>CC#N.C(Cl)Cl>[CH3:57][Si:54]([CH3:56])([CH3:55])[CH2:53][CH2:52][O:51][CH2:50][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:58])[CH3:59])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([F:35])=[CH:30][CH:29]=4)=[C:20]2[N:19]=[C:18]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[C:17]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccc(F)cc5c4)c3n2)CC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NBS (410.9 mg, 2.31 mmol) was added to a solution of 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 (1547 mg, 2.09 mmol) in CH3CN (50 mL) and CH2Cl2 (50 mL). After stirring at room temperature for 2 h, the mixture was concentrated in vacuo. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate: LCMS tR=1.88 Min (5 min run, UV254nm), Mass calculated for M+815.3, observed m/z 816.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Cc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Product: Cc1nc2c(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c4ccccc34)ccnc2[nH]c1=O

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly pink solid (56 mg, 71%).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:7]1[C:8]([O:14][CH3:15])=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1)[CH2:5][OH:6].[OH-].[K+].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:13][C:11]1[CH:12]=[C:7]([C@H:4]2[CH2:5][O:6][C:19](=[O:21])[NH:3]2)[C:8]([O:14][CH3:15])=[N:9][CH:10]=1
Reactant: COc1ncc(F)cc1[C@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ncc(F)cc1[C@H]1COC(=O)N1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
To a solution of (S)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride (897 mg, 3.46 mmol) in KOH (10 mL, 24.2 mmol, 2.42 M in water) was added THF (10 mL). The mixture was cooled to 0° C. and treated with triphosgene (1.03 g, 3.46 mmol). The mixture was allowed to warm to ambient temperature with stirring over 16 hours then partitioned between EtOAc (50 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was triturated with Et2O, filtered and dried under reduced pressure to afford (S)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (254 mg, 35% yield) as a white powder. 1H NMR (CDCl3) δ 7.98 (m, 1H), 7.44 (m, 1H), 5.61 (Br S, 1H), 5.13 (m, 1H), 4.83 (m, 1H), 4.16 (m, 1H), 3.96 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:10]=[CH:11]/[C@H:12]1[C@H:19]([OH:20])[CH2:18][C@H:17]2[C@@H:13]1[CH2:14][C:15](=[O:21])[O:16]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:10]=[CH:11]/[C@H:12]1[C@H:19]([O:20][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[CH2:18][C@H:17]2[C@@H:13]1[CH2:14][C:15](=[O:21])[O:16]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCCCCC(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)O[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCC(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of (1S,5R,6R,7R)-6-[(E)-3(RS)-t-butyldimethylsilyloxy-1-octenyl]-7-hydroxy-2-oxabicyclo-[3.3.0]octan-3-one (45) (4.69 g) in methylene chloride were added dihydropyran (5.17 g), and pyridinium p-toluenesufonate (0.77 g), and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to the silica gel column chromatography to give the title compound (46) as a mixture of the diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[C:10]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)(=[O:12])[CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-aminobenzonitrile (7.26 g) was added acetic anhydride (20 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and the separated crystals were collected by suction, washed with water and dried under reduced pressure to give 9.40 g of 4-acetamidobenzonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Cl)cc2)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of p-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(4-chlorophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 202°-204° C.