Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][N:5]2[N:4]=[C:3]([CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:13])=[O:24])=[CH:22][CH:21]=1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 42 and methanesulfonyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.66-11.72 (m, 1H), 8.31-8.43 (m, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.99-8.06 (m, 1H), 7.89-7.96 (m, 1H), 7.66-7.74 (bs, 1H), 7.36-7.45 (m, 4H), 4.46-4.49 (m, 2H), 3.68 (s, 2H), 2.94 (s, 3H); MS (ESI+) M/Z 421 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C@@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22])[C:16]([CH:26]3[CH2:28][CH2:27]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[CH2:5][C:6]([OH:8])=O)[CH2:3][CH2:2]1.Cl.[CH3:30][NH2:31]>>[CH:26]1([C:16]2[C:17]([O:19][C@@H:20]([CH3:25])[C:21]([F:23])([F:22])[F:24])=[CH:18][C:13]([C:11]([NH:10][C:4]([CH:1]3[CH2:2][CH2:3]3)([CH2:5][C:6]([NH:31][CH3:30])=[O:8])[CH3:9])=[O:12])=[N:14][CH:15]=2)[CH2:27][CH2:28]1
Reactant: CN
Reactant: C[C@H](Oc1cc(C(=O)NC(C)(CC(=O)O)C2CC2)ncc1C1CC1)C(F)(F)F
Agent: Cl
Product: CNC(=O)CC(C)(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-3-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]butanoic acid (example 247b) and methanamine hydrochloride as starting materials and isolated (180 mg, 83%); MS (ESI, m/z): 414.2 (M+H+).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH2:15](OC1C=CC=C2C=1C=CN2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.BrCC1CO1.[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[CH:6][N:5]2[CH2:4][CH:2]1[CH2:3][O:1]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: Oc1cccc2c1ccn2CC1CO1
Agent: BrCC1CO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(COc2cccc3c2ccn3CC2CO2)cc1

Procedure:
1-Oxiranylmethyl-4-hydroxy-indole: A mixture of 4-benzyloxyindole (223 mg, 1.0 mmol), 2-bromomethyl-oxirane (168 mg, 1.2 mmol) and 60% sodium hydride (60 mg, 1.5 mmol) in 5 mL THF was refluxed overnight. The solution was poured into NaHCO3 saturated solution (20 mL) and extracted with EtOAc. The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was removed in vacuo. The crude material was purified by column chromatography (1:4, hexane:ethyl acetate) to yield 200 mg of 4-benzyloxy-1-oxiranylmethylindole, which was hydrogenated by 5% Pd/C in 20 mL methanol under H2 (50 psi) to yield 70 mg (37%) of the title compound. 1H NMR (CDCl3): 7.10-7.03 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.56 (dd, J=0.9 Hz, J=3.3 Hz, 1H), 6.51 (dd, J=0.9 Hz, J=7.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.17-4.10 (m, 1H), 3.29-3.26 (m, 1H), 2.81-2.78 (m, 1H), 2.46-2.44 (m, 1H).
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])([O:10][C:11]2C=CC=CC=2)=[O:9])C=CC=CC=1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CO>[CH3:1][O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:33][CH:34]=1)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])([O:10][CH3:11])=[O:9]
Reactant: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (10.8 g, 19.3 mmol) in methanol (150 mL) is added potassium fluoride (11.2 g, 193 mmol) followed by 18-crown-6 (100 mg, 0.38 mmol). The solution is refluxed for 7 minutes in a preheated oil bath then stirred at room temperature for 3 hours. The volume is then reduced to 50 mL by evaporation under reduced pressure. The solution is cooled in an ice bath and treated with 2N hydrochloric acid (55 mL) and water (50 mL). The product is extracted with methylene chloride (3×70 mL). The organic layer is washed with brine then dried over sodium sulfate. The solution is filtered and concentrated in vacuo. The residue is crystallized from ether to give (S)-N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid m.p. 122°-123°, [α]D =-10.56° (c=0.86, CH3OH).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)#[CH:17]>>[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19]1)#[CH:17]
Reactant: C#CC1CCCNC1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Agent: Cl
Product: C#CC1CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 1.5 %

Procedure:
6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (10 mg, 2%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.60 g, 2.40 mmol) and 3-ethynyl piperidine HCl (0.42 g, 2.87 mmol) according to the general procedure of Example 2.
Reaction SMILES: S([O-])(=O)(=O)C.CS(O[CH2:11][C:12]([O:24][CH2:25][CH3:26])([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:13][CH2:14][CH3:15])(=O)=O.[Na].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CO>[N:28]1([CH2:11][C:12]([O:24][CH2:25][CH3:26])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:13][CH2:14][CH3:15])[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: CCCC(COS(C)(=O)=O)(OCC)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CO
Product: CCCC(Cn1cncn1)(OCC)c1ccc(Cl)cc1Cl
Temperature: 120 °C

Procedure:
The mesylate prepared in accordance with (a) is reacted with the sodium salt of 1,2,4-triazole. This is effected by dissolving 0.83 g of sodium in 30 ml of methanol, adding 2.5 g of 1,2,4-triazole and removing the solvent in vacuo. A solution of 8.55 g of the mesylate in 30 ml of dimethyl sulfoxide is added to the residual sodium salt. After being heated for 5 hours on a bath at 120° C., the mixture is cooled to room temperature and extracted with diethyl ether. The combined extracts are washed with water, dried over sodium sulfate and concentrated in vacuo. Yield of crude product 7.6 g. The crude product is purified by column chromatography (silica gel; 1:4 ethyl acetate/petroleum ether) and affords a colourless oil, which crystallises after a few days. Recrystallisation from 16 ml of petroleum ether gives 3.7 g of the end product. Melting point 67° C. 100 MHz-1H-NMR (CDCl3): δ=7.63 and 7.72 ppm (s, 2H of triazole); 7.0-7.4 ppm (m, 3H, aromatic); 4.8 ppm (m, 2H, --CH2N); 3.2-3.8 ppm (m, 2H, --OCH2 --CH3); 1.7-2.4 ppm (m, 2H, --CH2CH2CH3); 1.3 ppm (t, 3H, --OCH2CH3); 0.7-1.4 ppm (m, 5H, --CH2CH2CH3).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Br[C:19]1[CH:20]=[C:21]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27].C(=O)(O)[O-]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:26]([O:25][C:24]1[CH:19]=[CH:20][C:21]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:22][C:23]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=1)[CH3:27]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CCOc1ccc(S(N)(=O)=O)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCOc1ccc(S(N)(=O)=O)cc1-c1ccc(=O)n(C)c1
Temperature: 95 °C
Yield: 26.7 %

Procedure:
A mixture of the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl2 (10 mg, 8%) and 3-bromo-4-ethoxybenzene-1-sulfonamide (48 mg, 0.17 mmol) was suspended in 1,4-dioxane (880 μL) and saturated bicarbonate solution (aq) (220 μL). The mixture was heated to 95° C. using microwave irradiation (normal) for 60 min. The crude reaction mixture was filtered through a short plug of celite, the plug was washed with additional 1,4-dioxane (1 ml), and the combined filtrate was purified by prep-HPLC. The fractions were combined and lyophilized to give the title compound (14 mg, 27%) as a white solid. 1HNMR (DMSO, 400 MHz): δ 1.33 (t, J=6.9, 3 H), 3.49 (s, 3H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H), 7.89 (d, J=2.6 Hz, 1H). LCMS (M+H)+=309.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)=[O:7].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1OC
Reaction time: 8 h

Procedure:
1.3 g (4.33 mmol) of methyl 4-(3,4-dimethoxybenzoyl)benzoate was dissolved in 50 ml of ethanol. 7 ml of 1 N sodium hydroxide solution was added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the residue was washed with ethyl acetate and then filtered to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH3:13])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C#N)cc1[N+](=O)[O-]
Yield: 96.9 %

Procedure:
A suspension of 8.37 g of 4-hydroxy-3-nitrobenzonitrile, 27.64 g of anhydrous potassium carbonate and 6 mL of dimethyl sulphate in 60 mL of acetonitrile was stirred at reflux for 2 hours. The solvent was removed by evaporation in vacuo. The residue was taken up in 100 mL of water and extracted with 3×80 mL of chloroform. The combined organic layers were dried over sodium sulphate and the solvent was evaporated off to afford 8.8 g (98.8%) of Compound 18A as an ivory solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[N:19]([CH3:20])[C:18]4[CH:21]=[CH:22][C:23]([C@@:25]([NH2:34])([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH3:26])=[CH:24][C:17]=4[N:16]=3)=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:36][C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][CH2:14][C:15]3[N:19]([CH3:20])[C:18]4[CH:21]=[CH:22][C:23]([C@@:25]([NH:34][CH2:36][C:37]#[N:38])([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH3:26])=[CH:24][C:17]=4[N:16]=3)=[CH:11][CH:12]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(NCc3nc4cc([C@@](C)(N)C(=O)N5CCCC5)ccc4n3C)cc2)no1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(NCc3nc4cc([C@@](C)(NCC#N)C(=O)N5CCCC5)ccc4n3C)cc2)no1

Procedure:
Prepared analogously to Example 1k from (R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and bromoacetonitrile/potassium carbonate in acetone.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[C:19]2[CH3:29])(=O)=O)=CC=1>CN(C)C=O>[N:1]([CH2:16][CH2:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[C:19]1[CH3:29])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(-c3ccccc3)cc2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)cn1CCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
Sodium azide (327 mg, 5.02 mmol) was added to a solution of 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (1.19 g, 3.35 mmol) in dry dimethylformamide (10 mL) and heated to 90° C. and stirred for 1 h. The reaction mixture was allowed to cool to ambient temperature and partitioned between water (20 mL) and ethyl acetate (25 mL). After stirring for 5 min, the organic layer was separated and washed successively with water (2×30 mL), brine (2×30 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 1-(2-azidoethyl)-2-methyl-4-phenyl-pyrrole (650 mg, 86%) as a brown liquid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c3ncnc(N)c23)cc1OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 21.2 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml), 3,4-dimethoxyphenyl boronic acid (1.04 g, 5.746 mmoles) and sodium carbonate (2.03 g, 19.15 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.872 g, 0.754 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.220 g, 21% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.46 (s, 1H), 8.19 (s, 1H), 7.20 (s, 1H), 7.19 (d, J=9.3 Hz, 1H), 7.11 (d, J=8.1 Hz 1H), 3.81 (s, 6H).
Reaction SMILES: [Si]([N:5]=[N+:6]=[N-:7])(C)(C)C.[CH2:8]([CH:15]1[O:17][CH:16]1[CH2:18][OH:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[N:5]([CH:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:16]([OH:17])[CH2:18][OH:19])=[N+:6]=[N-:7]
Reactant: OCC1OC1Cc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(Cc1ccccc1)C(O)CO
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of freshly distilled Ti(OiPr)4 (9.5 mL, 32.1 mmol) and TMSN3 (8.4 mL, 64.1 mmol) was refluxed in dry benzene (20 mL) under nitrogen for 5 h until the solution became clear. To this was added a solution of the epoxy alcohol 8 (3.5 g, 21.3 mmol) in 40 mL dry benzene. The resulting mixture was heated under reflux for 15 min, cooled to room temperature and the solvent was removed in vaccuo. The concentrate was diluted with 20 mL of diethyl ether and treated with 15 mL of aq. 5% H2SO4. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography using petroleum ether:EtOAc (3:2) to give azido diol 9 (4.2 g, 96%) as a colorless solid. mp 80-81° C. (lit.10 mp 80.5-82° C.); IR: (CHCl3, cm−1): νmax 696, 753, 1039, 1106, 1242, 1554, 2105, 2923, 2960, 3280; 1H NMR (200 MHz, CDCl3): δ 1.79 (t, J=5.3 Hz, 1H), 2.47 (d, J=5.2 Hz, 1H), 2.80 (dd, J=14.2, 8.6 Hz, 1H), 3.02 (dd, J=14.1, 4.2 Hz, 1H), 3.59-3.81 (m, 4H), 7.24-7.32 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 37.0, 63.2, 65.6, 73.2, 126.9, 128.7, 129.3, 137.2; Anal. Calcd for C10H13N3O2: C, 57.96; H, 6.32; N, 20.28. Found: C, 57.85; H, 6.28; N, 20.22%.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.O.C1C(=O)N([Br:45])C(=O)C1>C(Cl)Cl.C1COCC1>[Br:45][CH2:20][C:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])[CH:18]=[CH:17]2)=[O:21]
Reactant: CC(=O)c1cccc2ccc(C(=O)N3CCOCC3)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc2ccc(C(=O)N3CCOCC3)nc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 1-(2-(morpholine-4-carbonyl)quinolin-8-yl)ethanone (0.438 g, 1.54 mmol) in DCM (5 mL) at 0° C. was added TEA (0.28 ml, 2.00 mmol) followed by TBSOTf (0.39 mL, 1.70 mmol). The resulting mixture was stirred at 0° C. for 50 min. The mixture was then partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted with DCM (3×). The combined organic layers were then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a brown oil. The resulting oil was taken up in THF (8 mL) and treated with water (0.44 mL, 24.7 mmol) and NBS (288 mg, 1.62 mmol). The resulting solution was stirred at RT for 20 min. The reaction mixture was then partitioned between water and Et2O, and the organic layer was separated and sequentially washed with saturated NaHCO3, water, and brine, then dried over MgSO4, filtered, and concentrated in vacuo to give a 2-bromo-1-(2-(morpholine-4-carbonyl)quinolin-8-yl)ethanone as a greenish-brown solid. This material was used in the subsequent step without purification, assuming the theoretical yield: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (d, J=8.6 Hz, 1H), 8.29 (dd, J=8.1, 1.3 Hz, 1H), 8.11 (dd, J=7.2, 1.4 Hz, 1H), 7.77-7.85 (m, 2H), 3.72 (s, 4H), 3.61-3.62 (m, 2H), 3.57-3.59 (m, 2H), 3.51-3.57 (m, 2H). m/z (ESI, +ve ion) 363.0/365.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([Cl:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+]>O.CN(C=O)C>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([Cl:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccc(O)c(Cl)c2oc2cccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2c(=O)c3c(Cl)cccc3oc2c1Cl
Reaction time: 6.5 h
Yield: 71 %

Procedure:
A mixture of 4,8-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.8 g), potassium carbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) was stirred at 60°-65° C. for 6.5 hours. After cooling the mixture, sodium hydroxide (4 g) and water (100 ml) were added and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from DMF gave 2.4 g of 4,8-dichloro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 270°-271° C. This compound showed a mass spectrum having a molecular ion peak at m/e 338.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:13][C:14]1[S:18][C:17]([C:19]([N:21]2[CH2:29][C:25]3([CH2:28][NH:27][CH2:26]3)[O:24][CH2:23][CH2:22]2)=[O:20])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:27]1[CH2:26][C:25]2([CH2:29][N:21]([C:19]([C:17]3[S:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[O:20])[CH2:22][CH2:23][O:24]2)[CH2:28]1
Reactant: OCCc1cccc(CBr)c1
Reactant: Cc1ccc(C(=O)N2CCOC3(CNC3)C2)s1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCOC3(CN(Cc4cccc(CCO)c4)C3)C2)s1

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.281 g) was added to a solution of (5-methylthiophen-2-yl)(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)methanone hydrochloride (example 33, step h) (0.29 g) and triethylamine (0.42 mL) in acetonitrile (15 mL) at 20° C. and the resultant mixture stirred for 3 hours at 20° C. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 3% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.32 g.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH2:6][OH:7].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH2:6][O:7][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@H](CO)OCCO
Solvent: c1ccncc1
Product: CO[C@H](COS(=O)(=O)c1ccc(C)cc1)OCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
1,5-dihydroxy-2(S)-methoxy-3-oxa-pentane (E4) (1.4 g, 10.3 mmole), prepared as described in Example 8, was dissolved in dry pyridine (10 ml) and treated at 0° C. with p-toluensulfonylchloride (6.4 g, 0.034 mole). The mixture was kept at 4° C. overnight, then was poured into an ice-water mixture and finally extracted with methylene chloride. The organic phase was washed with water, separated off, dried over anhydrous sodium sulphate, filtered off. The solvent was removed under reduced pressure. The crude material was chromatographed on a silicic acid column using methylene chloride as eluting agent to give 2.8 g (yield 62%) of pure title derivative,
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:41]=[CH:40][C:29]([O:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:28][CH:27]=1>O1CCOCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: Fc1ccc(-c2cc3c(Cl)ncnc3s2)cc1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(COc1ccc(Cl)cc1)N1CCN(c2ncnc3sc(-c4ccc(F)cc4)cc23)CC1
Temperature: 60 °C
Yield: 69.9 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (20 mg, 0.08 mmol) and triethylamine (42 μl, 0.3 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (25 mg, 0.1 mmol). The mixture was heated at 60° C. for 2 hours. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (27 mg, 75%).