Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:12])([F:13])([F:16])([F:14])[F:15])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Acetamidophenylsulphur pentafluoride (27.0 g) was added during 5 minutes to a stirred mixture of concentrated nitric acid and concentrated sulphuric acid (1 part:2 parts by volume) at 0-5° C. After 5 minutes acetic acid (1 part) was added and stirring continued at 5° C. for 1.5 hours. The mixture was added to ice/water, extracted (ethyl acetate) and the extract washed (sodium carbonate solution), dried (magnesium sulphate) and evaporated. The residue was triturated with ether to give 4-acetamido-3-nitrophenylsulphur pentafluoride (30.0 g), m.p.135-138° C.
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)=[O:10].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH3:21][C:12]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:10])=[CH:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)CCCC1=O
Reactant: Sc1ccccc1
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Sc2ccccc2)CCCC1=O
Reaction time: 1.5 h

Procedure:
4.0 g (0.0134 mol) of 3-hydroxy-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-2-enone (compound A2-B1) are suspended in 25 ml of oxalyl chloride, and 0.1 ml of dimethylformamide is subsequently added dropwise. After the vigorous evolution of gas has ceased, the mixture is held for 1.5 hours at a bath temperature of 45° C. and subsequently concentrated, and the residue (3-chloro-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-cyclohex-2-enone) is dissolved in 60 ml of methylene chloride. Triethylamine (3.7 ml, 0.0268 mol), dimethylaminopyridine (160 mg, 1.34 mmol) and 1.5 ml (0.0147 mol) of thiophenol are added at a temperature of 0-5° C. After 20 hours at a temperature of 22° C., the reaction mixture is concentrated and purified on silica gel (hexane/ethyl acetate 5:1). Trituration in hexane gives pure 2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-3-phenylsulfanylcyclohex-2-enone in the form of white crystals of melting point 124-125° C. 1H-NMR (CDCl3): 1.99, m, 2H; 2.41, m 4H; 2.80, s, 3H; 2.60: 7.40-7.60, m, 6H; 7.80 ppm, d(J, 8.2 Hz), 1H.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C.O>[NH2:1][C:2]1[C:11]([Br:15])=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Solvent: CC#N
Solvent: O
Product: CN1Cc2c(ccc(N)c2Br)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 7-amino-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinoline from D3 (7 g) in acetonitrile (200 ml), was added N-bromo succinimide (7.21 g) portionwise over 10 min. The reaction mixture was cooled in an ice/methanol bath to prevent any large exotherm. and then stirred under argon for 45 min. The reaction was allowed to warm to 25° C., diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness in vacuo. The resultant brown solid was purified using dry flash column chromatography with ethyl acetate. Combination of appropriate fractions gave the title compound as an orange gum (3.95 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][P:5]([O-:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].[H-].[Na+].CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>C1COCC1>[CH3:33][N:32]([CH3:34])[C:30](=[O:31])[CH2:29][P:5](=[O:12])([O:6][CH2:7][C:8]([F:11])([F:9])[F:10])[O:4][CH2:3][C:2]([F:1])([F:13])[F:14]
Reactant: CN(C)C(=O)CBr
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN(C)C(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Temperature: 10 °C
Yield: 34 %

Procedure:
Bis(2,2,2 trifluoroethyl)phosphite (5.0 mmol, 0.79 mL) was added to a solution of sodium hydride (0.420 g, 0.018 mol) and HMPA (8.6 mmol, 1.5 mL) at 10° C. in THF (20 mL). Immediately after addition, 2-bromo-N,N-dimethylacetamide (3.9 mmol) was added dropwise. The reaction temperature was maintained at 10° C. for 4.5 hours. The reaction was then quenched with saturated aqueous ammonium chloride (2 mL) and standard aqueous work-up was performed. Final purification by flash column chromatography (silica gel, 80% hexane, 20% ethyl acetate) yielded the desired compound (34%) as a colorless oil. c). To a solution of potassium tert-butoxide (705 mg, 6.33 mmol) in anhydrous THF (25 mL) at 0° C., bis(2,2,2-trifluoroethyl)phosphite (1.00 mL, 6.33 mmol) was added. 2-bromo-N,N-dimethylacetamide (12.66 mmol) was then added by syringe. Upon completion of the addition step, the reaction was allowed to proceed for one hour with monitoring by TLC. The reaction was then quenched with a saturated solution of aqueous ammonium chloride (20 mL). The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic extracts were washed with water (3×20 mL) and with a saturated sodium chloride solution (1×20 mL). The solvent was removed by rotary evaporation and the crude material was further concentrated under oil pump vacuum. The final product was purified by column chromatography (silica gel, 2:1 hexanes/ethyl acetate) yielding the desired compound (41%). (ii) From bis-(2,2,2-trifluoroethyl)phosphonoacetic acid.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>N1C=CC=CC=1>[C:8]1([S:5]([N:4]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[C:3]2[CH:9]=[CH:10][C:11]([S:5]([CH3:8])(=[O:7])=[O:6])=[CH:12][C:2]=2[I:1])(=[O:7])=[O:6])[CH:11]=[CH:12][CH:2]=[CH:3][CH:9]=1
Reactant: CS(=O)(=O)Nc1ccccc1I
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 197.4 %

Procedure:
To a solution of the compound obtained in Example 8 (3) (2.20 g) in pyridine (7.4 ml), benzenesulfonyl chloride (1.57 g) was added and the mixture was stirred at 15 to 30° C. for 1 hour and at 60° C. for 1 hour. Further, to the mixture was added benzenesulfonyl chloride (1.57 g) and the mixture was stirred at 60° C. for 15 hours, and then poured into a saturated aqueous ammonium chloride solution. The precipitates were filtered off, washed with water and ether successively and dried under reduced pressure to obtain 4.22 g of the desired products as a white crystal.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].Cl.[S:24]1[C:28]([NH2:29])=[N:27][CH:26]=[N:25]1>N1C=CC=CC=1>[S:24]1[C:28]([NH:29][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:22])([F:21])[F:1])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:27][CH:26]=[N:25]1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Reactant: Nc1ncns1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 13 %

Procedure:
Prepared using general procedure 15, method A. Under an N2 atmosphere, a mixture of 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride (13.0 g, 36.5 mmol), 1,2,4-thiadiazol-5-amine hydrochloride (5.0 g, 36.5 mmol), and pyridine (10 mL) was stirred at RT for 19 h. The crude product was purified via silica gel chromatography using 5% MeOH in CH2Cl2 giving N-(1,2,4-thiadiazol-5-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide as a clear oil (2.0 g). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=421.1; tR=2.85 min.
Reaction SMILES: [CH2:1](O)[CH3:2].[CH:4]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH:4]([CH:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([O:29][CH2:1][CH3:2])=[O:28])[CH2:21][CH2:22]1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To about 50 milliliters of ethanol is added 3.63 grams (10 millimoles) of [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetic acid (prepared as described in Example V) and 200 milligrams of p-toluenesulfonic acid and the mixture refluxed for about four hours whereupon a reaction takes place with the formation in the reaction mixture of the desired ester product as confirmed by chromatographic analysis. The reaction mixture is subjected to reduced pressure to evaporate the ethanol and to obtain a product residue which is then dissolved in dichloromethane. The dichloromethane solution is first washed with aqueous bicarbonate solution, then dried over potassium carbonate and finally evaporated under reduced pressure to recover an ethyl [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetate product as residue. The ester product which may be further purified by distillation under reduced pressure has a molecular weight of 391.5.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>ClCCl>[CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:23]([O:24][CH2:25][CH:26]1[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]3[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:39])[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCC1c3ccccc3-c3ccccc31)C2
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 0.5 mmol) in dichloromethane (3 mL) and triethylamine (100 mg, 138 μL, 1.0 mmol) was treated with 9H-fluoren-9-ylmethyl carbonochloridate (128.0 mg, 0.5 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was washed with 1 N HCl, water, 50% saturated bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a solution of 3-(9H-fluoren-9-yl)methyl 8-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate in DCM (2 mL), which was used directly for the next step. LC/MS m/z 435.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2
Reactant: [H][H]
Reactant: O=c1ccc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccc2[nH]c(=O)ccc12
Yield: 100.3 %

Procedure:
4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) is hydrogenated in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon as a catalyst under normal pressure with hydrogen until the reaction is completed. The catalyst is removed by filtration through diatomaceous earth, and the reaction solution is concentrated by evaporation in a vacuum. 3.8 g of the title compound is obtained as a yellow solid.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]=[C:10]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11]1.CI>C1COCC1>[CH3:2][C:12]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:10](=[CH2:9])[CH2:11]1
Reactant: C=C1CC(C(=O)OCC)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C=C1CC(C)(C(=O)OCC)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
To a stirred solution of LDA (60 mL, 54 mmol, 1.0 M in THF (150 mL) at −78° C., was added ethyl 3-methylenecyclobutanecarboxylate (5.0 g, 35.7 mmol) and the reaction mixture was slowly allowed to warm to 0° C. and stir for 20 min. The reaction mixture was again cooled to −78° C. and MeI (8.92 mL, 143 mmol) was added and the reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl and the aqueous layer was extracted with diethyl ether (3×5 mL). The combined organic layer was washed with an aqueous solution of 1.5N HCl, brine, then dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 1% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 258A as a pale yellow liquid (3.5 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.83-4.93 (m, 2H), 4.18 (q, J=7.18 Hz, 3.12-3.24 (m, 2H), 2.41-2.55 (m, 2H), 1.45 (s, 3H), 1.23-1.36 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18]>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:19][CH2:16][CH2:17][CH3:18]
Reactant: CCCN
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Solvent: CCO
Product: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C
Yield: 87.3 %

Procedure:
A mixture of 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (2.65 g, 8.9 mmol) and propan-1-amine (5.24 ml, 63.7 mmol) in ethanol (32 ml) was divided into 3 aliquots which were each heated under microwave radiation at 120° C. for 30 min. The reaction mixtures were cooled to room temperature, filtrated and pooled before the volatiles were evaporated. Purification by flash column chromatography (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (2.14 g, 87%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 191° C. MS m/z (relative intensity, 70 eV) 275 (M+, 2), 246 (32), 73 (5), 72 (bp), 56 (11).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 100 °C

Procedure:
A solution of (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 10.0 mmol) and triethylamine (2.8 ml, 19.9 mmol) in EtOH (40 ml) was added to a microwave vial containing commercially available Cl2Pd(dppf)2-DCM (0.41 g, 0.50 mmol) and potassium vinyltrifluoroborate (2.0 g, 15 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave (3R)-6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:7]=1)([CH3:5])[CH3:4].[NH2:27][CH2:28][C:29]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:30]=1[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH2:41][CH2:42][OH:43])[N:36]=[CH:35]2>CC(N(C)C)=O>[F:48][C:46]1[CH:45]=[CH:44][C:30]([O:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH2:41][CH2:42][OH:43])[N:36]=[CH:35]3)=[C:29]([CH2:28][NH:27][C:12]([NH:11][C:9]2[N:8]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:7]=[C:6]([C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[CH:10]=2)=[O:19])[CH:47]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)CO)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2nc(C(C)(C)CO)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
2,2,2-Trichloroethyl 3-(1-hydroxy-2-methylpropan-2-yl)-1-p-tolyl-1H-pyrazol-5-ylcarbamate (0.010 g, 0.024 mmol) was added to a minimal amount of DMA, 2-(5-(2-(Aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (prepared in steps E1-E6; 0.0079 g, 0.026 mmol) and DEA (0.0084 mmol, 0.048 mmol) were added, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to remove the majority of DMA. The residue was purified by silica gel chromatography using 5% MeOH in ethyl acetate to provide 7 mg of the title compound. MS M+1 (573).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:17]([Si:14]([O:7][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5]#[CH:6])([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC(O)CC(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC(CC(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a solution of 5-methyl-hex-1-yn-3-ol (5.0 g, 0.045 mol) in dry DMF (50 mL) were added imidazole (3.64 g, 0.054 mol) and tert-butyldimethylsilyl chloride (6.06 g, 0.054 mol). The resulting mixture was stirred at RT for 2.5 h and then treated with saturated NH4Cl (25 mL) and EtOAc (250 mL). The organic layer was washed with saturated NH4Cl (50 mL), water (4×100 mL), brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford the crude product (9.84 g, 97.5%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.10 (s, 3H), 0.13 (s, 3H), 0.90-0.88 (m, 15H), 1.53-1.46 (m, 1H), 1.65-1.58 (m, 1H), 1.87-1.77 (septet, J=6.6 Hz, 1H), 2.36-2.35 (t, J=1.84 Hz, 1H), 4.39-4.37(m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:16](OC(=O)C)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8])(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc(O)c(NC(C)=O)c1
Yield: 65.7 %

Procedure:
A solution of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (10.46 g.) and acetic anhydride (5.6 g.) in dry pyridine (50 ml.) was heated on a steam bath for 1.25 hours. The reaction mixture was poured into water (500 ml.), precipitating an oil. On cooling the oil solidified. The solid was removed by filtration and washed with water. After drying, ethyl 2-(3-acetamido-4-hydroxyphenyl)propionate (8.25 g.) was obtained, m.p. 137°-141°C.
Reaction SMILES: COP([CH2:7][C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([Cl:23])=[N:11][C:10]=2[CH:9]=1)(=O)OC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=[CH:7][C:8]2[S:16][C:15]3[C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:13][C:12]([Cl:23])=[N:11][C:10]=3[CH:9]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: COP(=O)(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)OC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a suspension of (2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)phosphonic acid dimethyl ester (3.0 g, 7.94 mmol) in THF (150 mL) at −78° C. was added LiHMDS (8.8 mL, 8.80 mmol, 1M solution in THF) and the resulting mixture stirred for 30 min then warmed to r.t. before the addition of a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.51 g, 8.82 mmol) in THF (20 mL) The reaction mixture was stirred at r.t. for 16 h then quenched with H2O and MeOH and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 5-100%) affording the title compound as a yellow solid (2.14 g, 63%). LCMS (method A): RT 3.97 min [M+H]+ 423.3
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[O:30]1CCOCC1>>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:30])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: C1COCCO1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Yield: 38 %

Procedure:
To solution of compound 5 (100 mg, 0.26 mmol) and Lawesson'reagent (104 mg, 0.26 mmol) in dioxane (3 mL) was heated at 150° C. for 30 min in a microwave reactor. The mixture was cooled, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexanes:EtOAc=20:1) to give compound 7 (30 mg, 38%) as a light orange solid.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]1([CH:31](Cl)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10][NH:11][CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Cl)c1ccccc1
Reactant: NCCNC(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NCCNC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
11 g of N-diphenylmethyl-ethylenediamine, 10.1 g of triethylamine and 7.0 g of 1-phenylethyl chloride are dissolved, while stirring, in 85 ml of acetonitrile and heated under reflux for 30 hours. The solution is concentrated by evaporation under reduced pressure, 50 ml of 10% sodium hydroxide solution are added and the mixture is extracted thoroughly by shaking with diethyl ether. The ether extracts are combined, dried over sodium sulphate and concentrated by evaporation. N-diphenylmethyl-N'-(1-phenylethyl)-ethylenediamine is obtained in the form of a yellow oil which can be purified chromatographically over silica gel with methanol/ethyl acetate (1:1) as the eluant and, for characterisation, can be converted into the dihydrochloride, having a melting point of 160° C., as described in Example 4.