Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][CH3:19])[CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].[ClH:33]>C(OCC)C.C(Cl)Cl>[ClH:33].[ClH:33].[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH:12]2[CH2:13][CH2:14][CH:15]([NH:18][CH3:19])[CH2:16][CH2:17]2)=[CH:7][C:6]=1[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(O[C@H]2CC[C@H](NC)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCC(NC)CC2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
A solution of trans-N-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-formamide in anhydrous THF at 0° C. may be treated with borane-THF complex in THF (1 M, excess). The reaction may be allowed to come to room temperature and may be monitored by LCMS until the reaction is complete. The reaction may be quenched with MeOH and the solvents may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N NH3 in MeOH) in DCM to give trans-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-methyl-amine. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt may be triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 439 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CCNCC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Temperature: 25 °C

Procedure:
3,4-Difluoronitrobenzene (1.4 mL, 2.01 g, 12.7 mmol) in piperidine (4 mL, 40.4 mmol) was heated in a sealed tube at 130° C. for 2 hours. The mixture was allowed to cool to room temperature and poured into H2O (150 mL). The title compound was separated by pipette. 1H NMR (300 MHz, DMSO-d6) δ 7.95-8.01 (m, 2H), 7.11-7.18 (m, 1H), 3.26-3.29 (m, 4H), 1.62-1.68 (m, 6H); MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([OH:23])=[C:8]([C:20](=[O:22])[CH3:21])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[C:20]([C:8]1[C:7]2[O:23][C:1](=[O:2])[NH:5][C:6]=2[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
51.1 mL (97.04 mmol) of a phosgene solution (20% by weight in toluene) are added at 0° C. to a solution of 22.7 g (88.22 mmol) of 1-(3-amino-5-benzyloxy-2-hydroxyphenyl)ethanone in toluene (200 mL). Then 30.7 mL (220.6 mmol) of triethylamine is added dropwise such that the temperature does not exceed 5° C. After 1 hour stirring at ambient temperature, a further 4.6 mL of phosgene solution and 12 mL of triethylamine are added at 0° C. The mixture is stirred for 1 hour at ambient temperature, diluted with dichloromethane and combined with saturated aqueous ammonium chloride solution (500 mL) and 2 N aqueous hydrochloric acid (10 mL). After the aqueous phase has been separated off it is exhaustively extracted with dichloromethane. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated down in vacuo, during which time a beige solid is precipitated. The precipitate is filtered off, washed with a little toluene, and dried at 50° C. in vacuo. Yield: 18.5 g (74%); Rf=0.19 (silica gel, toluene/acetone 95:10); ESI-MS: [M+H]+=284.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI.CCOC(C)=O>CN(C=O)C.CCCCCC>[CH3:15][O:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a stirred solution of 4-methyl-naphthalene-1-carboxylic acid (10 g, 53.70 mmol) in dry DMF (50 mL) was added potassium carbonate (11.14 g, 80.55 mmol) at room temperature. Resulting reaction mixture was stirred for 30 minutes at room temperature. Then reaction mixture was cooled to 0° C. and methyl iodide (11.44 g, 3.04 mL, 80.55 mmol) was added dropwise. Resulting reaction mixture was stirred for 3 hours at room temperature. Progress of reaction was monitored by TLC using 10% EtOAc in hexane. Rf of new spot and stating material was 0.7 and 0.1, respectively. After consumption of starting material, reaction mixture was quenched with ice cold water (150 mL) and extracted with EtOAc (2×150 mL). Combined organic layer was washed with water (300 mL), brine (200 mL) and dried over sodium sulphate. Organic layer was evaporated in vacuo to afford orange colored thick oil. Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 9% in EtOAc in hexane to afford colorless liquid (10.85 g, 99%). 1H NMR (400 MHz, CDCl3) δ: 2.73 (s, 3H), 3.98 (S, 3H), 7.34 (d, J=7.4 Hz, 1H), 7.54-7.63 (m, 2H), 8.04 (d, J=7.92 Hz, 1H), 8.08 (d, J=7.44 Hz, 1H), 8.95 (d, J=8.12 Hz, 1H); LC-MS (m/z): =201.10 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32]CC2C=CC=CC=2)=[C:28]([O:40]CC2C=CC=CC=2)[CH:27]=1)[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[OH:40][C:28]1[CH:27]=[C:26]([CH2:25][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[O:11])[CH:31]=[CH:30][C:29]=1[OH:32]
Reactant: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of (1R)-1-methyl-2-phenylcarbonyloxyethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (2.6 g, 4.85 mmol) in 40 mL of tetrahydrafuran was added 200 mg of 10% Pd—C pre-mixed with 10 mL of methanol under a nitrogen atmosphere. The resulting mixture was stirred under hydrogen at room temperature for 2 hrs. After filtration and washing with methanol, the filtrate was concentrated and chromatography of the residue (silica gel, 30% ethyl acetate in hexane) afforded 1.87 g (100%) of (1R)-1-Methyl-2-phenylcarbonyloxyethyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate. MS (ESI) m/z 460.20 (M+H)+ and 458.17 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(C)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(OC)c1
Yield: 97.4 %

Procedure:
A mixture of methyl 4-methyl-3-(methyloxy)benzoate (1.00 g, 5.55 mmol), N-bromosuccinimide (1.09 g, 6.10 mmol) and a catalytic amount of 2,2′-azobis(isobutyronitrile) (AIBN) was refluxed in carbon tetrachloride (40 ml) for 16 h. The reaction mixture was filtered and the solution was washed with brine (25 ml), dried over sodium sulfate and concentrated to give methyl 4-(bromomethyl)-3-(methyloxy)benzoate (1.4 g, 97% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([OH:45])=O)=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[C:55]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:60]=[CH:59][C:58]([CH2:61][CH:62]([C:64]2[S:65][CH:66]=[CH:67][N:68]=2)[NH2:63])=[CH:57][CH:56]=1>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:63][CH:62]([C:64]3[S:65][CH:66]=[CH:67][N:68]=3)[CH2:61][C:58]3[CH:57]=[CH:56][C:55]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[CH:60][CH:59]=3)=[O:45])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: NC(Cc1ccc(-c2ccccc2)cc1)c1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4ccc(-c5ccccc5)cc4)c4nccs4)ccc23)CC1
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.070 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-Dimethylformamide (1 mL) and N,N-Diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min., and the 2-biphenyl-4-yl-1-(1,3-thiazol-2-yl)ethanamine (20 mg, 0.070 mmol) was added. The reaction was stirred for 1 h. at r.t. The final product was purified by prep RP-HPLC (pH=10) to afford the desired compound (0.003 g, 20%) as an amorphous white solid. Analytical LCMS (M+H)+: m/z=550.0.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.S[C:13]1[O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](=[O:19])[CH:18]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCOC(C)=O>C1C=CC=CC=1.O>[N:24]1([C:13]2[O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[CH:18]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=c1cc(S)oc2ccccc12
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: O=c1cc(N2CCOCC2)oc2ccccc12
Yield: 44.8 %

Procedure:
Part B: Tosic acid (0.4 g, 2 mmol) is added to a solution of 2-mercapto-4H-1-benzopyran-4-one (3.56 g, 20 mmol) and morpholine (2.44 g, 2.44ml, 28 mmol) in benzene (400ml). After refluxing for 4 hours, the reaction mixture is transferred to a separatory funnel containing EtOAc and water. Extracting with EtOAc (2×), washing with combined organic layers with water and brine, and filtering through sodium sulfate yields 4.56 of crude material after evaporation of the solvent. Flash chromatography over silica gel (300 g, 2.5% MeOH/CHCl3, 50 ml fractions) yields 2.07 g of 2-(4-Morpholinyl)-4H-1-benzopyran-4-one (44.8%, fractions 22-32). Mp 160°-1° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][C:12]([C:14]1[C:23]2[C:22]3[N:24]([CH3:27])[N:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][CH:15]=1)=O)C>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12]([C:14]1[C:23]2[C:22]3[N:24]([CH3:27])[NH:25][CH2:26][C:21]=3[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][CH:15]=1)=[O:11]
Reactant: CCOC(=O)c1c[nH]c2c1-c1c(cnn1C)CCC2
Reactant: Nc1ccccc1F
Product: CN1NCC2=C1c1c(C(=O)Nc3ccccc3F)c[nH]c1CCC2

Procedure:
The title compound is prepared according to Example 9 using 2-fluoroaniline and 1-methyl-4,5,6,7-tetrahydro-1H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester. Electrospray mass spectrum: m/z 325 [M+1].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[O:2].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:11]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
4-formyl-phenol (5 g, 41 mmol), iodohexane (10.5 g, 49 mmol) and K2CO3 (8.5 g, 61 mmol) in acetonitrile (150 ml) were refluxed overnight under N2. After being cooled to room temperature, water (10 ml) was added and acetonitrile was evaporated. Water (150 ml) and Et2O (150 ml) were then added. The ethereal layer was extracted and washed with water (2×100 ml), brine (100 ml), dried over MgSO4, filtered and evaporated to dryness to afford 8.3 g (98%) of compound 1 as a slightly yellow oil after drying at 80° C. under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:14])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1CCc2cc(Br)c(F)cc2N1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(Cl)c2N1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroquinolin-2(1H)-one (122-3; 3 g, 0.0012 mol) in N,N-dimethylformamide (30 mL) was added N-chlorosuccinimide in N,N-dimethylformamide (3 mL) (1.4 g, 0.0105 mol) at 70° C. drop wise over a period of 2 h. Reaction mass was allowed to stir at 70° C. for 14 h. The reaction mixture was cooled and diluted with ice cold water. The precipitated solid was filtered and dried to obtain title compound. MS (M−1): 278.12.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.C([Si](C)(C)[O:24][CH:25]([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:26]([F:39])([F:38])[C:27]([O:30][Si](C(C)(C)C)(C)C)([CH3:29])[CH3:28])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:39][C:26]([F:38])([C:27]([CH3:28])([OH:30])[CH3:29])[CH:25]([C:40]1[S:41][C:42]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:43][CH:44]=1)[OH:24]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(O[Si](C)(C)C(C)(C)C)c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CC(Nc2nccc(-c3ccc(C(O)C(F)(F)C(C)(C)O)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-[1,3-Bis-(tert-butyl-dimethyl-silanyloxy)-2,2-difluoro-3-methyl-butyl]-thiophene (prepared from 2,2-Difluoro-3-hydroxy-3-thiophen-2-yl-propionic acid ethyl ester by treatment with MeMgBr (Step A of Method A) and TBDMS protection), followed by TBDMS cleavage with TBAF in THF.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]([O:17][CH2:18][P:19]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:12][O:13][CH2:14][O:15][CH3:16])C1C=CC=CC=1>C(O)C.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[CH:22]([O:21][P:19]([CH2:18][O:17][C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:12][O:13][CH2:14][O:15][CH3:16])([O:25][CH:26]([CH3:28])[CH3:27])=[O:20])([CH3:24])[CH3:23]
Reactant: COCOCC(CCOCc1ccccc1)OCP(=O)(OC(C)C)OC(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COCOC[C@H](CCO)OCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Palladium hydroxide on carbon (20%, 10 g) was added to a solution of 4-O-benzyl-2-O-(diisopropylphosphonomethyl)-1-O-methoxymethyl-1,2,4-butanetriol (21.9 g, 52.33 mmol) in a mixture of ethanol and cyclohexene (200 mL of each). The resulting mixture was heated at reflux for 6 hours. The mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel (methylene chloride:methanol=20:1 to 10:1) to give 16.79 g (98% yield) of the title compound as an oil.
Reaction SMILES: [OH-:1].[Na+:2].C[O:4][C:5](=[O:13])[C:6]([F:12])([F:11])[S:7](F)(=[O:9])=[O:8]>O>[C:5]([C:6]([F:12])([F:11])[S:7]([O-:1])(=[O:9])=[O:8])([OH:4])=[O:13].[Na+:2]
Reactant: [OH-]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Agent: [Na+]
Solvent: O
Product: O=C(O)C(F)(F)S(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound, triphenylsulfonium (1-pyrrolidonemethoxycarbonyl)-difluoromethanesulfonate was prepared as depicted in Scheme 1 above and as follows: Sodium hydroxide (6.400 g, 160 mmol) was placed in a 100 mL round-bottom flask fitted with a condenser and water (30 mL) was added. The suspension was stirred magnetically for 30 min, then cooled down to 0° C. with an ice-bath. Methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (9.605 g, 50 mmol) was added dropwise over 15 min. When the addition was complete, the mixture was left stirring under reflux for 18 hours. After this time, the mixture was cooled down to room temperature, filtered on a Buchner funnel to remove salts and the filtrate was acidified to pH=2 with aqueous HCl. The water was then removed under reduced pressure at 55° C. to give a colorless oil of sodium carboxydifluoromethanesulfonate. The next step was carried out assuming 100% conversion. 13C NMR (125 MHz, D2O) δ 113.69 (t), 165.53; 19F NMR (282 MHz, D2O) δ −108.83
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:36][CH2:35]2)CC2C=CC(OC)=CC=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1.[CH3:42][CH:43]1[CH2:45][O:44]1.C(O)(C(F)(F)F)=O>C(O)C.C1COCC1.ClC(Cl)C.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:42][CH:43]([OH:44])[CH3:45])[CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:34]2[CH2:36][CH2:35]2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1
Reactant: CC1CO1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: C1CCOC1
Solvent: COc1ccccc1
Solvent: CC(Cl)Cl
Product: CC(O)CN1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C(=O)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 28.9 %

Procedure:
A suspension of 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (16 mg, 0.028 mmol) and 2-methyloxirane (8.17 mg, 0.141 mmol) in Ethanol (0.8 mL) and THF (0.2 mL) in a sealed 1-dram vial was heated at 80° C. for 6 h. LC-MS indicated completion. After concentration, purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 20 mg of the PMB protected product. This was dissolved in 1 mL of dichloroethane and then 1 drop of anisole was added followed by 0.5 mL of TFA. The solution was heated at 60° C. for 1 h. LC-MS indicated completion, and then it was cooled and concentrated. The crude was dissolved in methanol and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated, purification via preparative HPLC gave the title compound as a yellow solid (4.1 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][S:11]([CH3:13])=[O:12])[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:38]=[CH:37][C:29]2[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1.[K].[OH:40]OS([O-])=O.[K+]>CO.O.C(#N)C.O>[CH3:14][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][S:11]([CH3:13])(=[O:40])=[O:12])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:38]=[CH:37][C:29]2[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1
Reactant: O=S([O-])OO
Reactant: Cc1cc(OCCS(C)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Agent: [K+]
Agent: [K]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Cc1cc(OCCS(C)(=O)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-((3S)-6-((1R)-4-(2,6-dimethyl-4-(2-(methylsulfinyl)ethoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (70 mg) in methanol (1.5 mL) and water (0.75 mL) is added potassium peroxomonoslufate (Oxone®) (150 mg). The mixture is stirred for 3 hour at room temperature and then potassium peroxomonoslufate (Oxone®) (80 mg) is added. After stirring for 12 hours at room temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100). The product thus obtained is dissolved in acetonitrile/water (1:1) and lyophilized to give the title compound. Yield: 7 mg; LC (method 4): tR=1.71 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[S:23])[NH2:13]
Reactant: NC(=O)c1ccc2ccccc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a solution of the above amide (10.0 g, 58 mmol) in dry tetrahydrofuran (250 ml) was added [2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphenate-2,4-disulfide] (Lawesson's reagent) (16.5 g, 41 mmol) and the resulting mixture was stirred at room temperature for 48 h. The volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml) and filtered through silicagel (100 ml) using ethyl acetate as eluent. The solvent was evaporated in vacuo and to the residue was added a mixture of ethyl acetate (25 ml) and heptane (25 ml). The precipitate was filtered off and washed with heptane (40 ml), dried in vacuo at 50° C. which afforded 9.0 g (83%) of naphthalene-2-carbothioic acid amide as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([OH:28])(=O)[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:38][CH2:39][C:40]1[CH:41]=[C:42]([CH2:46][N:47]2[C:55]3[C:50](=[C:51]([F:56])[CH:52]=[CH:53][CH:54]=3)[C:49]([NH:57][S:58]([C:61]3[S:62][C:63]([Cl:66])=[CH:64][CH:65]=3)(=[O:60])=[O:59])=[N:48]2)[CH:43]=[CH:44][CH:45]=1>CN(C)C=O.CO.CS(C)=O>[Cl:66][C:63]1[S:62][C:61]([S:58]([NH:57][C:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][C:51]=3[F:56])[N:47]([CH2:46][C:42]3[CH:41]=[C:40]([CH2:39][NH:38][C:25](=[O:28])[CH3:26])[CH:45]=[CH:44][CH:43]=3)[N:48]=2)(=[O:60])=[O:59])=[CH:65][CH:64]=1
Reactant: CC(=O)O
Reactant: NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(F)cccc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(F)cccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To a solution of HATU (122 mg, 0.198 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added at room temperature acetic acid (10.29 mL, 0.180 mmol) followed by N,N-diisopropylethylamine (0.094 mL, 0.539 mmol) and finally a solution of N-(1-{[3-(aminomethyl)phenyl]methyl}-4-fluoro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 39) (81 mg, 0.18 mmol) in anhydrous N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 30 min, and then partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine-water (1:1), passed through a hydrophobic frit and evaporated in-vacuo to yield a colourless oil. The residue was dissolved in MeOH-DMSO (1 mL) and purified by Mass Directed AutoPreparative HPLC MDAP (Sunfire C18 column 150 mm×30 mm i.d. 5 μm packing diameter at ambient temperature) eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) over 25 min. The appropriate fraction was evaporated in-vacuo to yield a colourless oil (5.9 mg, 6%). LCMS (System B): RT=2.53 min, ES+ve m/z 493/495 (M+H)+.