Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[CH:7][C:6]=1[F:13].[C:14](=[O:17])(O)[O-:15].[Na+].C(O)(=O)C>O.S(=O)(=O)(O)O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:14]([OH:15])=[O:17])=[CH:7][C:6]=1[F:13]
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCCBr)c(F)c1
Yield: 65 %

Procedure:
4-(2-Bromoethoxy)-3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL) and concentrated sulfuric acid (18 mL) was heated at 110° C. for 12 hours. The solution was then cooled to room temperature and neutralized with solid sodium bicarbonate. Acidification with glacial acetic acid gave a white solid precipitate, which was collected by filtration and dissolved in dichloromethane. The resultant solution was dried over sodium sulfate. The dichloromethane solution was then filtered and evaporated to give the product as a beige-colored solid (2.65 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.69 (d, J=12.0 Hz, 1H), 7.29 (dd, J=8.8 Hz, 8.4 Hz, 1H), 4.48 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[N:9][NH:8][C:7]=12.[CH3:12][Al](C)C.[NH4+].[Cl-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:4]1[CH:5]=[C:6]2[CH:10]=[N:9][NH:8][C:7]2=[C:2]([CH3:12])[N:3]=1
Reactant: C[Al](C)C
Reactant: Cc1cc2cn[nH]c2c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cn[nH]c2c(C)n1
Temperature: 65 °C
Reaction time: 60 h

Procedure:
To a vigorously stirred solution of 7-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine (3.65 g, 14.6 mmol) and Pd(PPh3)4 (845 mg, 0.73 mmol) in THF (65 mL) was added trimethylaluminum (14.6 mL, 29.3 mmol; 2 M sol. in toluene) under argon. The reaction mixture was stirred at 65° C. for 60 h, and then was cooled to RT and poured into a sat. aq. NH4Cl solution. The resulting suspension was filtered, the solid was washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3×). The combined organics were washed with brine, then dried (Phase separator) and concentrated under reduced pressure to give 5,7-dimethyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 148 [M+H]+, tR (HPLC conditions k): 0.50 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])[CH2:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
1-(3-Bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 14, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (13.0 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: [C:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].N12CCCN=C1CCCCC2>C(O)C.C1C=CC=CC=1.[Pd]>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:11][C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:12])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C(O)C1=CCc2ccccc21
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Pd]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CCc2ccccc21
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 3H-Indene-1-carboxylic acid (2.0 g, 13.3 mmol) in ethanol (35 mL) was added 10% Pd/C (200 mg). The reaction mixture was stirred under an H2 atmosphere for 1 h. The mixture was filtered through Celite and concentrated in vacuo. The residue was combined with p-nitrobenzyl bromide (5.8 g, 26.8 mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.4 mL, 16.0 mmol) in 65 mL of benzene, and was stirred at 50° C. for 20 hours. After this period the heterogeneous mixture was gravity filtered and the filtrate was evaporated in vacuo. The residue was combined with CH2Cl2 and was washed with 1N HCl (2×25 mL) and sat'd NaHCO3 (2×25 mL), and the resulting CH2Cl2 solution was dried over anhydrous Na2SO4. The crude solid was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield 3.61 g (95%) of the intermediate.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[C:16]2[CH:17]=[N:18][C:19]([NH:21][C:22]([NH:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:23])=[CH:20][C:15]=2[N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:13]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[C:16]2[CH:17]=[N:18][C:19]([NH:21][C:22]([NH:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:23])=[CH:20][C:15]=2[NH:14][N:13]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N1C(=O)c3ccccc3C1=O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(3-(1,3-Dioxoisoindolin-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (229 mg, 0.342 mmol) was dissolved in DCM (2 mL), charged with TFA (660 μL, 8.56 mmol) and triethylsilane (54.7 μL, 0.342 mmol), and stirred at room temperature for 30 min. The solvents were concentrated in vacuo and the residue was treated with triethylamine (1 mL). Purification via flash chromotagraphy (10-100% EtOAc/DCM) afforded (R)-1-(3-(1,3-dioxoisoindolin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C23H18N6O3 [M+1]+ 427. found 427.
Reaction SMILES: COC(C1CC2C(=CC=CC=2)C1)=O.[F:14][C:15]([F:33])([F:32])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:30][CH:29]3[NH:31][CH:25]([CH2:26][CH2:27][CH2:28]3)[CH2:24]2)=[CH:19][CH:18]=1.[CH3:34][O:35][C:36]([CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][C:44]=2[S:47](Cl)(=[O:49])=[O:48])[CH2:39]1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:34][O:35][C:36]([CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][C:44]=2[S:47]([N:31]2[CH:29]3[CH2:28][CH2:27][CH2:26][CH:25]2[CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:32])[F:33])=[CH:18][CH:19]=2)[CH2:30]3)(=[O:49])=[O:48])[CH2:39]1)=[O:37]
Reactant: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Agent: COC(=O)C1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 50 °C

Procedure:
4-|3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo|3.3.1|nonane-9-sulfonyl|-indan-2-carboxylic acid methyl ester: A mixture of 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane (60 mg, 0.21 mmol), 4-chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (120 mg, 0.44 mmol), potassium carbonate (200 mg, 1.4 mmol), and acetonitrile (3 mL) were heated at 50° C. for 2 h. The mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (9:1→4:1; hexanes:ethyl acetate) to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester: MS (ESI): 525.5 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:14]1([C:12]2[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([CH:27]=[CH2:26])=[CH:29][CH:30]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2cccc(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)c2)cc1

Procedure:
1.16 g (0.003 mol) of 2-(3-bromophenyl)-4,6-diphenyl-1,3,5-triazine, 0.74 g (0.005 mol) of 4-styreneboronic acid and 0.023 g (0.02 mmol) of tetrakispalladium phosphate are stirred under reflux for 24 h in 45 ml of THF and 30 ml of 1M sodium carbonate solution.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH3:22])[N:15]=1.C(Cl)(Cl)Cl>CS(C)=O.CCCCCC>[Cl:21][C:18]1[CH:17]=[C:16]([CH3:22])[N:15]=[C:14]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:19]=1[CH3:20]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cc1cc(Cl)c(C)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
A solution of 2,4,6-trimethylphenol (450 mg, 3.31 mmol) in 2 ml of DMSO was treated with NaH (60% in oil, 180 mg, 4.5 mmol). After 5min, 2,4-Dichloro-3,6-dimethyl-pyridine (528 mg, 3 mmol) was added. The mixture was heated in the oil bath of 130° C. for 6 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give 812.5 mg of crude material with two regioisomers. After silica gel column chromatography using 1:1 of CHCl3 :hexane as eluent, the title compound was isolated as white crystals (141 mg), mp 57-62° C.; high MS for C16H18CINO: calc, 275.1072, found 275.70172; IR(KBr) 2951, 2920,1592, 1564 cm-1; 1H NMR (CDCl3) δ6.87 (s, 2H), 6.77 (s, 1H), 2.39 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 2.03 (s, 6H) ppm. The regiochemistry was determined by X-ray structural analysis of the undesired regioisomer, 2-chloro-3,6-dimethyl-4-(2,4,6-trimethyl-phenyoxy)-pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(=O)O)cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(O)c1

Procedure:
The stirred solution of 2-(3-Hydroxy-4-methoxyphenyl)acetic acid (9.82 g, 53.90 mmol) and p-Toluenesulfonic acid monohydrate (1.15 g, 6.0 mmol) in abs ethanol (100 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[C:1]([N:39]1[CH2:38][CH2:37][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40]1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrous dichloromethane (130 mL) was added triethylamine (8.33 g, 82.5 mmol), 1-hydroxybenzotriazole (10.125 g, 75 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.25 g, 75 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C., and tert-butyl piperazine-1-carboxylate (13.97 g, 75 mmol) was added portion-wise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate (150 mL×2), 10% citric acid (150 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-isobutyrylpiperazine-1-carboxylate (15 g, yield 78%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.13-1.14 (d, J=6.8 Hz, 6H), 1.47 (s, 9H), 2.75-2.82 (m, 1H), 3.43-3.58 (m, 4H); LC-MS (ESI) m/z: 257(M+1)+.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(O)(=O)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCS
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 184.6 %

Procedure:
(a) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0g) and cysteamine hydrochloride (23.0g.) in acetic acid (200 ml.)was heated under reflux for 10 hours. Following cooling to 15°-20°, the solid which crystallised was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (45.5g), m.p. 189°-192°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][N:16]2[CH2:34][CH2:33][C:19]3([O:24][CH2:23][CH2:22][N:21]([C:25]([C:27]4[N:28]=[C:29]([CH3:32])[S:30][CH:31]=4)=[O:26])[CH2:20]3)[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:32][C:29]1[S:30][CH:31]=[C:27]([C:25]([N:21]2[CH2:20][C:19]3([CH2:33][CH2:34][N:16]([CH2:15][C:14]4[CH:13]=[CH:12][C:11]([CH2:10][CH:9]=[O:8])=[CH:36][CH:35]=4)[CH2:17][CH2:18]3)[O:24][CH2:23][CH2:22]2)=[O:26])[N:28]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4ccc(CCO)cc4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4ccc(CC=O)cc4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
TFA (0.030 mL) was added to a solution of (9-(4-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 16, step b) (0.16 g) in DCM (5 mL) at 0° C. and the resulting mixture stirred for 5 min. Dess-Martin periodinane (0.245 g) was added and the mixture allowed to warm to room temperature and stirred for 45 min. A mixture of saturated sodium thiosulphate solution (5 mL), saturated sodium bicabonate solution (5 mL) and ethyl acetate (20 mL) was then added and the resulting mixture stirred for 10 min. The aqueous phase was separated and extracted with ethyl acetate (20 mL). The combined organic solutions were washed with brine. AcOH (0.1 mL) was then added and the mixture dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a clear oil which was used immediately. Yield 0.16 g.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][NH:10]3)=[CH:4][C:3]=1[O:16][CH3:17].[Cl:18][C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21][N:22]([CH2:25][C:26](O)=[O:27])[C:23]=1[CH3:24].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][N:10]3[C:26](=[O:27])[CH2:25][N:22]2[C:23]([CH3:24])=[C:19]([Cl:18])[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(CN2CC3CC2CN3)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CC3CC2CN3C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-Chloro-3-methoxybenzyl)-2,5-diazabicyclo[2.2.1]heptane (96 mg), (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)acetic acid (96.8 mg), triethylamine (0.252 mL) in DMF (2 mL) was stirring at room temperature and a solution of T3P (50% in EtOAc, 0.55 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 h and purified on preparative HPLC to afford 1-[5-(4-Chloro-3-methoxybenzyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(4-chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)ethanone as white powder. LCMS (ES) M+H 477.0, Rf 3.975 min (acetonitrile/H2O 20-95% method).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH:1]([O:4][CH2:5][CH2:6][O:7][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
In a round bottom flask was placed 2-isopropoxy-ethanol (700 mg, 6.72 mmol) dissolved in methylene chloride (15 mL) and cooled to 0° C. in an ice bath. To this solution was added triethylamine (1.2 mL, 8.7 mmol) and para-toluenesulfonyl chloride (1.54 g, 8.06 mmol). The resulting solution was then slowly allowed to warm to 25° C. and was stirred for 16 h. After this time, the reaction was transferred to a separatory funnel and washed with water (15 mL). The aqueous layer was then extracted with methylene chloride (2×20 mL). The organic layers were combined and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 25% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid 2-isopropoxy-ethyl ester (1.41 g, 81%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43]>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[NH:34]/[C:3](=[N:2]\[OH:1])/[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)COC(=O)Cl
Reactant: N=C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)NO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)COC(=O)N/C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)=N\O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-Hydroxy-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamidine (0.13 g, 0.28 mmol, 1.0 equiv) in 2 Ml DMF was added pyridine (0.023 Ml, 0.31 mmol, 1:1 equiv). The solution was cooled to 0° C., then isobutyl chloroformate (0.04 Ml, 0.31 mmol, 1.1 equiv) was added dropwise via syringe. The reaction was allowed to warm to room temperature and stirred for 2 h. Extractive aqueous workup afforded the title compound which was used in the next step without further purification. (M+H)+571.4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:14]([Cl:37])=[C:15]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH:29]4[CH2:31][CH2:30]4)[C:25]4=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:24]4[N:23]=3)[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=2)[CH2:9][C@H:8]1[O:38][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:37][C:14]1[C:15]([NH:21][C:22]2[N:27]=[C:26]([NH:28][CH:29]3[CH2:30][CH2:31]3)[C:25]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:24]3[N:23]=2)=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][C@@H:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C@H:8]([O:38][Si:39]([CH:43]([CH3:45])[CH3:44])([CH:46]([CH3:48])[CH3:47])[CH:40]([CH3:41])[CH3:42])[CH2:9]1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1NS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Methanesulfonyl chloride (7.5 μl, 0.10 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg, 0.040 mmol) and triethylamine (17 μl, 0.120 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 0-40% ethyl acetate/dichloromethane). N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)methanesulfonamide (28 mg) was obtained as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[C:8]1([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[N:26])[CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[NH2:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][CH:18]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:19][CH2:20]1
Reactant: N#CCN1CCC(c2cccc3ccccc23)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCCN1CCC(c2cccc3ccccc23)CC1
Reaction time: 1 h

Procedure:
1.75 g of lithium aluminum hydride are added in fractions under a stream of nitrogen to a solution of 4.4 g of the compound from Example 4 in 150 ml of tetrahydrofuran. After stirring for 1 hour, the mixture is hydrolyzed with 1.75 ml of water, 3.5 ml of a 10% (wt/wt) sodium hydroxide solution and 7 ml of water. Filtration through celite, followed by evaporation of the solvent, yields an oily product which is used as it is in the following stage.