Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30].[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:30][CH2:29][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: NCc1cccs1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNCc2cccs2)cc1
Yield: 70.4 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-((thiophen-2-ylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.100 g; 0.288 mmol), thiophen-2-ylmethanamine (0.138 mL; 1.30 mmol) and sodium iodide (0.218 g; 1.44 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.086 g (71%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:30]#[N:31])[CH:37]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(C#N)c3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Reaction time: 25 h
Yield: 95.2 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 350 mg) in acetonitrile (7 mL) under nitrogen was treated with 3-cyanophenylboronic acid (99 mg) followed by aqueous sodium carbonate (2M, 0.677 mL). Nitrogen was bubbled through and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg) was added. The mixture was stirred at 85° C. for 25 h. The solvent was partially evaporated and the solution was purified by chromatography on silica using 50% ethyl acetate in isohexane and then ethyl acetate as eluent to afford the sub-titled compound as a solid (316 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[CH:26]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=1)[CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>CN(C=O)C>[CH3:50][O:49][C:47]([C:44]1[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][CH:26](/[CH:25]=[CH:24]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[CH:46][CH:45]=1)=[O:48]
Reactant: O=C1CCCN1CCCCl
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
119 mg (0.74 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No. 91152-30-6] and 240 mg (0.74 mmol) of anhydrous cesium carbonate are added to a solution of 169 mg (0.37 mmol) of methyl 4-[(4E)-5-(2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoate in 2.5 ml of dry DMF, and the mixture is then stirred at 60° C. for 12 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The residue is purified by preparative HPLC. This gives 169 mg (purity 94%, 0.27 mmol, 74% of theory) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)(O)[O-].[Na+].[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)(Cl)Cl>[Br:19][CH2:20][C:21]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:22]
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1cc(OC(F)(F)F)ccc1O
Temperature: 0 °C
Yield: 87.1 %

Procedure:
2-amino-4-[(trifluoromethyl)oxy]phenol (3.0 g, 15.5 mmol) was dissolved in 100 mL of chloroform. 54 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (2.1 mL, 23.3 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 2 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.77 min and m/e 314 [M+1+. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic phases were dried over Na2SO4, filtered and concentrated to give 2-bromo-N-{2-hydroxy-5-[(trifluoromethyl)oxy]phenyl}acetamide (4.23 g, 13.5 mmol, 87%) as a brown amorphous solid. MS (ES) m/e 314 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29]C1C=CC(C2CCC3C(=CC=C(OC4N=CC(N)=CC=4)C=3)O2)=CC=1>C(OCC)(=O)C.CCCCCCC>[F:29][C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)=[CH:2][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1

Procedure:
N-{6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl] methane sulfonamide in Example 46 starting from 442 mg of 6-[2-(4-fluorophenyl)-chroman-6-yloxy]-pyridin-3-ylamine (Example 76). The product was passed through silica gel using ethyl acetate-heptane (10:3) as an eluant and then crystallised from diethyl ether. 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, 1H, J 2.8 Hz), 7.72 (dd, 1H, J 8.9, 2.8 Hz), 7.40 (m, 2H), 7.08 (m, 2H), 6.92-6.87 (m, 4H), 6.74 (s, 1H), 5.03 (dd, 1H, J 10.4, 2.3 Hz), 3.01 (m, 1H), 3.00 (s, 3H), 2.80 (m, 1H), 2.19 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:55][S:56]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36]([O:37][CH2:38][CH3:39])([O:40][CH2:41][CH3:42])=[O:43])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1)(=[O:58])=[O:57]
Reactant: CS(=O)(=O)Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of diethyl (4-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.45 g, 0.66 m mol) in DCM (1.68 mL), cooled to 0° C., was slowly added triethylamine (0.185 mL, 1.33 mol) followed by methanesulfonyl chloride (0.13 mL, 1.66 mmol) and 4-dimethylaminopyridine (0.81 mg, 6.60 pmol). The mixture was stirred at rt overnight. After 16 hrs, a precipitate formed. The organic layer was re-dissolved in DCM and washed with water (2×), dried over sodium sulfated, filtered and concentrated in vacuo to a solid. The crude product was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded, 3×12 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% 7N NH3 (MeOH) in DCM] to afford 220 mg (44%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.48 (br. s., 1H), 8.33 (s, 1H), 7.82 (d, J=8.08 Hz, 1H), 7.40 (d, J=8.59 Hz, 1H), 7.06 (d, J=2.02 Hz, 1H), 6.96 (d, J=7.58 Hz, 1H), 4.74-4.80 (m, 1H), 4.51 (s, 2H), 4.09 (quin, J=7.20 Hz, 4H), 3.89 (s, 3H), 3.34 (s, 1H), 3.29 (br. s., 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.64 (br. s., 1H), 2.29 (d, J=11.37 Hz, 2H), 1.69-2.00 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 756.19/757.23 (100/90) [MH+]. HPLC: tR=1.53 min (Micromass TOF: polar—3 min).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C3C4C(=CC=CC=4)C=NC=3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.Br[C:28]1[S:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34]>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:28]3[S:29][CH:30]=[CH:31][C:32]=3[C:33]#[N:34])[CH2:15][CH2:16]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C#CC=C2CCN(c3cncc4ccccc34)CC2)n1
Reactant: N#Cc1ccsc1Br
Product: Cc1cccc(C#CC=C2CCN(c3sccc3C#N)CC2)n1
Yield: 22 %

Procedure:
Following the procedure reported for the compound of Example 234 and using 2-bromo-3-cyanothiophene instead of 4-bromoisoquinoline the title compound was prepared. Purification was done by RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording the compound of the title. Yield: 22%.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:15])(=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[SH:9].[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24]>O>[OH:24][C:18]1[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]2[S:9][C:8]3[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6](=[O:15])[C:20]=2[CH:19]=1
Reactant: Cc1cccc(O)c1C
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(O)cc2c(=O)c3ccccc3sc2c1C
Reaction time: 0.08 h

Procedure:
Concentrated sulphuric acid (300 ml) was slowly added to thiosalicylic acid (30.9 g) and the mixture was stirred for 5 minutes to ensure thorough mixing. To the stirred mixture was added slowly over a period of 30 minutes 2,3-dimethyl-phenol (138 g). After the addition, the mixture was stirred at room temperature for 1 hour, and then at 80° C. for 2 hours, after which it was left to stand at room temperature overnight. The resulting mixture was poured carefully with stirring into 10 times its volume of boiling water after which it was boiled for a further five minutes, cooled, and filtered. The residue was recrystallised from acetone to give 2-hydroxy-3,4-dimethyl-thioxanthone as a yellow product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13](Br)[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=3[Cl:25])[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4]
Reactant: CCc1nc2c(Br)nc(C)cn2c1C(=O)OC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nc(C)cn2c1C(=O)OC
Yield: 107.4 %

Procedure:
8-Bromo-2-ethyl-6-methylimidazo[1,2-a]pyrazine-3-carboxylic acid methyl ester (0.30 g, 1.0 mmol) was dissolved in a mixed solvent of toluene (5.6 mL) and methanol (1.4 mL). Then 2,4-dichlorobenzeneboronic acid (0.382 g, 2.0 mmol) and tetrakistriphenylphosphine palladium complex (116 mg, 0.1 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After the reaction mixture was allowed to cool, the solvent was removed. Then the residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give the title compound (391 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](Cl)=O.[NH2:10][NH:11][C:12]([NH2:14])=[S:13].CS(O)(=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: NNC(N)=S
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1nnc(N)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chlorocarbonyl-propionic acid methyl ester (4.4 g, 21 mmol) is added dropwise to a stirred suspension of thiosemicarbazide (4.0 g, 44 mmol) in THF (25 ml) at 0° C. After stirring at room temperature for 18 h the product which precipitates is removed by filtration and washed with diethyl ether. This product (7.1 g, 34 mmol) is suspended in toluene (30 ml) at 0° C. and methane sulfonic acid (3.37 ml, 52 mmol) is added dropwise to the stirred reaction. The reaction is heated at 70° C. for 3 hours then concentrated at reduced pressure. Methanol (30 ml) is added followed by slow addition of aqueous ammonia, with stirring, until the solution is basic. The titled compound which precipitates is removed by filtration and purified by chromatography on silica, eluting with chloroform-methanol (10:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([SH:8])[CH:7]=1.[C:10](OCC)(=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].O.Cl>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:8][C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccc(F)cc1S
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(F)cc2s1

Procedure:
A solution of 5-fluoro-2-aminobenzenethiol (0.94 g, 6.6 mmol) in diethyl oxalate (1.8 mL, 13 mmol) is heated at reflux for overnight. The solution is poured into a mixture of water (9.8 mL), conc. HCl (3.3 mL), and EtOH (4.6 mL). The material is extracted with CHCl3 (3×100 mL). The combined organic extracts are dried over MgSO4, filtered and concentrated to yield an oil. The material is purified by chromatography (25% hexanes/75% CHCl3) to afford a solid that is recrystallized from petroleum ether (0.16 g, 11%). MS for C10H8NO2SF: m/z 226 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 76.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.26 g, 0.44 mmol) prepared in Example 58a, triethylsilane (0.35 mL), trifluoroacetic acid (0.44 mL) and dichloromethane (4.4 mL), to yield the title compound (0.15 g, 77%) as a colorless solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[CH3:11])(C(C)(C)C)(C)C.Cl>C(Cl)Cl.CCOCC>[CH3:17][C:15]1[N:14]=[CH:13][N:12]([C@@H:10]([CH3:11])[CH2:9][OH:8])[CH:16]=1
Reactant: Cc1cn([C@@H](C)CO[Si](C)(C)C(C)(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cn([C@@H](C)CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-4-methyl-1H-imidazole (0.425 g, 1.67 mmol) in DCM (5 mL) was added 3M HCl in ether (10 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was dissolved in MeOH, and solid NaHCO3 was added. The mixture was stirred at room temperature for 1 h. The solid was filtered and washed with MeOH. The combined organic layers were concentrated to afford the title compound (0.212 g). 1H NMR (CDCl3): δ 7.33 (s, 1H), 6.63 (s, 1H), 4.18-4.12 (m, 1H), 3.78-3.47 (m, 2H), 2.10 (s, 3H), 1.42 (d, 3H); LCMS: 141 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21]Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:19][O:20][CH3:21])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCn1ncc(Cl)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 583.7 %

Procedure:
4,5-Dichloro-2H-pyridazin-3-one (30 g, 182 mmol), N,N-diisopropylethylamine (47.5 mL, 258 mmol) and 4-dimethylaminopyridine (2.20 g, 18.2 mmol) were dissolved in 200 mL of methylene chloride, to which was slowly added dropwise chloromethyl methyl ether (16.6 mL, 21.8 mmol) while maintaining at 0° C. The mixture was stirred for 3 h at room temperature. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution, distilled under reduced pressure, and separated-purified by column chromatography (10% methylene chloride/ethyl acetate) to give the title compound (26.6 g, Yield: 70%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][OH:9])=[NH:7])#[N:2].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=O>ClCCl>[Cl:20][CH2:21][C:22]1[O:9][N:8]=[C:6]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=2)[C:1]#[N:2])[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cccc(C(=N)NO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(-c2noc(CCl)n2)c1

Procedure:
3-cyano-N-hydroxy-benzamidine (1.0 g, 6.2 mmol), triethylamine (1.5 ml, 10.6 mmol) and chloroacetyl chloride (0.74 ml, 9.3 mmol) in dichloromethane (12 ml). Purification was performed by decolorizing with silica gel. 1H NMR (CDCl3), d (ppm): 8.40 (s, 1H), 8.32 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 4.77 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH:6]=[O:7]
Reactant: C1=COCCC1
Reactant: Cc1cc(C=O)ccc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (3.0 g, 22.03 mmol) in 45 mL methylene chloride was added 3,4-dihydro-2H-pyran (5.0 mL, 54.8 mmol) and pyridinium p-toluenesulfonate (0.55 g, 2.19 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with three portions of methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered, and concentrated. Silica gel flash chromatography of the residue (10% ether/hexanes to 20% ether/hexanes) afforded 4.35 g of the title compound of Step A. MS 221.1 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[Sn](C)(C)C.[OH:22][CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=2)[CH2:25]1>O1CCOCC1.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:16][CH:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[C:33]1[CH:32]=[CH:31][C:30]([N:26]2[CH2:25][C@H:24]([CH2:23][OH:22])[O:28][C:27]2=[O:29])=[CH:35][CH:34]=1
Reactant: O=C1O[C@H](CO)CN1c1ccc(I)cc1
Reactant: CC(=O)NCC1CC(c2ccc([Sn](C)(C)C)c(F)c2)=NO1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CC(=O)NCC1CC(c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3)c(F)c2)=NO1
Temperature: 90 °C
Reaction time: 16 h
Yield: 0.9 %

Procedure:
N-({3-[3-Fluoro-4-(trimethylstannyl)phenyl]-4,5-dihydroisoxazol-5-yl]methyl}acetamide (600 mg, 1.5 mmol), (5S)-5-(hydroxymethyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (319 mg, 1.0 mmol) and 2-trifurylphosphine (23 mg, 0.1 mmol) were dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture placed under an atmosphere of argon. Tris(dibenzylidineacetone)dipalladium (0) chloroform adduct (52 mg, 0.05 mmol) was added and the reaction mixture stirred for 16 hours at 90° C. Silica gel (0.5 g) was added and the mixture concentrated in vacuo. Purification by column chromatography (10 g silica gel bond elut: 0% to 5% methanoydichloromethane) yielded an off white solid. This was dissolved in dimethylsulphoxide (0.5 ml) and purified by reverse phase preparative HPLC using a gradient from 20% acetonitrile/water to 70% acetonitrile/water to give 3.7 mg of the desired compound.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]1([C:11]2(C(O)=O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O.ClCCl>[C:5]1([C:11]2([NH2:1])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: NC1(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Following the procedure described in N. W. Werner et.al., J. Org. Syn. Coll. Vol. 5, 273-276, sodium azide (0.915 g, 14.1 mmol) is slowly added to a solution of 1-phenyl-cyclopropanecarboxlic acid (1.0 g, 6.1 mmol) in concentrated sulfuric acid (5 ml) and dichloromethane (10 ml). The sodium sulfate precipitated out of solution. The reaction mixture is heated to 50 degrees C. for 17 hours and then cooled to 0 degrees C. The mixture is basified to pH=11 with sodium hydroxide (1N) and extracted with dichloromethane (2×). The organic layers are combined, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (silica gel; isopropyl alcohol/chloroform/ammonium hydroxide 4/95/1) to give the title compound, MS (ESI+) for C9H11N m/z (M+H)+=134.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:11][C:12]#[N:13]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]#[N:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: N#CCBr
Product: CC(C)N1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-Isopropyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=168.1; 1HNMR(DMSO-d6) 3.70 (s, 2H), 2.70-2.40 (m, 9H), 0.95 (d, 6H).