Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH3:33].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][N:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:33]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CNCCCCN(C)C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(C)CCCCN(C)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 150 °C
Yield: 23 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.1 g), N-(4-dimethylaminobutyl)-N-methylamine (Intermediate 78, 1.07 g) and triethylamine (0.42 g) in NMP (6 mL) was stirred and heated in a sealed tube at 150° C. for 3 days. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%) followed by repurification by HPLC (C18) to give (1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.03 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[N:17]=[N:18][C:19]([Cl:23])=[CH:20][C:21]=2[CH3:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[N:17]=[N:18][C:19]([Cl:23])=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1cc(Cl)nnc1-c1c(-c2ccc(Cl)cc2)c(C)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1c(Cl)nnc(C)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
0.30 g of 5-(4-chlorophenyl)-4-(6-chloro-4-methyl-3-pyridazinyl)-6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, the, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.31 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.26 g of 3-chloro-5-(4-chlorophenyl)-4-(6-chloro-4-methyl-3-pyridazin yl)-6-methylpyridazine (hereinafter, described as compound (13) of the present invention (13).).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20]O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])[CH:2]([CH3:4])[CH3:3].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.CCN(CC)CC.[BH3-]C#N.[Na+]>O1CCOCC1.O=[Mn]=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[C:22]([F:24])([F:25])[F:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc3ccc(CO)cc3o2)cc1C(F)(F)F
Reactant: O=C(O)C1CNC1
Agent: O=[Mn]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc(-c2nc3ccc(CN4CC(C(=O)O)C4)cc3o2)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
To a solution of [2-(4-isobutyl-3-trifluoromethyl-phenyl)-benzooxazol-6-yl]-methanol (1 eq) in dioxane (0.2 M) is treated with MnO2 (10 eq). The resulting mixture is refluxed for 20 minutes and filtered through celite. After concentration, the residue is redissolved in MeOH (0.2 M) and is added azetidine-3-carboxylic acid (2 eq) and Et3N (1.8 eq). The resulting mixture is heated at 50° C. for 1 hour. After cooling to room temperature, NaBH3CN (3 eq) is added in portions. The final compound is purified by preparative LCMS. 1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.66 (d, J =8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.57 (s, 2H), 4.34 (m, 4H), 3.70 (m, 1H), 2.76 (d, J=6.8 Hz, 2H), 2.03 (m, 1H), 0.95 (d, J =7.2 Hz, 6H). MS: (ES+): 433.2 (M+1)+.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][C:5]#[N:6].[CH2:9]([NH2:13])[C:10]#[C:11][CH3:12]>C(#N)C>[C:5]([NH:4][C:3](=[N:13][CH2:9][C:10]#[C:11][CH3:12])[S:2][CH3:1])#[N:6]
Reactant: CSC(=NC#N)SC
Reactant: CC#CCN
Solvent: CC#N
Product: CC#CCN=C(NC#N)SC

Procedure:
A solution of dimethyl cyanodithioiminocarbonate (10.00 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) was stirred at 25° for 0.5 hour, and then at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound, mp 180°-183°.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>CCOC(C)=O>[CH2:17]([O:7][C:6](=[O:8])[C@H:2]([C@@H:3]([CH3:5])[OH:4])[NH:1][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
To a stirred suspension of Boc-Thr-OH (21.91 g, 0.1 mol) in EtOAc (200 ml) at 0° C., TEA (14 ml, 0.1 mol) and bromoacetophenone (19.0 g, 0.1 mol) were added. The reaction mixture was allowed to warm to 20° C., stirred for 2 days and then diluted with EtOAc (500 ml). After washing successively with aq HCl (200 ml, 0.1 N), H2O (100 ml), aq NaHCO3 (200 ml, 1 N) and brine (200 ml), drying (Na2SO4), filtered and concentrated in vacuo, the residue was triturated with Et2O and filtered. The resulting solid was dried in the dark to yield D3 (28.6 g, 85%). Rf=0.55 (hex-EtOAc 1:1, silica); M.p.=114.2° C.; [α]D22−29.4 (c 2, EtOAc).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([OH:20])=O)[N:8]=2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([NH:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:20])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1C(F)(F)F
Reactant: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)O)c1=O
Product: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)NCC(NC(=O)OC(C)(C)C)c2ccccc2C(F)(F)F)c1=O

Procedure:
Analogously to the procedure of Example 63, 47 mg (146 μmol) of the compound of Example 52A were reacted with 49 mg (161 μmol) of tert-butyl {2-amino-1-[2-(trifluoromethyl)phenyl]-ethyl}carbamate. This gave 60 mg (68% of theory) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].CN([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]=2[Cl:17])[NH:10][CH:9]=1)C.CI.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[C:1]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:15]=2[Cl:17])[NH:10][CH:9]=1)#[N:2]
Reactant: CN(C)Cc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Reactant: [C-]#N
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: N#CCc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
Potassium cyanide (7.36 g, 113 retool) was added to a solution of 3-dimethylaminomethyl-4-chloro-5-benzyloxy-indole (9.30 g, 29.5 mmol) in sieve-dried DMF (150 ml). Methyl iodide (17.2 g, 121 mmol) was added dropwise, while stirring over 15 minutes, and stirring was continued for a further hour. The mixture was poured into 10% aqueous sodium sulphate and extracted with diethyl ether. The combined extracts were dried (Na2SO4) and evaporated to dryness leaving an oil which crystallised. Recrystallisation from methanol gave 3-cyanomethyl-4-chloro-5-benzyloxyindole (5.56 g), m.p. 130°-2° C.
Reaction SMILES: [CH:1]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([C:27]1[N:28]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[S:56](=[O:59])(=[O:58])[NH2:57])=[CH:46][CH:45]=2)[C:29](=[O:42])[N:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[N:31]=1)[CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1>>[CH2:23]([C:27]1[N:28]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[S:56](=[O:59])(=[O:58])[NH:57][C:8]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:10])=[CH:46][CH:45]=2)[C:29](=[O:42])[N:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[N:31]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)C1CCCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C2CCCCCC2)cc1

Procedure:
The title compound was prepared from cycloheptanecarboxylic acid (2.0 equivalents), CDI (2.0 equivalents), 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) (1.0 equivalent), and DBU (2.0 equivalents) according to the procedure of Example 7, to give a 69% yield of the desired material after flash chromatography, as a glassy solid, mp 146°-149° C., homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 655 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(C=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.26 g, 10.0 mmol) and benzyl bromide (3.42 g, 20.0 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.76 g, 20.0 mmol), and the mixture was stirred at 70° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound (2.90 g, yield 92%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]2)=[CH:4][C:3]=1[O:16][CH3:17].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[Br:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH2:13]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Yield: 13.2 %

Procedure:
A mixture of 1-(4-hydroxy-3-methoxyphenyl)phenyl-methanone (14 g, 61.4 mmol), K2CO3 (13 g, 92.1 mmol), and 1,3-dibromopropane (28 g, 86 mmol) in acetonitrile (400 ml) was heated at reflux for 4 hours. The reaction was followed by thin layer chromatography. At the end of the reaction, the inorganics were filtered off and the solvent was removed on a rotary evaporator. The residue was purified on a flash chromatographic column (SiO2, 140 g, eluted with 4:1 hexane:dichloromethane, 1,2 l) to give a partially solidified material: 15.44 g (72%). Recrystallization twice from ethanol gave 2.84 g of 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone as white crystals, m.p.=88°-89° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:19]Br.O>CN(C)C=O>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:3][C:2]=2[O:1][CH2:19]1
Reactant: BrCBr
Reactant: O=C(CCc1ccc(O)c(O)c1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc2c(c1)OCO2)N1CCCC1
Reaction time: 4 h

Procedure:
0.92 g of N-[3-(3,4-dihydroxyphenyl)-propionylpyrrolidine was dissolved in 10 ml of N,N-dimethylformamide and then 1.2 g of dibromomethane and 1.2 g of potassium carbonate anhydride and 100 mg of cupric oxide were added to the solution and the resulting solution was stirred at 130°-140° C. for 4 hours. After cooling, the solution was poured over iced water, extracted with ethyl acetate, washed with water and then dried with sodium sulfate anhydride. The solvent was removed by evaporation under reduced pressure and the residue was purified by chromatography on a silica gel column with a mixed solvent (chloroform:methanol=100:l) and thus 0.59 g of oily N-[3-(1.3-benzodioxol-5-yl)propionyl]pyrrolidine was obtained.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[CH2:28][CH2:29][CH:30]=O.Cl>>[F:27][C:22]1[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[C:21]=1[CH2:28][CH2:29][CH2:30][N:2]([CH3:1])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:8]1
Reactant: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: O=CCCc1c(F)cc(F)cc1F
Agent: Cl
Product: CN(CCCc1c(F)cc(F)cc1F)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Condensation of 15 (460 mg, 1.9 mmol) and 3-(2,4,6-trifluorophenyl)-propionaldehyde (360 mg, 1.9 mmol), following the procedure described in Example 45, Step 2, followed by conversion to the HCl salt, gave 6-(trans-4-{[3-(2,4,6-trifluorophenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (275 mg, 32%), as a white solid: mp 235-238° C.; IR (KBr): 2949, 1772, 1632, 1603 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 11.54 (s, 1H), 9.78 (s, 1H), 7.26-7.18 (m, 3H), 7.00 (s, 2H), 3.32-3.27 (m, 1H), 3.26-3.04 (m, 2H), 2.71 (d, J=5 Hz, 3H), 2.58-2.54 (m, 1H), 2.66-2.62 (m, 2H), 2.12-1.86 (m, 6H), 1.68-1.48 (m, 4H); ESI (m/z): 419 [M+H]+; HPLC: method A, 6.30 minutes (98.8%); Anal. Calcd for C23H25F3N2O2.HCl: C, 60.73; H, 5.76; N, 6.16. Found: C, 60.43; H, 5.71; N, 5.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[N:32][CH:33]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(Br)cn1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: COc1ccc(C#Cc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)cn1

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 2-methoxy-5-bromo-pyridine.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([CH3:12])[Cl:11]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:12])([CH3:9])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](C)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)CCc1ccccc1
Yield: 84 %

Procedure:
Reaction between styrene and dimethylchlorosilane with platinum catalyst (no substance acting as auxiliary catalyst). 526 mg Styrene and 408 mg dimethylchlorosilane were introduced into a glass tube, and 2.5 mg of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) were added. The tube was sealed with Teflon tape and a rubber septum and then placed in a 50° C. oil bath where it was heated for 30 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 98% and a phenethyldimethylchlorosilane yield of 84%. The ratio between the phenethyldimethylchlorosilane and (α-methylbenzyl)dimethylchlorosilane was 4.7:1.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=[N:16]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].Br[C:30]1[C:31]([CH3:36])=[N:32][NH:33][C:34]=1[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:30]3[C:31]([CH3:36])=[N:32][NH:33][C:34]=3[CH3:35])[CH:17]=[N:16]2)[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Cc1n[nH]c(C)c1Br
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: C1COCCO1
Solvent: O
Product: Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
A mixture of tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (381 mg, 0.981 mmol, from Example 1, step 2), 4-bromo-3,5-dimethyl-1H-pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (310 mg, 2.9 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was purged with N2 and stirred at 110° C. for 2 h. The reaction mixture was filtered, diluted with EtOAc, then washed with water. The organic layer was concentrated and purified on silica gel (eluting with 0-100% EtOAc/hexanes followed by 0-10% MeOH/dichloromethane) to give tert-butyl 3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine-1-carboxylate (90 mg, 26%). LCMS calculated for C18H25N6O2 (M+H)+: m/z=357.2. Found: 357.2. This intermediate was treated with 4.0 M hydrogen chloride in dioxane (1.2 mL, 4.9 mmol) in methylene chloride (1 mL) at rt for 2 h. The mixture was stripped to dryness to give the desired product. LCMS calculated for C13H17N6 (M+H)+: m/z=257.1. Found: 257.1.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:13]O)[CH:9]=[CH:10][C:11]=1[F:12].C(N(CC)CC)C.S([Cl:31])(C)(=O)=O>C(Cl)Cl>[Cl:31][CH2:13][C:8]1[CH:9]=[CH:10][C:11]([F:12])=[C:6]([CH:7]=1)[O:5][CH2:4][C:3]1[C:2]([CH3:1])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1COc1cc(CO)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1COc1cc(CCl)ccc1F
Reaction time: 6 h

Procedure:
To a stirred solution of (3-(2,6-dimethylbenzyloxy)-4-fluorophenyl)methanol (Step B, 3.7 g, 14.21 mmol), triethylamine (5 g, 50 mmol) in CH2Cl2 (50 ml) was added mesyl chloride (10.34 g, 90.2 mmol) at 0° C. under argon. The reaction mixture was stirred for 6 hours, washed with 10% Na2CO3, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 5:1) to give the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+:19].[K+].[OH-].[K+]>>[OH:3][CH:2]([CH2:7][C:6](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:1]([O-:5])=[O:4].[K+:19]
Reactant: CC(=O)c1ccccn1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: O=C(CC(O)C(=O)[O-])c1ccccn1

Procedure:
The condensation of glyoxylic acid with the 2-acetylpyridine 4 is carried out according to an aldolization in a basic medium (potassium carbonate) (Scheme 3) (Coates and McKillop, 1992). This step was optimized from 31% to 65% by simply increasing the number of equivalents of the base to 3 eq., whereas the yield from this condensation drops in a more basic medium of potassium hydroxide (Coates and McKillop, 1992). The potassium 2-hydroxy-4-oxo-4-(pyridin-2-yl)butanoate 5 obtained subsequently becomes cyclized, at the reflux of acetic acid in the presence of hydrazine monohydrate, so as to form the intermediate 6 which becomes dehydrated in situ so as to give the 6-(pyridin-2-yl)-2H-pyridazin-3-one 7 with an overall yield of 65%.
Reaction SMILES: [OH-].[NH4+].O.[C:4]([NH:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][SH:10])(=[O:6])[CH3:5]>C(O)(C)C>[NH4+:7].[C:4]([NH:7][C@H:8]([C:11]([O-:13])=[O:12])[CH2:9][SH:10])(=[O:6])[CH3:5]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)N[C@@H](CS)C(=O)[O-]
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of concentrated ammonium hydroxide (52 ml., 0.78 mole) and 20 ml. water is added in 10 minutes to a stirred mixture of N-acetyl-L-cysteine (114.2 g., 0.7 mole) in 1.2 liters of isopropanol under an atmosphere of nitrogen. During the addition the mixture thickens and the temperature increases to 35°C. The mixture is stirred overnight, collected and washed with isopropanol to yield 110 g. (87%) of product having a melting point of 156°-158°C. (dec.) (uncorr.). Crystallization of this product from water-isopropanol with cooling to -10°C. provides analytically pure N-acetyl-L-cysteine ammonium salt, M.P. 147.5°-150°C. (dec.) (corr.); [ α ]D25 + 20.6°(c 5,H2O).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([NH2:33])[CH2:29][CH2:28]1)[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:33][N:30]3[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CCN1CCN(N)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(NC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A cold (−40° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) in EtOAc (20 mL) was treated with 4-ethylpiperazin-1-amine (0.12 g). T3P (50% in EtOAc, 0.84 mL) and DIPEA (0.24 mL) were added simultaneously and the reaction mixture was stirred for 30 min at −40° C. before being quenched with ice-cold water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.280 g of crude compound. Purification by combi-flash chromatography (eluting with 2% MeOH in CH2Cl2) followed by purification on a preparative TLC plate (eluting with 10% MeOH in CH2Cl2) afforded 60 mg (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(4-ethylpiperazin-1-yl)acrylamide. 1H NMR (400 MHz, CF3COOD) δ: 10.75 (s, 1H), 8.31-8.29 (d, J=10.2 H), 7.98 (s, 1H), 7.21-7.23 (d, 1H), 6.08-6.10 (d, 1H), 3.52-3.54 (m, 3H), 3.36 (s, 1H), 3.11 (m, 8H), 1.19-1.22 (m, 3H); LCMS for C19H21F6N6O [M+H]+ 463.40. found 463.23 (RT 2.43 min, purity: 98.63%).