Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28](OCCl)=[O:29]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:5]=[C:4]([C:3]4[NH:27][C:28](=[O:29])[O:1][N:2]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Reactant: O=COCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)[nH]3)c1)C2=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 110.6 %

Procedure:
(S)—N′-hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (200 mg, 0.52 mmol) obtained in Step 1 of Example 75 was dissolved in pyridine (3.0 mL), and the mixture was stirred at 90° C. for 4 hours after adding chloromethyl formate (0.12 mL, 1.56 mmol) under ice-cooled conditions. The mixture was diluted with chloroform, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (236 mg, quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12](O)[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:15])[N:3]=1.S(Cl)(Cl)=O.ClC1C(C(Cl)C)=CC2C(=CC=CC=2Cl)N=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH:12]([N:39]2[C:35](=[O:45])[C:36]3[C:37](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:38]2=[O:40])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:15])[N:3]=1
Reactant: CC(O)c1cc2c(Cl)cccc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(Cl)c1cc2c(Cl)cccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C

Procedure:
Added DCM (2 mL) to 1-(2,5-dichloroquinolin-3-yl)ethanol (200 mg, 826 μmol). Added thionyl chloride (301 μl, 4131 μmol). Obtained a clear colorless solution within minutes. Concentrated reaction mixture to dryness on the rotavap to obtain an oil, which was used without further purification. LC-MS (+esi, M+H+=260.0). Dissolved 2,5-dichloro-3-(1-chloroethyl)quinoline (215 mg, 825 μmol) in DMF (2 mL) and added phthalimide (127 mg, 866 μmol) and K2CO3 (228 mg, 1650 μmol). Submerged in oil bath and began heating to 55° C. After 10 min the temperature of the oil bath was raised to 80° C. After 30 more minutes the reaction mixture was partitioned between EtOAc:H2O. The organic layer was washed with water (3×), dried with sodium sulfate, filtered, and concentrated. The crude was solid was chromatographed on 12 g silica gel column with 0-20% EtOAc:Hex. The desired fractions were combined and concentrated to yield a white crystalline solid. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.99 (d, J=7.04 Hz, 3H) 5.93 (q, J=7.17 Hz, 1H) 7.64-7.70 (m, 2H) 7.71-7.76 (m, 2H) 7.77-7.83 (m, 2H) 7.88-7.93 (m, 1H) 8.95 (s, 1H). LC-MS (+esi, M+H+=371.0)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]([C:16]1[O:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.C(O)C>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[O:20][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2ccc(N3CCOCC3)cc2)o1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
The reaction flask was flushed with nitrogen and charged with 4-(4-bromo-phenyl)-morpholine (2.134 g, 8.81 mmol), 5-formyl-furan-2-boronic acid (1.832 g, 13.10 mmol) and sodium carbonate (3.016 g, 28.46 mmol). A mixture of 1,2-dimethoxyethane (35 mL), ethanol (10 mL) and water (13 mL) was added and the reaction mixture was stirred for 10 min under a nitrogen atmosphere. Dichlorobis(triphenylphosphine) palladium(II) (0.205 g, 0.29 mmol) was added and the mixture was stirred and heated at 80° C. for 18 h. The mixture was cooled to room temperature and partitioned between ether (250 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash Silica (100 mL, 20% ethyl acetate in hexanes) to afford 5-(4-morpholin-4-yl-phenyl)-furan-2-carbaldehyde (1.36 g, 60%). 1H NMR (400 MHz, CDCl3): δ 3.26 (2H, dd, J=5.2, 3.6 Hz), 3.87 (2H, dd, J=5.2, 3.6 Hz), 6.69 (1H, d, J=4.0 Hz), 6.93 (2H, m), 7.26 (1H, s), 7.30 (1H, d, J=4.0), 7.74 (2H, m), 9.58 (1H, s). ESI-MS: 258.0.
Reaction SMILES: [F:1][CH:2]([F:23])[CH2:3][N:4]1[C:9]2[N:10]=[CH:11][S:12][C:8]=2[C:7]([OH:13])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[I:20])[S:5]1(=[O:22])=[O:21].N1C=CC=C[CH:25]=1.Cl[C:31]([O:33]C)=[S:32]>ClCCl>[C:31](=[O:32])([S:33][CH3:25])[O:13][C:7]1[C:8]2[S:12][CH:11]=[N:10][C:9]=2[N:4]([CH2:3][CH:2]([F:1])[F:23])[S:5](=[O:21])(=[O:22])[C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[I:20]
Reactant: O=S1(=O)C(c2ccccc2I)=C(O)c2scnc2N1CC(F)F
Reactant: COC(=S)Cl
Reactant: c1ccncc1
Solvent: ClCCl
Product: CSC(=O)OC1=C(c2ccccc2I)S(=O)(=O)N(CC(F)F)c2ncsc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
150 mg (0.3 mmol) of 1-(2,2-difluoroethyl)-3-(2-iodophenyl)-1H-[1,3]thiazolo[4,5-c][1,2]thiazin-4-ol 2,2-dioxide (compound I-a-14) were dissolved in 5 ml of dichloromethane, and 0.04 ml (0.48 mmol) of pyridine was added at RT. The reaction mixture was stirred at RT for 5 min, and then 0.03 ml (0.38 mmol) of methyl chlorothioformate was added and the mixture was stirred at RT for a further 4 h. After removing the solvent under reduced pressure, the residue was purified by column chromatography (SiO2, gradient ethyl acetate/n-heptane 10:90 to 75:25). This gave 144 mg of compound I-c-16.
Reaction SMILES: [C:1]([O:7]C)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[CH2:11]([C:18]#[N:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H][H].Cl>C1(C)C=CC=CC=1.O>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:7])[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]#[N:19]
Reactant: N#CCc1ccccc1
Reactant: COC(=O)C(C)(C)C
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)C(=O)C(C#N)c1ccccc1

Procedure:
116 grams (1 mole) of methyl pivalate, 60 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) and 234.3 grams (2 moles) of benzyl cyanide were reacted in 750 ml of dry toluene at 60° C. until the end of the evolution of hydrogen. There were added 500 ml of water to the cooled reaction solution, the mixture stirred and the aqueous phase acidified with HCl to pH 3 after the separation and then extracted with chloroform. After concentrating the chloroform the oil residue was fractionated at 0.6 Torr. 110.6 grams (55% of theory) of 4,4-dimethyl-2-phenyl-3-oxopentanenitrile came over at 111° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:16]=[C:17]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[N:19][CH:20]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:28]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]([O:24][CH3:28])([CH3:22])[CH3:23])[CH:16]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: CC(C)(O)c1cncc(-c2nc3cc(F)c(F)cc3n2C2CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(C)(C)c1cncc(-c2nc3cc(F)c(F)cc3n2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 2-[5-(1-Cyclopropyl-5,6-difluoro-1H-benzimidazol-2-yl)pyridin-3-yl]propan-2-ol (from Example 38 Step E) (0.086 g, 0.26 mmol) in tetrahydrofuran (1.3 mL) was added sodium hydride (60% dispersion in mineral oil, 0.026 g, 0.65 mmol). After 1 hour, iodomethane (0.024 mL, 0.389 mmol) was added. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 344.03 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.9 H, 1 H), 8.79 (d, J=2.0 Hz, 1 H), 8.29 (t, J=2.0, 2.0 Hz, 1 H), 7.58 (dd, J=10.3, 7.3 Hz, 1 H), 7.40 (dd, J=9.7, 7.1 Hz, 1 H), 3.59-3.57 (m, 1 H), 3.16 (s, 3 H), 1.63 (s, 3 H), 1.60 (s, 3 H), 1.20-1.17 (m, 2 H), 0.79-0.76 (m, 2 H).
Reaction SMILES: NC1C=C(C(F)(F)F)C=C(Cl)C=1OC1C=CC([N+]([O-])=O)=C(C=1)C(OC)=O.S(Cl)(Cl)=O.CS(N)(=O)=O.[CH3:36][S:37]([NH:40][C:41](=[O:63])[C:42]1[CH:47]=[C:46]([O:48][C:49]2[CH:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:52]=[CH:51][C:50]=2[Cl:59])[CH:45]=[CH:44][C:43]=1[N+]([O-])=O)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH3:36][S:37]([NH:40][C:41](=[O:63])[C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([O:48][C:49]2[CH:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:52]=[CH:51][C:50]=2[Cl:59])[CH:47]=1)(=[O:38])=[O:39]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2cc(C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Agent: COC(=O)c1cc(Oc2c(N)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: CS(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1

Procedure:
The acid from (b) (0.8 g) was treated with thionyl chloride followed by methanesulphonamide and pyridine as described in paragraph (d) above for compound 32. The product was recrystallised from a mixture of ether and petroleum (b.p. 40°-60°) to give compound 31 with a melting point of 132°-133°.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Br:11][C:12]([CH3:17])([CH3:16])[C:13](Br)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:13](=[O:14])[C:12]([Br:11])([CH3:17])[CH3:16])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(C)(C)Br)cc1OC
Yield: 42.9 %

Procedure:
A mixture of veratrole (1,3-dimethoxybenzene) (13.8 g), 2-bromoisobutyryl bromide (23.0 g) and aluminium chloride (14.0 g) was heated for 1 hour at 70°-80° C. After cooling, ice and hydrochloric acid were added to the reaction mixture which was then extracted with ether. The extract was washed first with water and then with 1N NaOH-solution, dried and the solvent evaporated in vacuo, yielding a pale yellow oil (12.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([NH2:19])=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:33][C:34]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:35]=1[C:36](Cl)=[O:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([NH2:19])=[O:18])[N:10]([C:36](=[O:37])[C:35]3[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:34]=3[F:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)COc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)COc1ccccc1C1SC(c2ccc(Cl)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 2-(2-(5-(4-chlorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenoxy)acetamide is added DIEA (2.0 mmol) and 2,4,6-tri-fluorobenzoyl chloride (2.0 mmol) and the reaction mixture is stirred for 12 hours at room temperature. After evaporation of the solvent, the residue is purified by automated chromatography (hexane/EtOAc) to give 2-{2-[5-(4-chloro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetamide: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.27 (d, J=8.8, 2H), 7.15 (m, 2H), 7.14 (d, J=8.4 Hz, 2H) 6.99 (bs, 1H), 6.84 (t, J=6.4 Hz, 3H), 6.66 (d, J=8.4 Hz, 1H), 6.53 (t, J=8.0 Hz, 2H), 5.29 (bs, 1H), 4.47 (d, J=1.6 Hz, 2H); LC/MS: (ES+) 506.2 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([NH:24][CH2:25][C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:21]1([N:24]([CH2:25][C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:22][CH2:23]1
Reactant: Cc1nnc(CNC2CC2)o1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)o1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with cyclopropyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=420.6 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-])=O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OC)(C)(C)C.[Pd]>[C:12]1([NH:18][C:19](=[O:20])[NH:1][C:4]2[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: [Pd]
Solvent: COC(C)(C)C
Product: O=C(Nc1ccccc1)Nc1ccc(CO)cc1
Reaction time: 0.5 h

Procedure:
30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off. 24 g (200 mmol) of phenyl isocyanate were added to the filtrate at 15° C. with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 43 g (89%).
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH:19]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(5,6,7,8-Tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzonitrile (may be prepared as described in Description 11) (assumed 0.148 mmol) was dissolved in dichloromethane (2 ml) and acetic acid (2 drops). Cyclobutanone (17 μl, 0.22 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added and the mixture stirred at room temperature for 1 hour. Methanol was added and the solution poured onto a 2 g SCX column which was eluted with methanol then 2M ammonia in methanol. The basic fractions were evaporated and the residue purified by flash chromatography eluting with 0-5% 2M ammonia in methanol/dichloromethane to give the title compound (E32).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.S(OC)(O[CH3:25])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:25]
Reactant: CCOC(=O)c1cn2c3c(c(Cl)ccc3c1=O)CCN2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(Cl)ccc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To 810 mg (2.8 mmol) of the compound (144) obtained in Example 29, 5 ml (55 mmol) of dimethyl sulfate was added, and the solution was heated for at 120° C. for 5.5 hours. After air-cooling, to 45 ml of ice/water containing 7.5 g (55 mmol) of anhydrous potassium carbonate, was added the solution, and was stirred for 1 hour. The solution was extracted with 50 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 8 g, eluent solvent; chloroform:methanol=100:1) to obtain 371 mg of the subject compound (145) in a 46% yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C.O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnc([N+](=O)[O-])c(O)c1
Reactant: OCc1ccccc1F
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc([N+](=O)[O-])c(OCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g of methyl 5-hydroxy-6-nitronicotinate, 1.62 ml of (2-fluorophenyl)methanol, and 3.99 ml of tributylphosphine in 40 ml of THF was added 2.54 ml of diethyl azodicarboxylate under ice-cooling, followed by stirring for 1 hour under ice-cooling and at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.58 g of methyl 5-[(2-fluorobenzyl)oxy]-6-nitronicotinate.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:32])[CH2:26][C:27](=[O:31])[CH:28](Br)[CH3:29].O>CC(C)=O>[CH3:23][O:24][C:25]([CH2:26][C:27](=[O:31])[CH:28]([O:8][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:9])[CH3:29])=[O:32]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CC(=O)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 22.5 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of biphenyl-4-carboxylic acid (800 g, 4.03 mol) in acetone (4.6 L) was treated with triethylamine (0.6 L, 4.3 mol, 1.07 eq) dropwise over 13 min while maintaining the temperature at 15-30° C. 4-Bromo-3-oxo-pentanoic acid methyl ester (880 g, 4.21 mol, 1.04 eq) was added dropwise over 21 min at 15-30° C. The mixture was stirred overnight at room temperature. Water (9.6 L) was added dropwise over 85 minutes at 15-30° C. The mixture was stirred for 2 h. The precipitated product was collected by filtration and washed twice with water (1 L). The product was dried under vacuum at 50° C. to afford 1291 g (98% yield, 96% HPLC purity) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH2:12][CH2:13][O:14][CH2:15]SC)[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]O>O>[CH3:1][O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH2:12][CH2:13][O:14][CH2:15][S:22]([CH3:26])(=[O:24])=[O:21])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCOCSC
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc2c(c1)ncn2CCOCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
A solution of 1-(2-methylsulfanylmethoxyethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (3.0 g. 10.7 mmoles) in methanol (30 mL) was cooled to 0° C. and to this was added a solution of oxone (4.88 g, 7.94 mmoles) in water. The solution was stirred at the ambient temperature for 12 h. It was quenched with 5% sodium bicarbonate solution and extracted with EtOAc. Removal of solvent gave 2.0 g (60%) of 1-(2-methane-sulfonylmethoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester. MS-ESI m/z 313(M+1): 1H NMR (300 MHz, DMSO-d6) δ 2.9 (s, 3H), 4.0 (s, 3H), 4.25 (t, 2H), 4.65 (t, 2H), 4.75 (s, 2H), 7.85 (d, 2H), 8.0 (dd, 1H), 8.35 (s, 1H), 8.5 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][Si](C)(C)C)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
To (2-methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol) in MeOH was added K2CO3 (1.82 g, 13.2 mmol). After stirring for 5 h, the reaction was filtered then concentrated. The residue was diluted with EtOAc then washed with H2O. The aqueous phase was back-extracted with EtOAc two times then the organic phases were combined, washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (5-10% MeOH—CH2Cl2 gradient) to afford (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.62 g, 6.6 mmol, quantitative yield). LCMS-ESI+: calc'd for C22H27N4O3: 395.2 (M+H+). Found: 395.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[S:29][C:28]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[S:29][C:28]([S:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)(=[O:31])=[O:32])=[CH:27][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)N5CCN(C)CC5)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 76%). MS (ISP) 580.0 [(M+H)+]; mp 229° C.