Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:8](=[O:21])/[C:9]/1=[C:10](\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH2:11]Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:8](=[O:21])/[C:9]/1=[C:10](\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH2:11][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(/CCl)NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(/CN1CCOCC1)NCc1ccccc1
Yield: 98 %

Procedure:
The mixture of the above obtained methyl[(4Z)-4-[1-(benzylamino)-2-chloroethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (XIII), 0.32 g), morpholine (1 eq.) and DIPEA (1 eq.) was stirred at room temperature in toluene (3 mL) under nitrogen for 0.5 h at 90° C. Additional 0.5 eq. of morpholine wad added to push reaction to completion. The solvent was removed in vacuo. The resulting brown residue was proved to be the pure methyl[(4Z)-4-[1-(benzylamino)-2-morpholin-4-ylethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (0.37 g). Yield 98%. MS (ESI+): 483.9; MS (ESI−): 481.8.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=[O:17])#[N:2].[OH-].[K+].O.Cl>C(O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:16]([OH:18])=[O:17])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2cccc(C#N)c2)c1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(-n2ncc(C(=O)O)c2C#N)c1
Yield: 62.4 %

Procedure:
Approximately 7.7 g of 5-cyano-1-(3-cyanophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester was dissolved in 75 ml of hot ethanol. To the reaction mixture was added 3.2 g of potassium hydroxide dissolved in ethanol. A small amount of water was added to the reaction mixture which was immediately poured into water. The solution was then acidified with concentrated hydrochloric acid and the precipitated solid was collected by filtration and dried to provide 4.3 g of 5-cyano-1-(3-cyanophenyl)-1H-pyrazole-4-carboxylic acid. MP=190°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10][F:34])=[CH:4][CH:3]=1
Reactant: CCC(CCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCC(CCF)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 1 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-1-hydroxypentan-3-yl)-1H-indol-4-yl)methanesulfonamide (20 mg, 0.05 mmol), as described in Example 40 Step I, in DCM (5 mL) was added DAST (16 mg, 0.1 mmol) at 0° C. The mixture was stirred for 1 h, then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate. The combined organics were washed with water (5 mL) and brine (5 mL), dried over MgSO4, filtered and concentrated. The resulting crude product was purified by Pre-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title racemic compound as a white solid. The racemic compound was submitted to chiral SFC separation using IC (30% MeOH (0.1% DEA)/CO2, 4.6×250 mm, 41° C.) to give two separated enantiomers. LC/MS m/z=409.1[M+H]+.
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[C:32]([F:33])=[CH:31][C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C@H:15]3[C@H:20]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH2:19][CH2:18][C:17](=O)[N:16]3[C:10]=2[CH:9]=1.Cl>C1COCC1.C(OCC)(=O)C>[Br:7][C:8]1[C:32]([F:33])=[CH:31][C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C@H:15]3[C@H:20]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH2:19][CH2:18][CH2:17][N:16]3[C:10]=2[CH:9]=1
Reactant: COC(=O)N[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Borane-tetrahydofuran complex (1.0 M in THF, 970 mL, 970 mmol) was added dropwise to a stirred solution of methyl (±)-(cis)-(7-bromo-8-fluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamate (105.2 g, 242 mmol) in THF (1 L). The resulting mixture was stirred at ambient temperature for 3 h. Subsequently, hydrochloric acid (1M) was added dropwise until evolution of gas ceased (±550 mL). The resulting mixture was stirred for 1 h and then diluted with ethyl acetate; the organic layer was washed with water and brine. After drying (MgSO4) the solvent was evaporated under reduced pressure to yield the crude title compound (98.5 g, 97%). (m/z)=421+423 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 34.2 %

Procedure:
0.30 g (0.00082 mol) of 7-chloro-3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one was dissolved in 40 ml of tetrahydrofuran, treated with 2.3 ml (0.01 65 mol) of dipropylamine and boiled at reflux for 20 hrs. The solution was completely freed from the solvents, the residue was chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent and recrystallized from ethyl acetate/n-hexane. There was obtained 0.12 g (34%) of 7-chloro-3-(4-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 105°-107°.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)=O>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=2)=[CH2:14])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C(C)=O)cc1Cl
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 19.5 mL, 31.3 mmol, 1.16 eq.) was added dropwise over 20 min to a solution of 1,3-dibromobenzene (3.59 mL, 29.7 mmol, 1.1 eq) in 30 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed was stirred at −78° C. for 30 min. A solution of 3-chloro-4-methoxyacetophenone (5 g, 27 mmol, 1.0 eq.) in 20 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated solution of ammonium chloride and water. 2 N HCl was then added to reach pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (10 mL of acetic acid, 0.3 mL of sulfuric acid) and the reaction mixture was stirred for 3 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate (gradient 0-4%). The desired product was obtained as a yellow oil (4.36 g, Yield: 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][NH:27][CH2:28][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][N:27]([C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])[CH2:28][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CNC4)ccc1OCc1ccccn1
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 31A (38 mg, 0.094 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (22 mg, 0.13 mmol) to yield 18 mg (37%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.Br[C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C.C([O-])(O)=O.[Na+].CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][CH:32]=[C:23]([C:6]2[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1C=O
Reactant: COC(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccnc2C=O)c1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
A stirred solution of 3-Tributylstannanyl-pyridine-2-carbaldehyde (256 mg, 0.65 mmol) and methyl 3-bromobenzoate (128 mg, 0.59 mmol) in DMF (2.1 mL) was degassed with Ar for 5 minutes, after which PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuO (34 mg, 0.43 mmol) was added and the mixture heated to 110° C. overnight. The reaction was cooled to room temperature, and diluted with saturated aqueous NaHCO3 (15 mL) and EtOAc (40 mL). The organic phase was separated, washed with brine (3×15 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 60:40) gave 3-(2-Formyl-pyridin-3-yl)-benzoic acid methyl ester (25 mg, 17%) as a white solid. 1H NMR (CDCl3) δ 3.92 (s, 3H), 7.47-7.56 (m, 2H), 7.58 (d, 1H, J=4.9 Hz), 8.03 (s, 1H), 8.07-8.20 (m, 1H), 8.86 (dd, 1H, J=4.9, 1.8 Hz), 10.08 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 2-fluoro-5-(trifluoromethyl)benzaldehyde 75 (77.7 mg, 0404 mmol). PTSA (153.8 mg, 0809 mmol) was added and the reaction mixture stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 76 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(2-fluoro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 76 was eluted at 34% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10]>C1C=CC=CC=1>[CH3:8][C:9]1[CH2:10][CH:3]2[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]2[CH2:12][C:11]=1[CH3:13]
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(C)C(=C)C
Solvent: c1ccccc1
Product: CC1=C(C)CC2C(=O)OC(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of maleic anhydride (5.4 g, 55 mmol) in benzene (50 ml) was added dropwise 2,3-dimethyl-1,3-butadiene (6.3 ml, 55 mmol), and stirred overnight at 25° C. After separating the insoluble materials by filtration, the filtrate was concentrated under reduced pressure to give 9.5 g of 5,6-dimethyl-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione.
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH:13]([OH:15])[CH3:14])[CH:6]=[CH:5][C:4]1=2>[Pd].COCCOCCOC>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC(O)Cn1ccc2c1CCCC2=O
Agent: [Pd]
Solvent: O
Solvent: COCCOCCOC
Product: CC(O)Cn1ccc2c(O)cccc21
Yield: 78.5 %

Procedure:
10 g of palladium on carbon at 5% by weight and containing 50% water were added to a solution of 19.3 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β-hydroxypropyl)indole, obtained in the preceding stage, in 300 cm3 of diglyme. The temperature of the reaction medium was raised to the reflux temperature of diglyme for 5 hours, after removing the water by azeotropy. The catalyst was then filtered off on celite and then the diglyme was evaporated off. 17 g of crude product were obtained. After chromatography on silica gel (heptane/ethyl acetate=1/4), 15 g of viscous product were obtained, which product was crystallized by the addition of 15 cm3 of dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:18]=3)=[CH:11][N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:18]=3)=[CH:11][N:10]=2)=[CH:7][N:6]=[C:5]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[N:4]=1
Reactant: COc1nc(SC)ncc1-c1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Reactant: C1CCNC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(N2CCCC2)ncc1-c1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
A solution of 4-methoxy-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyri-dine-2-yl)-2-(methylthio)pyrimidine (0.28 g, 0.67 mmol) in DCM (10 mL) was treated with mCPBA (0.20 g, 0.80 mmol), stirred at RT for 3 h, treated with pyrrolidine (0.50 mL, 6.1 mmol) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over MgSO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to afford 4-methoxy-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidine (0.19 g, 64%). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.37 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.5 Hz, 1H), 4.00 (s, 3H), 3.84 (s, 3H), 3.55 (s, 5H), 2.18 (s, 3H), 1.93-1.92 (m, 4H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(=O)([O-])[O-].[F:16][C:17](=[C:22]([F:24])[F:23])[CH2:18][C:19](Cl)=[O:20]>ClCCl.O>[F:16][C:17](=[C:22]([F:24])[F:23])[CH2:18][C:19]([NH:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1)=[O:20]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: COc1cc(OC)nc(N)n1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)CC(F)=C(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
To an ice-cooled stirred suspension of 2-amino-4,6-dimethoxypyrimidine (1.55 g, 10 mmol) in dichloromethane (50 mL) and potassinm carbonate (2.76 g, 20 mmol) in water (20 mL) was added 3,4,4-trifluoro-3-butenoyl chloride (3.17 g, 20 mmol). The reaction mixture was stirred in cold for 10 min and at r.t. for 15 min. The organic layer was washed with 3N HCl (2×25 mL), saturated sodium bicarbonate (25 mL) and brine, and dried. Evaporation of the solvent gave 0.296 g (10%) of the title compound as a white solid. m.p. 127°-130° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[CH2:4]1.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]=1[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[CH2:4]2)=[CH:14][C:13]=1[CH3:20]
Reactant: O=S1(=O)CCCC(CBr)C1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2CCCS(=O)(=O)C2)cc(C)c1Br
Temperature: 130 °C
Reaction time: 8 h

Procedure:
3-(Bromomethyl)tetrahydro-2H-thiopyrane 1,1-dioxide (1 g) is dissolved in 40 mL of N,N-dimethylformamide. 4-Bromo-3,5-dimethylphenol (885 mg) and cesium carbonate (2.85 g) are added and the reaction mixture is stirred at 130° C. overnight. The reaction mixture is concentrated under vacuum. Water is added and the mixture is extracted with ethyl acetate, The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Yield: 800 mg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:15])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2ccc(Br)cc12
Product: Clc1nccc2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 7-bromoisoquinolin-1-ol (1.0 g, 4.46 mmol, 1.00 equiv) in POCl3 (5 mL). The reaction mixture was stirred for 60 min at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 20 mL of DCM, washed with 3×10 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The title compound was obtained as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:44])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.023 ml benzoylchloride (0.2 mmol). After 4 h of stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 85 mg yellow solid which was purified by column chromatography (10 g silicagel, dichloromethane/methanol 30:1). 71 mg product as a light yellow solid (73%) was obtained. MS (ISP) 605.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[C:10]([F:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][C:31]#[N:32])[C:15]=2[C:14]2[C:9]1=[C:10]([F:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Oc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A mixture of 9-benzyl-8-fluoro-9H-carbazol-4-ol (1.0775 g, 0.0037 mol), potassium carbonate (0.6284 g, 0.0046 mol), bromoacetonitrile (0.6 mL, 0.0086 mol) and DMF (12 mL) is stirred at room temperature for 4 h. The mixture is then partitioned between water and dichloromethane. The aqueous layer is also washed with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to a residue, which is then partitioned between water and ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated to a residue. The resulting residue is chromatographed on silica gel (100 mL) using ethyl acetate/hexane (20/80) followed by dichloromethane (100 %). The solids are recrystallized from ethyl acetate/heptane to give 0.8869 g (73%) of the title compound; mp 134-134.25° C.; MS (ESI+) for C21H15FN2O m/z 353.1 (M+Na)+; IR(drift) 1578, 1500, 1458, 1439, 1369, 1344, 1335, 1323, 1278, 1235, 1144, 1080, 793, 739, 695 cm−1; 1H NMR (CDCl3) δ5.05, 5.71, 6.75, 7.16, 7.24, 7.41, 8.07. Anal. Calcd for C21H15FN2O: C, 76.35; H, 4.58; N, 8.48. Found: C, 76.15; H, 4.63; N, 8.35.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Br[CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:1]1([CH2:7][CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:14])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1ccnn1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Add 1H-1,2,3-triazole (250 g; 3.51 mol), N-(2-bromoethyl)phthalimide (942 g; 3.52 mol) and 1500 mL of DMF to a 5-L roundbottom flask fitted with a mechanical stirrer, nitrogen inlet and temperature probe. Cool the mixture to 15° C. Stir the mixture until all of the solids are nearly dissolved and then cool in an ice-water bath. Add cesium carbonate (1145 g; 3.51 mol) in portions over 10 min. The reaction mixture exotherms to 21° C. Allow the mixture to stir and come to RT overnight. Pour the reaction mixture into a 12-L flask containing 8 L of ice-water. Stir the suspension for 30 min and then filter and rinse the solid with 3 L of water. Air-dry for 2 h. Recrystallize the mixture of regioisomers from 7 L of absolute ethanol. Isolate the solid by filtration and air-dry. Recrystallize again from 16 L of absolute ethanol. Isolate the solids by filtration and rinse with fresh ethanol (1000 mL). Vacuum-dry the solids at 40° C. to give the title compound, 292.7 g (34%) as a white solid. MS (EI) m/z 243 [M+1]+.