Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 4.5 h

Procedure:
Preparation (3R,3aR,6R,6aS)-tert-Butyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (35b). Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and anti-(33b) (100 mg, 0.25 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 4.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (2×3 mL) to obtain (3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: [C:1]([C:3]1(C(O)=O)[C:5]([CH3:7])([CH3:6])[CH:4]1[CH:8]=[C:9]([Cl:11])[Cl:10])#[N:2].N>CN(C)C=O.O>[Cl:10][C:9]([Cl:11])=[CH:8][CH:4]1[C:5]([CH3:6])([CH3:7])[CH:3]1[C:1]#[N:2]
Reactant: CC1(C)C(C=C(Cl)Cl)C1(C#N)C(=O)O
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(C#N)C1C=C(Cl)Cl
Temperature: 130 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
1-Cyano-2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid (1.5 g) was dissolved in dimethylformamide (10 ml) and the solution was saturated with gaseous ammonia at 20° C. The solution was then stirred at 130° C. for 18 hours, then diluted with water (150 ml) and extracted with pentane. The extracts were dried (MgSO4) and the solvent was removed under reduced pressure to give the required 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane nitrile, yield 82%.
Reaction SMILES: O=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][C:2](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=O)Nc1ccccc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cl)=Nc1ccccc1C

Procedure:
The suspension of ethyl 2-oxo-2-(o-tolylamino)acetate (2.0 g, 10 mmol) and triphenylphosphine (4.0 g, 15 mmol) in carbon tetrachloride (150 mL) was refluxed overnight. The reaction was cooled down and filtered. The filtrate was collected and concentrated and used it without further purification. MS (m/z) 226 [M+H]+.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][N:15]=2)=[N:13]1
Reactant: CCCNC(=O)c1ccc(C#N)nc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 66.2 %

Procedure:
A mixture of methyl thiosalicylate (2.2 g, 13.3 mmol), 6-cyano-N-propylnicotinamide (1.2 g, 6.5 mmol), triethylamine (2.0 ml, 14.3 mmol) and toluene (4 ml) was refluxed for 5 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from diisopropylether-chloroform to give the titled compound (1.4 g, 67%) as crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[CH:11]=[CH:12][C:7]([NH:42][CH:39]5[CH2:41][CH2:40]5)=[N:8][C:9]=4[CH3:36])[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:29])([F:30])[F:31])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: NC1CC1
Product: Cc1nc(NC2CC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 60 °C
Reaction time: 25.5 h
Yield: 42 %

Procedure:
A mixture of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (130.4 mg, 0.219 mmol) and cyclopropylamine (2.0 mL) was stirred at 60° C. for 25.5 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (45.6 mg, 0.909 mmol, 42%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:37]I.O>CN(C=O)C>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][N:11]([CH3:37])[N:12]=1
Reactant: CI
Reactant: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 121.4 %

Procedure:
A mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-(2H-tetrazol-5-yl)-amine (8.5 g, 10 mmol) and sodium hydride (0.81 g, 30 mmol) in DMF (150 mL) was stirred at 0° C. for 20 minutes. Thereafter, methyl iodide (3.5 g, 20 mmol) was added and the resulting mixture was stirred at 0-10° C. for 30 minutes. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography over 230-400 mesh silica gel. Elution of the column with 10% acetone in hexanes gave the pure product as a colorless solid (6.3 g), yield: 75%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:31])=[O:30])=[CH:25][C:24]=2[C:38]#[N:39])=[C:18]([C:40]2[N:44]([CH3:45])[N:43]=[CH:42][CH:41]=2)[CH:17]=1)C)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[C:38]([C:24]1[CH:25]=[C:26]([S:29]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)(=[O:30])=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][NH:7][CH3:6])=[CH:17][C:18]=1[C:40]1[N:44]([CH3:45])[N:43]=[CH:42][CH:41]=1)#[N:39]
Reactant: CN(Cc1ccccc1-c1ccc(Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)c(-c2ccnn2C)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccccc1-c1ccc(Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
tert-Butyl-{[4′-{2-cyano-4-[(1,3-thiazol-2-ylamino)sulfonyl]phenoxy}-3′(1-methyl-1H-pyrazol-5-yl)biphenyl-2-yl]methyl}methylcarbamate (Preparation 65, 64 mg, 0.01 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.2 mL) was added and the reaction was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC to afford the title compound (22 mg, 37%) as a white solid as the trifluoroacetate salt.
Reaction SMILES: C(#N)C.[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=O)[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>C1(C)C=CC=CC=1>[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:25])[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1
Reactant: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=S

Procedure:
To 30 ml of acetonitrile was added 1.25 g (0.004 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-(trifluoromethyl)-1,4-benzoxazepine-5(4H)-one and 0.92 g (0.002 mole) of phosphorus pentasulfide and the reaction mixture heated to reflux for 4 hr. After cooling, 30-40 ml of toluene was added and the mixture filtered. The filtrate was washed with 3×50 ml of saturated potassium carbonate, charcoaled, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl ether to give 0.65 g (50%) of yellow, analytically pure crystals, m.p., 146°-48° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br-:12].[Br:13][CH2:14][CH2:15][CH2:16][N+:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>C(#N)C>[Br-:13].[Br-:12].[CH2:18]([N+:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:16][CH2:15][CH2:14][N+:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:19]
Reactant: Cc1ccnc2ccccc12
Reactant: CC[N+](CC)(CC)CCCBr
Agent: [Br-]
Solvent: CC#N
Product: CC[N+](CC)(CC)CCC[n+]1ccc(C)c2ccccc21
Yield: 87.6 %

Procedure:
4-Methylquinoline (470 mg, 3.3 mmol), (3-bromopropyl)triethylammonium bromide (1.0 g, 3.3 mmol), and 10 mL acetonitrile were stirred at 90° C. in a pressure vessel for 64 h. After cooling down, the solvent was removed under vacuum and the residue was purified by column chromatography (SiO2, gradient from CH2Cl2 to MeOH) to furnish 1-(3-triethylammoniopropyl)-4-methylquinolinium dibromide as a white solid (1.29 g, 88%). 1H NMR (400 MHz, CD3OD): δ 1.35 (t, J=7.4 Hz, 9 H), 2.54 (m, 2 H), 3.10 (s, 3 H), 3.39 (q, J=7.2 Hz, 6 H), 3.60 (t, J=8.0 Hz, 2 H), 5.18 (t, J=8.0 Hz, 2 H), 8.04 (d, J=6.0 Hz, 1 H), 8.09 (t, 1 H), 8.33 (t, 1 H), 8.61 (d, 1 H), 8.65 (d, 1 H), 9.43 (d, J=6.0 Hz, 1 H); HRMS (FAB+): m/z=365.1581 [M-Br]+ (calcd for C19H30BrN2: 365.1587).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: Nc1ccc(I)cn1
Product: Nc1ccc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (300 mg, 1.0 mmol) and commercially available 2-amino-5-iodopyridine (230 mg, 1.0 mmol) according to general procedure II. Obtained as a white solid (210 mg, 53%). MS (ISP) 379.2 [(M+H)+]; mp 241-244° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClC1C=CC=CC=1Cl>[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: c1ccc(-c2ccco2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Product: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-Phenyl-furan (119) (50 mg, 0.28 mmol) and (3-bromo-phenyl)-acetic acid (134 mg, 0.63 mmol) were dissolved in ortho-dichlorobenzene (4 ml). P2O5 (202 mg, 1.42 mmol) was added as a suspension in ortho-dichlorobenzene (2 ml). The reaction mixture was heated to 80° C. for 2 h and cooled to room temperature overnight. After the addition of further P2O5 (202 mg, 1.42 mmol), heating was resumed at 90° C. for 3 h. The reaction mixture was cooled to 0° C. and quenched with H2O (15 ml). The organic layer was separated and the aqueous layer was washed with DCM (3×10 ml). The combined organic layers were dried (MgSO4), filtered and the DCM removed in vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gel column and flushed with heptane (100 ml). The title compound was then eluted with 10% EtOAc in heptane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[OH:18])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[C:27](F)=[CH:28][C:29]([F:54])=[C:30]([S:32]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=2[O:52][CH3:53])[C:36]2[N:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:31]=1>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[CH:10][C:9]=2[O:18][C:27]2[C:26]([Cl:25])=[CH:31][C:30]([S:32]([N:35]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=3[O:52][CH3:53])[C:36]3[N:37]=[CH:38][C:39]([F:42])=[CH:40][N:41]=3)(=[O:33])=[O:34])=[C:29]([F:54])[CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cc(C(F)(F)F)ccc2O)ccn1
Reactant: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnc(N)c3)cc2F)c(OC)c1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
2-(2-Aminopyridin-4-yl)-4-(trifluoromethyl)phenol (Preparation 17, 0.93 g, 3.6 mmol) was taken up in dimethylsulfoxide (40 mL) and potassium carbonate (0.95 g, 6.9 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 19, 1.73 g, 3.64 mmol). The reaction mixture was stirred for 18 hours then diluted with water (120 mL) and the solid collected by filtration. The filtrate was extracted with ethyl ether. The solid was dissolved in dichloromethane and combined with the ether extract. The combined organic solution was dried over anhydrous magnesium sulfate, treated with activated carbon and filtered through a pad of diatomaceous earth. The solvent was concentrated in vacuo to give a thick oil. The oil was purified by silica gel column chromatography (0 to 5% methanol in dichloromethane gradient elution) and concentrated in vacuo to afford the title compound as a glass (2.24 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]3[N:16]=[CH:17][NH:18][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[C:8]1([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[CH:9]=1
Reactant: [H][H]
Reactant: Clc1ccc(-c2cccc(Cc3c[nH]cn3)c2)cc1
Agent: [Pd]
Solvent: CO
Product: c1ccc(-c2cccc(Cc3c[nH]cn3)c2)cc1

Procedure:
Prepared in analogy to Example 67 from 4-(4′-chloro-biphenyl-3-ylmethyl)-1H-imidazole, hydrogen and palladium in methanol. White crystalline solid. MS (ISP): 235.1 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[Br:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:32][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:18]([Cl:17])[CH:19]=1)=[O:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Br
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Br)cc1Cl

Procedure:
The product was prepared according to general working method I from (2-bromo-4-trifluoromethyl-phenoxy)-acetic acid (139b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]([O:31][C:29]([N:23]1[CH2:28][CH2:27][N:26]([C:4](=[O:5])[C:3]2[CH:7]=[C:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)[CH:9]=[CH:10][C:2]=2[F:1])[CH2:25][CH2:24]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (100 mg, 0.33 mmol), tert-butyl piperazine-1-carboxylate (187.3 mg, 1.0 mmol), HATU (255 mg, 0.67 mmol), and DIPEA (0.5 ml, 3.0 mmol) were dissolved in DMF (25 ml) and stirred at room temperature for 24 h. The reaction mixture was partitioned between DCM and water (50 ml each), and the organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford target compound (100 mg, 64%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(N(CC)CC)C>[N+:1]([C:4]1[C:5]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3,5-dinitro-1-carboxy-2-chlorobenzene (53 g) in acetonitrile (500 mL) and triethylamine (100 mL) was added benzylamine at 0° C. in a dropwise fashion. The reaction was allowed to warm to ambient temperature and stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to afford the crude product, 3,5-dinitro-1-carboxy-2-(benzyl)aminobenzene. The product was dissolved in methanol/12N HCl (400 mL, 3:1, v/v), and was hydrogenated at 60 psi for 3 hours until H2 intake stopped. The solvent was removed under reduced pressure to afford the crude product, 2,3,5-triamino-1-carboxybenzene. To the product in pyridine (400 mL) was added isobutyric anhydride (200 mL), and the reaction mixture was stirred at ambient temperature for 14 hours. The solvent was removed under reduced pressure to afford the crude product, 2,3,5-tri(isopropylcarbonylamino)-1-carboxybenzene. The product was refluxed in methanol/12N HCl (500 mL, 4:1, v/v) for 16 hours to afford the desired product, 2-isopropyl-4-methoxycarbonyl-6-aminobenzimidazole, after removal of the solvents under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].O>O1CCCC1>[F:8][C:4]1[CH:3]=[C:2]([CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)[OH:19])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a solution of 1-bromo-3-fluorobenzene (10.0 g, 57.1 mmol) in tetrahydrofuran (100 mL) was added n-BuLi (1.6M, 35.7 mL, 62.8 mmol) at −78° C. and the mixture was stirred at that temperature for 20 minutes. To the mixture was added 3-fluorobenzaldehyde (7.80 g, 62.8 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was added water and the product was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 10.1 g of bis(3-fluorophenyl)methanol. To a solution of this compound (6.60 g, 30.0 mmol) in diisopropylether (50 mL) was added phosphorus tribromide (5.41 g, 20.0 mmol) with ice-cooling and the mixture was stirred at that temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropylether. The organic layer was washed with water and saturated with aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 5.61 g of the title compound. Yield 53%. Oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 100 °C

Procedure:
To a solution of the 1-benzyl-4-[3-(4-fluorobenzoyl)propyl]piperidine (0.6 g) synthesized in 4) in dioxane (1 ml) was added 3 ml of pyrrolidine and the mixture was heated at 100° C. for 16 hours. Thereafter, the procedure of Example 37 was repeated to give 0.58 g of 1-benzyl-4-[3-(4-pyrrolidinobenzoyl]propyl]piperidine as colorless crystals melting at 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1Cl.C(#N)CC.Cl[Si](C)(C)C.[I-:27].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[I:27]
Reactant: CN(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CCC#N
Product: CN(Cc1cnc(I)c(Cl)c1)C1=CC(=O)OC1
Yield: 29.9 %

Procedure:
150 mg (0.55 mmol) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one (10), 1.2 ml of propionitrile, 140 μl of chlorotrimethylsilane (1.10 mmol) and 247 mg of sodium iodide (1.65 mmol) are heated under reflux for 2 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (5:1) gives 60 mg (29% of theory) of 4-[[(5-chloro-6-iodopyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[OH:12][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][CH:6]=2)[CH2:9][O:10][CH2:11]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C2(O)COC2)cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2(O)COC2)cc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a stirred solution of 3-(4-aminophenyl)oxetan-3-ol (1.19 g, 6.66 mmol, 1.0 eq) in acetone (20 mL) was added pyridine (1.05 g, 13.29 mmol, 2.0 eq) and phenyl chloroformate (1.05 g, 6.68 mmol, 1.1 eq) at 0° C. and the mixture was stirred at 0° C. for 30 min. The solvent was evaporated. The resulting residue was purified by CC using EtOAc/PE (3:7) as eluent to get phenyl 4-(3-hydroxyoxetan-3-yl)phenylcarbamate (1.2 g, 63%) as a white solid (TLC system: EtOAc/PE (7:3), Rf: 0.7).