Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1>[Zn]>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][C:15]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Cc1cccc(C)c1
Reactant: O=C(O)c1ccccc1
Agent: [Zn]
Product: Cc1ccc(C(=O)c2ccccc2)c(C)c1
Temperature: 25 °C

Procedure:
Benzoic acid (0.31 g, 2.5 mmol), m-xylene (0.53 g, 5.0 mmol), [bmim][NTf2] (0.50 g) and M(NTf2)2 (M=Co (0.14 g, 0.25 mmol), or Zn (0.15 g, 0.25 mmol) were placed in flasks equipped with stirrers and condensers. The contents of the flask were heated under reflux (ca 140-150 ° C.) for 2 days, then cooled to room temperature. The products were analysed by gas chromatographic analysis and found to give 93 and 87% conversions (for Co and Zn bis-triflimide reactions respectively) to 2,4-dimethylbenzophenone and, it is believed to be, 2,6-dimethylbenzophenone (11:1 isomer ratio in both cases). The results show that zinc and cobalt bis-triflimide have been found to catalyse the benzoylation of m-xylene with benzoic acid. The reaction is slower that the corresponding reaction with benzoyl chloride. The catalyst was recycled and the reaction was repeated. The results of the repeat experiment are shown in Table 4.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccnc1-c1ccc(F)cc1

Procedure:
A mixture of methyl 2-chloropyridin-3-carboxylate (6.8 g.), 4-fluorobenzeneboronic acid (7.2 g.), 1M. aqueous sodium carbonate (40 ml.), Pd(dppb)Cl2(1.2 g.), ethanol(10 ml.) and toluene(150 ml.) was stirred at reflux under an inert atmosphere for 5 hr. The reaction was then cooled, the oganic layer separated, the aqueous extracted with toluene and then the Icombined extracts dried and evaporated to dryness. The product was purified by flash column chromatography eluting wth ethyl acetate/iso-hexane(9:1,8:2,7:3) to give methyl 2-(4-fluorophenyl)pyridin-3-carboxylate as a white solid(7.5 g.)
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:22])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].CO[C:25](OC)([N:27]([CH3:29])[CH3:28])[CH3:26]>>[CH3:28][N:27]([CH3:29])/[C:25](/[CH3:26])=[CH:2]/[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:22])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:3]
Reactant: CC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Reactant: COC(C)(OC)N(C)C
Product: C/C(=C\C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12)N(C)C
Yield: 57.4 %

Procedure:
A solution of N-(2-acetylthiophen-3-yl)-2-(naphthalen-1-yl)acetamide (197 mg, 0.64 mmol) in N,N-dimethylacetamide dimethyl acetal (0.3 mL, 2.05 mmol) was heated at 80° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried (sodium sulfate), filtered and concentrated to give the desired N-(2-(3-(dimethylamino)but-2-enoyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (139 mg, 58%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]3[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:12]([F:15])([F:13])[F:14])=[C:2]([Cl:1])[C:7]=2[Cl:8])=[CH:28][C:27]=1[F:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2Cl)cc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2,3-dichloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 197, step 5) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=546.2 [M−H+].
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(#N)N(C)C>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][Br:22])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: O=C(c1ccccc1)c1ccc(-c2ccc(CBr)cc2)cc1
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A mixture of 26.1 g of 4-benzoyl-4'methylbiphenyl, 18.6 g of N-bromosuccinimide and 0.18 g of azaisobutyronitrile in 600 mL of carbon tetrachloride was heated to boiling for 4 hours. The brown solution obtained was filtered and evaporated. The residue was recrystallized from cyclohexane. There are obtained 29.9 g (89%) of 4'-(bromomethyl)-4-biphenylyl phenyl ketone as colorless crystals with a m.p. of 110°-112° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>>[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])[CH2:4][CH2:3]2)[C:15]=1[C:16]#[N:17]
Reactant: CC(C)C(=O)N1CCC(O)CC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)C(=O)N1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22a from 1-(4-hydroxypiperidin-1-yl)-2-methylpropan-1-one (Example 143c) and 2-amino-6-fluorobenzonitrile as an off-white solid (87%). MS 288 (MH+).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-(6-fluoropyridin-3-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (5.0 g, 11.9 mmol, (2RS,3SR) form: (2RS,3RS) form=10:1) in methanol (20 ml) was added 2N aqueous sodium hydroxide solution (11.9 ml, 23.8 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (2RS,3RS)-3-(6-fluoropyridin-3-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionic acid (3.75 g, (2RS,3SR) form: (2RS,3RS) form=10:1, 80%) as an amorphous compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([CH3:5])[CH3:4].[CH3:16][C@@H:17]1[CH2:19][O:18]1.O>O1CCCC1.CCOCC>[CH:3]([C:6]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:16][C@H:17]([OH:18])[CH3:19])([CH3:5])[CH3:4]
Reactant: CC(C)c1c(F)ccc2[nH]ccc12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)c1c(F)ccc2c1ccn2C[C@@H](C)O
Yield: 81 %

Procedure:
A suspension of 0.16 g of sodium hydride dispersion in 22 ml of tetrahydrofuran was treated with 0.38 g of 4-isopropyl-5-fluoroindole at 0° and stirred at this temperature for I hour. After the addition of 0.6 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 120 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). 0.41 g (81%) of (R)-1-(4-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as a yellow oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (78 mg, 75%), MS (ISP) m/z=415.5 [(M+H)+], mp 194.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2,2-dimethyl-propionic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]([NH:15][CH2:16]CCC)=[O:14])(=[O:11])=[O:10].C(Cl)(Cl)=O.ClCC1C=CC=CC=1S(N=C=O)(=O)=O.S(N=C=O)(N=C=O)(=O)=O.NC1[N:53]=[C:52]([O:54][CH3:55])[CH:51]=[C:50]([O:56][CH3:57])[N:49]=1>C1(C)C(C)=CC=CC=1.N12CCC(CC1)CN2.C(#N)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]([NH:15][C:16]1[N:53]=[C:52]([O:54][CH3:55])[CH:51]=[C:50]([O:56][CH3:57])[N:49]=1)=[O:14])(=[O:10])=[O:11]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccccc1CCl
Agent: C1CN2CCC1CN2
Agent: O=C(Cl)Cl
Agent: O=C=NS(=O)(=O)N=C=O
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2CCl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
A solution of 2-(chloromethyl)-N-(butylaminocarbonyl)benzene sulfonamide (1.33 g, 4.38 mmol) and diazabicyclo[2.2.2]octane (5 mg) in xylene (12 ml) was heated at reflux and contacted in portions with phosgene (1.0 ml. condensed phase). After 2.0 hrs at reflux, the mixture was cooled to room temperature, decanted, and volatiles were removed to give 1.56 g of crude product. The IR spectrum of 2-(chloromethyl)-benzenesulfonyl isocyanate featured a strong band at 2250 cm-1. The crude sulfonyl isocyanate was contacted with acetonitrile (10 ml) and 2-amino-4,6-dimethoxypyrimidine (0.68 g, 4.4 mmol) and stirred for 16 hrs. Filtration gave 1.18 g of white solid, mp 192°-193°. The sample was dissolved in 0.5N NaOH, filtered and pH adjusted to 6.5. The mixture was cooled and filtered and the solid washed with ice water and dried to give 0.90 g of white solid. 1H nmr δDMSO-d6TMS 12.7 (brd s, 10.50 (s, 1H) 8.13-7.97 (m, 1H), 7.73-7.40 (m, 3H), 5.90 (s, 1H), 5.10 (s, 2H), 3.87 (s, 6H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]=O)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br-].[C:21]([C:23]1[CH:48]=[CH:47][C:26]([CH2:27][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:25][CH:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]=[CH:27][C:26]3[CH:47]=[CH:48][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=Cc3ccc(C#N)cc3)CC2)CC1
Reaction time: 72 h

Procedure:
A mixture of 5.6 g of trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanecarboxaldehyde, 10.6 g of p-cyanobenzyl-triphenylphosphonium bromide and 200 ml of dioxan was treated with 14.5 g of powdered potassium carbonate and the mixture was heated to boiling for 72 hours. After cooling, the mixture was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel with hexane/diethyl ether (vol. 4:1), thereby obtaining 6.0 g of p-[2-[trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexyl]vinyl]benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:25])[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C)C=O.C(OC(=O)C)C>[CH2:37]([O:25][C:10]1[C:9]2[C:8](=[O:26])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[C:19](=[O:20])[C:18]=2[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2)[CH:36]=[CH2:35]
Reactant: COCOc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1c2c(c(OCOC)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxymethyl ether 6 (0.0172 g, 0.045 mmol) was dissolved in 1.5 mL dry dimethylformamide (DMF). Ground K2CO3 (0.0186 g, 0.135 mmol) was added, followed by allyl bromide (0.0077 mL, 0.09 mmol). The mixture was stirred at room temperature overnight, then diluted with 100 mL of ethylacetate, washed with saturated NH4Cl solution, dried (MgSO4), and concentrated to give crude 10. The crude product 10 was chromatographed on silica gel, eluting with ethylacetate and hexanes to give white solid allyl, methoxymethyl diether 10: (0.0063 g, 33%). 1H NMR (CDCl3) δ 9.1 (dd, 1H), 8.8 (dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 6.1 (m, 1H), 5.8 (s, 2H),5.5 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS: 423 (M+1); 445 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:33][CH2:34][O:35][CH3:36])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: COCCBr
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCOC
Temperature: 90 °C
Reaction time: 48 h
Yield: 16.6 %

Procedure:
A mixture of 3-(2-Fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (234 mg, 0.55 mmol), potassium carbonate (91 mg, 0.66 mg), sodium iodide (103 mg, 0.69 mmol) and 1-bromo-2-methoxy-ethane (0.057 mL, 0.61 mmol) in DMF (5 mL) was stirred a 90° C. for 2 days. It was cooled to room temperature, diluted with water and extracted into ethyl acetate. The organic layer was separated then washed with water followed by brine, then dried (Na2SO4), filtered and concentrated to give a residue which was purified by flash chromatography (Si-PPC, ether:pentane, gradient 20:80 to 50:50) to provide the title compound as a yellow oil (44 mg, 16%). LCMS (method B): RT=2.56 min, M+H+=483.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:25]1[N:26]=[C:27]([CH3:49])[N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3>N1C=CC=CC=1>[C:1]([O:8][CH:9]([C:25]1[N:26]=[C:27]([CH3:49])[N:28]([C:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:29]=1)[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(C)n1)CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1)C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
Acetic anhydride (1.31 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(2-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.42 g) in pyridine (20 ml). After being stirred at room temperature for 6 hours, the solution was evaporated in vacuo. The residue was diluted with chloroform, washed with 5% aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated in vacuo, the residue was subjected to column chromatography on silica gel (5% methanol-chloroform). The fractions containing the product were evaporated in vacuo and crystallized from n-hexane-ether to give 7-[(acetoxy)(2-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (1.3 g).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([O:14][CH2:15][C:16]#[CH:17])=[N:5][C:6](F)=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>>[NH2:1][C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]([Cl:2])=[C:4]([O:14][CH2:15][C:16]#[CH:17])[N:5]=1
Reactant: N
Reactant: C#CCOc1nc(F)c(C(F)(F)F)cc1Cl
Product: C#CCOc1nc(N)c(C(F)(F)F)cc1Cl

Procedure:
Starting from 3.1 g (0.182 mol) of ammonia and 10 g (0.039 mol) of 3-chloro-6-fluoro-2-propargyloxy-5-trifluoromethylpyridine, 4.1 g (42.3% of theory) of the title compound of m.p. 56°-58° C. (Table II, No. 2.035) and 2.7 g (27% of theory) of reisolated starting material were obtained after stirring for 3 hours at 110° C. under the same conditions as described in Example III.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C=O.Cl.O.[Cl:24][CH2:25]Cl>>[Cl:24][CH2:25][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:17])([F:18])[F:16]
Reactant: ClCCl
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1OC
Agent: C=O
Agent: Cl
Solvent: O
Product: COc1cc(CCl)c(CCNC(=O)C(F)(F)F)cc1OC
Reaction time: 3 h
Yield: 77 %

Procedure:
In a three-necked flask, mix N-[2-(3,4-dimethoxyphenyl)ethyl]-2,2,2-trifluoroacetamide (35 g, 126 mmoles) and 37% aqueous formaldehyde (776 mL, 1.014 mole) in 120 mL of dichloromethane at 0° C. To the resulting two-phase mixture slowly add, at 0° C., 345 mL of 37% aqueous hydrochloric acid solution and heat at 40° C. After being in contact for 3 hours, hydrolyse the mixture using 250 mL of water and wash the aqueous phase with dichloromethane (2×100 mL). Combine the organic phases, dry them over MgSO4 and carry out drying in vacuo to obtain a beige meringue (38.2 g). The product obtained is recrystallised from toluene to obtain 31.5 g of a white powder corresponding to the title compound.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH:25]=O.N1CCCCC1>C(O)C>[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH:25]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of 5-aminosulfonyl-2-oxindole (84 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 88 mg (71% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide.
Reaction SMILES: [I:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(=O)(=O)(O)O>>[I:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)CI)cc1
Agent: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)CI)cc1

Procedure:
A mixture of 63.7 g. of N-[p-(iodomethylsulfonyl)-phenyl]acetamide and 360 ml. of 5.5 N sulfuric acid is stirred and heated at reflux until all of the solid dissolves. After cooling, the crude, solid product separates; it is collected, washed with cold water and air-dried. After crystallization from methanol, 26 g. of p-(iodomethylsulfonyl)aniline is obtained; m.p. 169.5°-72° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:3][CH2:2]1.C1(CN2C3C=CC(C4C=CC(C#N)=CC=4)=CC=3N=C2COCC2(C3C=CC=CC=3)CCN(C)CC2)CC1>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(C(F)(F)F)ccc3n2CC2CC2)(c2ccccc2)CC1
Agent: CN1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Product: CN1CCC(COCc2nc3cc(C(F)(F)F)ccc3n2CC2CC2)(c2ccccc2)CC1
Yield: 30.7 %

Procedure:
N-Methylation of tert-butyl 4-(((1-(cyclopropylmethyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (35 mg, 0.064 mmol) was carried out as described in the preparation of 4-(1-(Cyclopropylmethyl)-2-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-1H-benzo[d]imidazol-5-yl)benzonitrile obtain the title compound (9 mg, 31%) as a free base. 1H-NMR (500 MHz, CD3OD) δ 7.93 (s, 1 H), 7.71 (d, J=8.5 Hz, 1 H), 7.60 (d, J=8.5 Hz, 1 H), 7.40-7.25 (m, 5 H), 4.77 (s, 2 H), 3.88 (d, J=6.4 Hz, 2 H), 3.62 (bs, 2 H), 3.41 (m, 2 H), 2.93 (m, 2 H), 2.78 (s, 3 H), 2.54 (m, 2 H), 2.21 (m, 2 H), 1.04 (m, 1 H), 0.53-0.46 (m, 2 H), 0.33-0.29 (m, 2 H). 19F NMR (471 MHz, CD3OD) δ −69.0.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20]N(C)C)[CH:18]=O)=[CH:13][CH:12]=1>CO>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:20]=[C:6]([C:4]#[N:5])[C:7](=[O:8])[NH:9][CH:18]=2)=[CH:13][CH:12]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O

Procedure:
To a solution of 37.6 g. of sodium methoxide in 650 ml. of methanol is added 29.24 g. of cyanoacetamide followed by 26.1 g. of 2-(4-chlorophenyl)-3-(dimethylamino)-2-propenal. The resulting solution is heated at reflux temperature for 16 hours to separate a yellow solid. Then 50 ml. of glacial acetic acid is added and the mixture is diluted with water, causing a new yellow solid to separate. This solid is collected by filtration and is washed with water to give 60.5 g. of the product of the Example m.p. 285°-290° C.