Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Cl:1][CH2:2][CH2:3][C:4]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:17])[C:8]2([CH3:18])[CH3:7])=[O:5]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)C(=O)Nc2ccc(C(=O)CCCl)cc21
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
Under nitrogen atmosphere, add chloropropionyl chloride (1.54 mL, 16.13 mmol) to a mixture of 3,3-dimethyl-1,3-dihydro-indol-2-one (2.0 g, 12.41 mmol) and aluminium trichloride (10.26 g, 76.92 mmol) in carbon disulphide (70 mL). Heat under reflux for 3 h then allow to cool. Decant off the solvent and replace it carefully with ice/water (200 mL). Allow the resultant suspension to stir for 20 min before filtering off the product and washing with water (80 mL). Dry in vacuo to obtain the desired intermediate as a pale brown solid (3.08 g, 99%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32]([CH:29]5[CH2:30][CH2:31][O:26][CH2:27][CH2:28]5)=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (22.3 mg, 74%), MS (ISP) m/z=443.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and tetrahydro-2H-pyran-4-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C(O)(C)C>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH2:14][C@@H:13]([OH:12])[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: N#Cc1ccc(OC[C@H]2CO2)cc1
Reactant: CCC[S@](=O)CCCNCC
Solvent: CC(C)O
Product: CCC[S@](=O)CCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1
Yield: 102.4 %

Procedure:
A mixture of 3 g of ethyl (3-(S*)-propylsulfinyl)propylamine and 3.18 g of (R)-4-(oxiranylmethoxy)-benzonitrile was refluxed for 16 h in 25 ml of isopropyl alcohol. After evaporation of the solvent, the crude product was dissolved in 2M hydrochloric acid, washed with ether, the solution brought to pH 11.5 with 2M sodium hydroxide and extracted with dichloromethane. Evaporation of the organic phase gave 6.11 g of an oil,
Reaction SMILES: [Cl-].[OH:2][C@H:3]([CH3:15])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[NH3+:14].[N:16](OCCC(C)C)=O.O>ClCCl.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][O:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:14][N:16]=[C:5]2[CH2:4][C@H:3]([OH:2])[CH3:15]
Reactant: COc1ccc([NH3+])c(CC[C@@H](C)O)c1
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[nH]nc(C[C@@H](C)O)c2c1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a stirred suspension of the product from step C (2.66 g, 11.5 mmol) in dichloromethane (150 mL) at ambient temperature was added isoamyl nitrite (2.47 mL, 18.4 mmol, 1.6 equiv.). After 30 minutes tetrabutylammonium acetate (5.54 g, 18.4 mmol, 1.6 eq) was added and the mixture was stirred for 2 hours. Water was added to the mixture and the organic layer was separated and washed with 2 N NaOH and water. After drying and evaporation the crude product was purified by column chromatography (gradient of 20% to 40% ethyl acetate in hexane) to give an oil (1.58 g) that crystallized from ethyl acetate/hexane (1:1) to afford a solid (1.30 g, 55%): mp 89-91° C.; LC/MS (+APCI) m/z 207 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.[Cu]I.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>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:27]#[C:26][CH2:25][OH:28])[CH:17]=3)[N:12]([CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Yield: 85 %

Procedure:
A suspension of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide; (Ex. 1, 0.13 g), propargyl alcohol (0.035 mL), CuI (0.028 g), and Pd(PPh3)2Cl2 (0.013 g) in 11 mL diethylamine is stirred at room temperature for 18 h. The solid in the reaction is filtered, washed with water, and dried. The solid is dissolved in CH2Cl2 and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affords the desired product as a tan solid (0.094 g, 85%). Physical characteristics are as follows: m.p. 229-231° C.; 1H NMR (300 MHz, DMSO-d6) δ9.92, 8.19, 7.96, 7.40, 5.45, 4.55, 4.36, 4.24; IR (drift) 3365, 3273, 1656, 1598, 1551, 1479, 1410, 1351, 1284, 1034, 1028, 821, 812, 671, 646 cm−1; MS (ESI) m/z 382.1 (M+H)+; HRMS (FAB) calcd for C20H16ClN3O3+H1 382.0958, found 382.0963.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:56])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:48][CH3:49])[C@H:43]([C:45](O)=[O:46])[CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:82][CH:83]([CH:88]1[CH2:95][C:94]2[C:89]1=[CH:90][CH:91]=[CH:92][CH:93]=2)[C:84]([O:86][CH3:87])=[O:85].C(NC(C)C)(C)C>ClCCl.CN(C)C=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:20])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:48][CH3:49])[C@@H:43]([CH3:44])[C:45]([NH:82][CH:83]([CH:88]3[CH2:95][C:94]4[C:89]3=[CH:90][CH:91]=[CH:92][CH:93]=4)[C:84]([O:86][CH3:87])=[O:85])=[O:46])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:56])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: COC(=O)C(N)C1Cc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NC(C(=O)OC)C1Cc2ccccc21)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To a mixture of #105 (225 mg, 0.289 mmol, 1 eq.) in dichloromethane (15 mL, 0.02 M) and N,N-dimethylformamide (1 mL) was added HATU (136 mg, 0.347 mmol, 1.2 eq.). After five minutes, a solution of amine #102 (72.4 mg, 0.318 mmol, 1 eq.) and diisopropylamine (203 mL, 1.16 mmol, 3 eq.) in dichloromethane (5 mL) was added. After 24 hours, the reaction mixture was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo onto silica gel, and purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) to give the single enantiomer #106 (210 mg, 76%) as a clear oil. LC-MS: m/z 953.1 [M+H+], retention time=3.99 minutes; 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers, characteristic signals: 7.76 (d, J=7.5 Hz, 2H), 7.57-7.64 (m, 2H), 7.40 (dd, J=7.5, 7.4 Hz, 2H), 7.28-7.34 (m, 2H), 4.82-4.88 (m, 1H), 3.95-4.01 (m, 1H), 3.76 and 3.82 (2 s, total 3H), 3.30, 3.31, 3.34 and 3.35 (4 s, total 6H), [1.20 (d, J=7.0 Hz) and 1.20 (d, J=7.0 Hz), total 3H].
Reaction SMILES: [OH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=2[N:3]=1.FC(F)(F)C(O)=O.C(OCC)C>C(Cl)Cl>[OH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(O)nc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(O)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.9 g (2.25 mmol) of tert.butyl 4'-[(2-hydroxybenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate are dissolved in 10 ml of methylene chloride and treated with 10 ml of trifluoroacetic acid. The solution is stirred for 2 hours at ambient temperature and then evaporated to dryness on a rotary evaporator. The oily residue is dissolved in 50 ml of methylene chloride and extracted by shaking twice using water. The organic phase is dried using magnesium sulphate and evaporated to dryness. The crystalline residue thus obtained is mixed with a small amount of diethylether, filtered under suction and dried in vacuum at 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([Cl:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>>[C:40]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([Cl:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)c(Cl)c2)ccn1
Temperature: 35 °C
Reaction time: 13 h
Yield: 63 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (125 mg, 0.28 mmol) in acetic anhydride (6.0 mL) was added triethylamine (0.4 mL). The reaction mixture was stirred at 35° C. for 13 hours, then filtered, and the filter cake was washed with petroleum ether (6 mL), MeOH (3 mL), and ethyl acetate (6 mL) respectively to give the title compound as a light blue solid (87 mg, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([OH:12])[C:4]=1[CH3:13])#[N:2].[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:11]1[C:3]([C:1]#[N:2])=[C:4]([CH3:13])[C:5]([OH:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1c(C#N)ccc(C(=O)O)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(O)c(C(=O)O)cc(Br)c1C#N
Temperature: 15 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 4-cyano-2-hydroxy-3-methylbenzoic acid (5.50 g) in DMF (50.0 mL) was added N-bromosuccinimide (5.50 g) under ice-cooling, and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.40 g: containing DMF).
Reaction SMILES: [N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23]Br.C([O-])(O)=O.[Na+].O>CN(C=O)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1ccc2nc(N3CCNCC3)[nH]c2c1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2nc(N3CCN(Cc4c(Cl)cccc4Cl)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the benzoimidazole from step (a) above (96 mg, 0.36 mmol), 2,6-dichlorobenzyl bromide (86 mg, 0.36 mmol, Aldrich) and NaHCO3 (151 mg, 1.8 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. Water (10 mL) was then added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (5 mL) and brine (5 mL) then dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 40% EtOAc/hexane. The material was recrystallized from EtOAc/hexanes to give the title compound as a white solid. M.p. 254-256° C. MS (ESI, pos. ion) m/z: 429 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:6]([N+:11]([O-:13])=[O:12])=[CH:7][C:8]=1[O:9]C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:6]([N+:11]([O-:13])=[O:12])=[CH:7][C:8]=1[OH:9]
Reactant: COc1cc(CCCCC(=O)O)c([N+](=O)[O-])cc1OC
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCCCc1cc(O)c(O)cc1[N+](=O)[O-]

Procedure:
A solution containing 42.0 g of the product obtained in Example 40 in 100 ml of acetic acid and 150 ml of 48% hydrobromic acid was refluxed for 10 h. 1 l of saturated Na2SO4 -solution was added to the reaction mixture and extracted with ether. The solvent was evaporated in vacuo and the residue crystallized from ethyl acetate-petroleum ether. Yield 7.9 g (19%), m.p. 111°-114° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=[O:21])[CH3:20])[N:3]=1.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([C:4]1[N:3]=[C:2]([C:22]#[N:23])[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:21])[CH3:20]
Reactant: CC(=O)c1nc(Cl)c2ccccc2c1-c1cccc(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(=O)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
A mixture of 1-[1-chloro-4-(3-fluorophenyl)isoquinolin-3-yl]ethanone (100 mg, 0.334 mmol), zinc cyanide (78 mg, 0.66 mmol) and tetrakis(triphenylphosphine)palladium(0) (77 mg, 0.067 mmol) in dry N,N-dimethylformamide (1.1 mL) was stirred at 130° C. overnight. The mixture was filtered, diluted with water, extracted with dichloromethane. The combined extracts were dried over MgSO4, concentrated and purified on silica gel (0-60% ethyl acetate in hexane) to give the desired product (6 mg, 6%). LCMS calculated for C18H12FN2O (M+H)+: m/z=291.1; Found: 291.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:15]([C:10]1([CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1(CCCC)CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC1(CCCC)CNCCC1O

Procedure:
A mixture of 1-benzyl-3,3-di-n-butyl-4-hydroxypiperidine (0.9 g, 2.97 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred at ambient temperature in hydrogen atmosphere (1 atm.) for 8 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-di-n-butyl-4-hydroxypiperidine as oil. Yield 0.5 g (85%), C14H27NO, m/z 214 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([C:19]#[N:20])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-:29].[Na+]>O>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)([C:19]([NH2:20])=[O:29])[CH2:17][CH2:18]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: N#CC1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 500 ml 90% sulfuric acid were slowly added at 0° C. 152 g (493 mmol) 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile. The mixture was stirred at ambient temperature for 16 h, then cooled to 0° C., diluted with 200 ml water, pH was adjusted to 9 by addition of 5N NaOH and the aqueous mixture extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated: 155 g 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carboxylic acid amide as light brown crystals: MS (ISP): 328.3 MH+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Cl)c(Cl)c1Cl
Yield: 64.3 %

Procedure:
A solution of 2,3,4-trichlorobenzenesulfonyl chloride (15 mg, 0.055 mmol), 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) and dry pyridine (12 μL) in CH2Cl2 (200 μL) was stirred at room temperature over night. The solvent was evaporated and the crude product was purified by preparative HPLC (ACE C8, 5 μm 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/CH3CN) to give 13 mg (65%) of the title compound. MS (ESI+) calcd for C13H8Cl3N5O2S 402.946428, found 402.946188.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:4]2[N:3]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[C:17]([I:19])=[C:4]2[N:3]=1
Reactant: Cc1cccc(-c2cc(Cl)nc3cc(C)nn23)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1cccc(-c2cc(Cl)nc3c(I)c(C)nn23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
5-Chloro-7-(3-methylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine (381 mg) is dissolved in CH2Cl2 (70 mL) and N-iodosuccinimide (NIS, 467 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (580 mg). 1H NMR (CDCl3, 300 MHz) δ 7.76 (m, 2H), 7.45 (m, 3H), 6.84 (s, 1H), 2.50 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:37]([N:38]2[CH2:44][CH2:43][CH2:42][N:41]([CH3:45])[CH2:40][CH2:39]2)=[CH:36][C:12]2[NH:13][C:14]([C:16]3[C:20]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:19][N:18](C4CCCCO4)[N:17]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[F:8][C:9]1[C:37]([N:38]2[CH2:44][CH2:43][CH2:42][N:41]([CH3:45])[CH2:40][CH2:39]2)=[CH:36][C:12]2[NH:13][C:14]([C:16]3[C:20]([NH:21][C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[O:23])=[CH:19][NH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: CN1CCCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCCN(c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 60 mg of N-[3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide in solution in 1 mL of dichloromethane. The reaction medium is stirred at 22° C. for 16 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography. The elution is carried out with pure dichloromethane and then with a mixture of dichloromethane containing 5% of ammoniacal methanol. 29 mg of N-{3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are obtained in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.42 to 2.27 (m, 8H); 2.90 (s, 3H); from 3.18 to 3.65 (m, 12H); 7.20 (d, J=7.0 Hz, 1H); 7.56 (d, J=12.0 Hz, 1H); 8.00 (s, 1H). ES mass spectrum: m/z=439 (M−H)—base peak.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=O)=[CH:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.Cl.[Cl:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([S:45]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46])[CH:39]=[CH:38]2>>[ClH:34].[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:51]3[CH2:50][CH2:49][N:48]([S:45]([C:40]4[CH:39]=[CH:38][C:37]5[C:42](=[CH:43][CH:44]=[C:35]([Cl:34])[CH:36]=5)[CH:41]=4)(=[O:47])=[O:46])[CH2:53][CH2:52]3)=[O:19])=[CH:16][C:11]=2[NH:10][CH:9]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: O=C(c1ccc2nc[nH]c2c1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 3, 4 or 10 except for the use of methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][C:19](O)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24].CCCP(=O)=O>CN(C=O)C>[CH3:1][N:2]1[C:7]2=[C:8]3[N:9]([C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24])[CH2:17][CH2:18][C:19]3=[O:20]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCC(=O)O)cc2n(C)c1=O
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CC3
Temperature: 25 °C

Procedure:
3-(1,3-Dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propanoic acid (step 2) (2.11 g, 6.63 mmol) and propylphosphonic anhydride (4.34 g, 6.63 mmol) 50% in DMF was heated to 100° C. overnight. The reaction mixture was cooled to RT and the precipitate isolated using suction filtration. The isolated orange solid was washed with Et2O and dried in a vacuum oven at 50° C.