Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(F)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-[(4-fluoro-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-di-hydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 4-fluoro-benzoic acid. MS calcd. for C26H21ClFN3O3 [(M+H)+] 478.1, obsd. 477.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[N:12]=1.O.[NH2:20][NH2:21]>O1CCCC1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10]/[C:9](=[N:20]/[NH2:21])/[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: NN
Reactant: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Solvent: C1CCOC1
Solvent: O
Product: N/N=C1\COc2nc(Br)c(-c3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
In a 15 ml vial was 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-thione (100 mg, 0.311 mmol) and hydrazine monohydrate (0.049 ml, 1.557 mmol) in tetrahydrofuran (5 ml) to give a brown solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the crude residue was slurred in diethyl ether. The supernatant solvent was removed and the brown solid vas dried until constant weigh to afford the title compound (90 mg, 90%). It was used for the next step without further purification. LCMS (Method D): RT 0.770 min, M+1=321.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:24][CH3:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.BrC[CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][CH2:28][CH2:29][S:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:9][CH2:10]2)[C:22]2[C:17]([CH:16]=1)=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH3:25]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: CCc1cc2cc(F)ccc2n1C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2cc(F)ccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1

Procedure:
A mixture of 1-(1-Benzyl-piperidine-4-yl)-2-ethyl-5-fluoro-1H-indole (2.4 g), 1-(3-Bromo-propylsulfanyl)4-fluoro-benzene (2.4 g), acetonitrile and potassium carbonate is heated under reflux for 5 h. The solvent is removed and the resulting oil is purified with flash column chromatography (1:1 ethyl acetate:petrol ether). The fraction containing the product is freed from solvent and the resulting oil crystallized with ethanol. Yield is 1.2 g (30%) of colourless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([CH2:19][NH:20][C:21](=[O:36])[O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14]2)=[O:6].[CH3:37]I>CN(C)C=O>[CH3:37][N:20]([CH2:19][CH:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][C:5]([O:4][CH3:3])=[O:6])[CH2:14]1)[C:21](=[O:36])[O:22][CH:23]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COc1cccc2c1CCC(CNC(=O)OC(c1ccccc1)c1ccccc1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCC(CN(C)C(=O)OC(c1ccccc1)c1ccccc1)C2
Reaction time: 7 h
Yield: 59.1 %

Procedure:
60% Sodium hydride (10.2 mg) was added to a stirred solution of benzhydryl N-[[1,2,3,4-tetrahydro-5-(methoxycarbonylmethoxy)-2-naphthyl]methyl]carbamate (117 mg) and methyl iodide (36 mg) in N,N-dimethylformamide (1.2 ml) under ice cooling and the mixture was stirred at the same temperature for 7 hours, then another 60% sodium hydride (10.2 mg) and methyl iodide (36 mg) was added thereto. The resulting mixture was stirred at room temperature for 3 days and extracted with ethyl acetate. The extract was washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel to afford benzhydryl N-methyl-N-[[1,2,3,4-tetrahydro-5-(methoxycarbonylmethoxy)-2-naphthyl]methyl]carbamate (71 mg) as an oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])(=[O:18])=[O:17]
Reactant: C=CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCOS(C)(=O)=O

Procedure:
To a solution of 5-hexen-1-ol (5.0 mmol) and triethylamine (5.5 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (5.5 mmol) dropwise at −5° C. The mixture was continuously stirred until the reaction was complete (˜2 h). Dichloromethane (50 mL) was added to the mixture followed by washing with 10% sodium bicarbonate solution (2×15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate and concentrated to give 5-hexenyl methanesulfonate, which was used next without further purification. The methanesulfonyl ester (4.0 mmol) and sodium azide (10 mmol) were dissolved in 8:1 DMF—H2O (16 mL) and stirred overnight at 50° C. The mixture was allowed to cool to room temperature, diluted in 50 mL of water, and extracted with diethyl ether (3×30 mL). The ethereal layers were combined, washed with brine (2×15 mL), dried over sodium sulfate, and concentrated in vacuo to give 5-hexenyl azide. The azide (5.0 mmol) was dissolved in diethyl ether (50 mL) and lithium aluminum hydride (5.0 mmol) was added in three portions under argon in a water bath. The grayish suspension was vigorously stirred for ˜40 min and then quenched by the addition of water (5 mL). Sodium hydroxide solution was added to dissolve the solid and the resulting solution was extracted with diethyl ether (5×30 mL). The organic phase was dried over sodium sulfate and concentrated to give amine 13 (57% yield from the alcohol). 1H NMR (250 MHz, D2O): δ 6.11–5.95 (m, 1H), 5.26–5.14 (m, 2H), 3.14 (t, J=7.3 Hz, 2H), 2.25 (m, 2H), 1.87–1.75 (m, 2H), 1.67–1.58 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9](=[O:18])[C:8]=2[CH:19]=1>O.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH:9]([OH:18])[C:8]=2[CH:19]=1
Reactant: O=c1c2ccccc2ccc2ccc(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1c2ccccc2C=Cc2ccc(Cl)cc21

Procedure:
A solution of 0.30 gram (0.0078 mole) of sodium borohydride in 5 milliliters of water was added to a solution of 0.75 gram (3.2 millimoles) of 3-chloro-5H-dibenzo[a,d]cyclohepten-5-one in 50 milliliters of methanol and the resulting mixture heated for 15 minutes at reflux temperature to obtain 3-chloro-5H-dibenzo[a,d]cyclohepten-5-ol intermediate in the reaction mixture. The solvent was evaporated and the residue intermediate slurried with water, filtered, washed and dried at 65° C. in vacuum oven for three hours.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[N:3]1.Cl.[Cl:15][C:16]1[C:17]([CH2:22][NH2:23])=[N:18][CH:19]=[CH:20][N:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH2:22][NH:23][C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][C:10]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]2=3)=[O:13])=[N:18][CH:19]=[CH:20][N:21]=1
Reactant: NCc1nccnc1Cl
Reactant: Cn1ncc2c1CCCC2C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cn1ncc2c1CCCC2C(=O)NCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.9 %

Procedure:
To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylic acid (6 g, 33 mmol) and (3-chloropyrazin-2-yl)methanamine hydrochloride (6 g, 33 mmol) in 200 mL of DCM was added TEA (9 g, 88 mmol) dropwise. The resulting mixture was stirred at room temperature for 5 mins, and then HATU (12.5 g, 33 mmol) was added to the solution in portions at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added, the DCM layers was separated, and washed with brine, dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/THF=5/1 v/v %) to afford N-((3-chloropyrazin-2-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxamide (1.5 g, 15%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:13]([CH3:14])[CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)OC(=O)Cc1ccc(F)cc1

Procedure:
A mixture of 4-fluorophenylacetic acid (123.0 g), 2-propanol (96.0 g), p-toluenesulphonic acid (9.6 g) and benzene (1.3 l) is refluxed for 7 hours with a Dean-Stark separator. The solution is washed with a 10% aqueous solution of sodium carbonate (2×500 ml) and with water (2×500 ml). After drying over magnesium sulphate, the solvent and the excess 2-propanol are evaporated in vacuo. The residue is distilled (51°-53°/3·10-2Torr) to yield isopropyl 4-fluorophenylacetate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cc(Br)ccc1Cl
Reactant: C1CNCCN1
Product: CS(=O)(=O)c1cc(N2CCNCC2)ccc1Cl

Procedure:
Beginning with 5-bromo-2-chloro-methanesulfonyl-benzene and piperazine, the title compound was recovered by the procedure described in Example 1. MS m/z (rel. intensity, 70 eV)) 274 (M+, 20), 234 (40), 232 (bp), 153 (9), 56 (12).
Reaction SMILES: [F:1][C:2]1[C:3]([F:18])=[C:4](F)[C:5]([F:16])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C1CCN2C(=NCCC2)CC1.Cl.[N+:31]([CH3:34])([O-:33])=[O:32]>>[F:16][C:5]1[C:4]([CH2:34][N+:31]([O-:33])=[O:32])=[C:3]([F:18])[C:2]([F:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(F)c(F)c(C[N+](=O)[O-])c(F)c1C(=O)OC
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
200 g of dimethyl tetrafluorophthalate was dissolved in 400 ml of nitromethane (Ishikawa, Suzuki & Tanabe: Nippon Kagaku Kaishi, 1976, 200) and the solution was cooled on an ice-salt bath. At an internal temperature of 15°-20° C. 171 g of 1,8-diazabicyclo[5,4,0]-7-undecene was added dropwise over a period of 30 minutes. After completion of the dropwise addition, the mixture was further stirred at an internal temperature of 10° C. for 30 minutes, then, the mixture was poured into a mixture of 1.5 liters of 1N hydrochloric acid and 1 liter of ice.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13][NH:12]2)=[CH:2]1.N1C=CC=CC=1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:37](Cl)=[O:38]>ClCCl>[F:32][C:33]([F:47])([F:48])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:42]=1)[C:37]([N:12]1[C@H:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13]1)=[O:38]
Reactant: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)NCC1=O
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.8 %

Procedure:
To an ice-cooled solution of (5R)-5-(1H-indol-3-ylmethyl)-1-[3-(ethoxycarbonyl)propyl]piperazin-2-one (0.56 g) and pyridine (0.26 ml) in dichloromethane (10 ml) was added a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.45 g) in dichloromethane (1 ml). The solution was stirred for 40 minutes at the same temperature. After concentration, the residue was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium bicarbonate solution, water, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of dichloromethane-methanol (from 0% to 5% gradient solution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-[3-(ethoxycarbonyl)propyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.34 g) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH:34]([CH3:37])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH:34]([CH3:37])[CH2:35][OH:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: CC(N)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(CO)NC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Yield: 40 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (4:1) and treated with 2-amino-1-propanol as for example 34. After workup, the residue was triturated with hexane, then dried to give 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxy-1-methylethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (40%) as a cream solid; m.p. (EtOAc/Hexane) 198-202° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.10 (br s, 1H), 8.26 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.72 (dd, J=10.2, 1.7 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.58 (s, 1H), 4.73 (t, J=5.8 Hz, 1H), 3.97 (p, J=6.7 Hz, 1H), 3.47-3.39 (m, 1H), 3.38 (s, 3H), 3.37-3.33 (m, 1H), 1.12 (d, J=6.7 Hz, 3H). HRMS (FAB+) calcd for C16H18FIN3O3 446.0377 (M+), found 446.0383. HPLC 95.1% (254 nm).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:28][C:35](=[O:37])[CH3:36])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A solution of 6-(1-Azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (68.2 mg, 0.143 mmol) and triphenylphosphine (56.3 mg, 0.215 mmol) in tetrahydrofuran (5.0 mL) and water (0.10 mL) was stirred at 60° C. for 20 hr. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine as a white solid (67.2 mg). To a solution of 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (67.9 mg) and pyridine (0.12 mL, 1.48 mmol) in tetrahydrofuran (5.0 mL) was added acetyl chloride (0.051 mL, 0.717 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (33.1 mg, 0.067 mmol, 47%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:4]=2[N:3]1[CH:13]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:14](=[O:29])[N:15]1[CH2:19][CH2:18][C@H:17]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]2)[CH2:16]1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44](Cl)(=[O:46])=[O:45].C(Cl)Cl>CN(C1C=CN=CC=1)C>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44]([N:6]1[C:5]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:4]=2[N:3]([CH:13]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:14](=[O:29])[N:15]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]3)[CH2:16]2)[C:2]1=[O:1])(=[O:46])=[O:45]
Reactant: CCCN1CCN([C@H]2CCN(C(=O)C(c3ccccc3)n3c(=O)[nH]c4ccc(C#N)cc43)C2)CC1
Reactant: COc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCN1CCN([C@H]2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccccc4OC)c4ccc(C#N)cc43)C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a solution of 2-oxo-3-{2-oxo-1-phenyl-2-[(S)-3-(4-propyl-piperazin-1-yl)-pyrrolidin-1-yl]-ethyl}-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (70 mg, 0.15 mmol), DMAP (catalytic amount) and 2-methoxybenzenesulfonyl chloride (37 mg, 0.18 mmol) in CH2Cl2 (3 mL) SilicaBond-diethylamine resin (Silicycle; 1.04 mmol/g; 570 mg, 0.59 mmol) was added. The reaction mixture was agitated at room temperature for 24 hours, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 4% methanol in CH2Cl2 as eluent to afford 1-(2-methoxy-benzenesulfonyl)-2-oxo-3-{2-oxo-1-phenyl-2-[(S)-3-(4-propyl-piperazin-1-yl)-pyrrolidin-1-yl]ethyl}-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (55 mg, 57%) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:17][N:16]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:16]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)nn1-c1ccc2ccccc2c1
Reaction time: 48 h
Yield: 70 %

Procedure:
To the solution of 2-naphthylboronic acid (5.00 g, 29.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (4.48 g, 29.1 mmol) in 100 mL dry dichloromethane (DCM) were added pyridine (4.7 mL, 58.2 mmol) and anhydrous powder of copper(II) acetate (7.94 g, 43.7 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 2 days under argon. The mixture was diluted with DCM. It was filtered through a celite bed. The blue filtrate was washed with water (X2), dried over MgSO4, concentrated, purified by silica column to yield ethyl 3-methyl-1-(2-naphthyl)-1H-pyrazole-5-carboxylate and its regioisomer in a 1:1 ratio in 70% yield. Rf 0.59 (1:2 EtOAc: hexane), M+H 281; regioisomer, ethyl 5-methyl-1-(2-naphthyl)-1H-pyrazole-3-carboxylate, Rf 0.44 (1:2 EtOAc:hexane). ES-MS: (M+H)+281.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[NH:13]([C:15](=[O:20])[C:16](OC)=[O:17])[NH2:14]>CO>[NH:13]([C:15](=[O:20])[C:16]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:17])[NH2:14]
Reactant: COC(=O)C(=O)NN
Reactant: NCc1cccc2ccccc12
Solvent: CO
Product: NNC(=O)C(=O)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.25 ml 1-aminomethylnaphthalene are added to a solution of 1.0 g methyl hydrazino-oxo-acetate in 10 ml of methanol. The solution is stirred for 16 h at ambient temperature and then some of the methanol is eliminated. The precipitate is separated off, washed with diethyl ether, and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1.CS(C)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:36]4[CH2:37][CH2:38][CH:33]([N:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:34][CH2:35]4)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1c(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cnn1-c1ccc(Cl)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c([N+](=O)[O-])c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.6 %

Procedure:
1-(4-Chlorophenyl)-N-(4-chloro-3-nitrophenyl)-5-methylpyrazole-4-carboxamide (1.6 g) and 4-morpholinopiperidine (2.4 g) were added to dimethyl sulfoxide (20 ml) and the mixture was stirred at a refluxing temperature for 1.5 h. After cooling to room temperature, water was added and the precipitated solid was collected by filtration and extracted with chloroform. The organic layer was washed with 30% potassium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform/methanol) and recrystallized from hydrous dimethylformamide to give the title compound (0.7 g), melting point: 195–200° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CCCCC>[C:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][C:20](=[NH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Sc1ccccc1
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCC
Product: N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1
Yield: 69.4 %

Procedure:
Procedure as described for Amidine I using the following amounts and modifications: 10.06 g of 2-phenylthioaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.20 mL of benzonitrile (51.0 mmol). After refluxing overnight, the solution was green-brown. Addition of water yielded a light brown solution with suspended solid. Solution was taken to dryness, resuspended in 75 mL of pentane, filtered, washed with 10 mL of pentane and dried in vacuo yielding 10.56 g (69%) of beige powder. NMR (400 MHz, C6D6): 7.76 (d, 2H), 7.42 (d, 2H), 7.31 (d, 1H), 7.1-6.8 (m, 8 H), 6.78(t, 1H), 4.08 (s, 2H).