Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[C:28]([CH3:43])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=6[CH3:43])[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1cc(F)ccc1-n1c(C)ccc(C(=O)O)c1=O
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-n1c(C)ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
N-[6-(4-Amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 1-(4-fluoro-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (130 mg, 0.51 mmol) and HATU (230 mg, 0.60 mmol) were suspended in N,N-dimethylformamide (3.0 mL), and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) was added. After stirring at room temperature for 8 hr, the reaction mixture was diluted with ethyl acetate (5.0 mL) and tetrahydrofuran (5.0 ml). The mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration. The obtained precipitate was recrystallized from ethanol/water to give the title compound (130 mg, 50%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.Cl.CN.C([O-])(=O)C.[Na+].[N+:19]([CH3:22])([O-:21])=[O:20]>O.ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:22][N+:19]([O-:21])=[O:20])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Cl)ccc1C=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
A mixture of 4-chloro-2-methylbenzaldehyde (1.56 g, 10.1 mmol), methylamine hydrochloride (0.44 g, 6.5 mmol), and sodium acetate (0.53 g, 6.5 mmol) in nitromethane (4 mL) was vigorously stirred at ambient temperature for 24 hours. The reaction mixture was diluted with water (20 mL) and dichloromethane (40 mL). The organic layer was dried over sodium sulfate and evaporated to afford 4-chloro-2-methyl-1-(2-nitrovinyl)benzene as a light brown solid (1.87 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[C:3]=1[C:4]([OH:6])=O.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[C:3]2[C:4](=[O:6])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[NH:17][C:7]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1c(Cl)c([N+](=O)[O-])cc([N+](=O)[O-])c1Nc1ccc(OCc2ccccc2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: O=c1c2cc(OCc3ccccc3)ccc2[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c12

Procedure:
A mixture of 9.7 g of 2-chloro-3,5-dinitro-6-[[4-(phenylmethoxy)phenyl]amino]benzoic acid, 200 ml of 1,2-dichloroethane, 20 ml of phosphorus oxychloride, and 1.0 ml of N,N-dimethylaniline was heated under reflux for 30 minutes. Upon cooling, a solid formed which was collected and washed with 1,2-dichloroethane providing the title compound, mp 217°-220° C.
Reaction SMILES: CNN.[Si:4]([O:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[O:27][N:28]1C(=O)C2=CC=CC=C2C1=O)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>C(Cl)Cl>[NH2:28][O:27][C@@H:14]1[C@@H:13]([CH2:12][O:11][Si:4]([C:7]([CH3:10])([CH3:8])[CH3:9])([CH3:5])[CH3:6])[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15]1
Reactant: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CNN
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Cold methylhydrazine (1.6 ml, 30 mmol) was added to a stirred solution of 5'-O-(t-butyldimethylsilyl)-3'-O-phthalimidothymidine (2, 4.6 g, 9.18 mmol) in dry CH2Cl2 (60 ml) at 5°-10° C. After 10 minutes white precipitation of 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalizine occurred. The suspension was stirred at room temperature for 1 h. The suspension was filtered and precipitate washed with CH2Cl2 (2×20 ml). The combined filtrates were concentrated and the residue purified by silica gel column chromatography. Elution with CH2Cl2 :MeOH (100:0→97:3, v/v) furnished the title compound (3.40 g, 100%) as white solid. Crystallization from CH2Cl2 gave white needles, m.p. 171° C.; 1H NMR (CDCl3) δ0.05 [s, 6, (CH3)2 ], 0.90 [s, 9, (CH3)3 ], 2.22-2.58 (2m, 2, 2'CH2), 3.9-4.08 (m, 3, 5'CH2, and 3'H) 4.30 (m, 1, 4H) 5.5 (br s, 2, NH2) 6.2 (m, 1, 1'H) 7.45 (s, 1, C6H) 8.9 (br s, 1, NH).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH2:17][C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8].O>CN(C=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH2:17][C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cc1csc2cncn12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1csc2cncn12
Temperature: 70 °C
Reaction time: 8.5 h
Yield: 92.4 %

Procedure:
Potassium thioacetate (365 mg) is added to a solution of 427.7 mg of (3R,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methyl-3-methanesulfonyloxypyrrolidine in 4.5 ml of DMF, and the mixture is stirred under an argon stream at 70° C. for 8.5 hr. The reaction solution is cooled, water is added thereto, and the mixture is extracted four times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 374.7 mg of the title compound as a brown viscous material.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=O)C.O>C(OCC)C>[C:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([CH:21]=[O:20])[CH2:24]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 56.5 %

Procedure:
A 1.2 M solution of diisobutylaluminum hydride in toluene (30.8 ml, 36.9 mmol) was added at −78° C. to a solution of (3R)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (4.13 g, 16.1 mmol) in diethyl ether (30 ml). The reaction mixture was stirred for 2.5 h at −78° C. Water (9.6 ml) was added dropwise. The reaction mixture was warmed to room temperature. The precipitation was removed by filtration through a plug of celite. The celite was washed with tert-butyl methyl ether (3×100 ml). The liquids were combined and dried over magnesium sulfate. The solvent was removed in vacuo, to give 1.94 g of crude (3R)-3-formylpiperidine-1-carboxylic acid tert-butyl ester, which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccccc2Cl)cc1
Yield: 45.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2-chlorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 2-chlorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.033 g (45%) of the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[N:10]=1.[CH3:16][CH2:17][O:18][C:19]([C@H:21]1[CH2:25][CH2:24][C:23](=[O:26])[N:22]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20].O>O1CCCC1.C([Li])CCC>[C:30]([O:29][C:27]([NH:22][C@H:21]([CH2:25][CH2:24][C:23]([C:14]1[C:9]([F:8])=[N:10][C:11]([F:15])=[CH:12][CH:13]=1)=[O:26])[C:19]([O:18][CH2:17][CH3:16])=[O:20])=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: Fc1cccc(F)n1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)nc1F)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.653 mL) in tetrahydrofuran (30 mL), n-butyl lithium (1.57 M solution in hexane, 2.97 mL) was added at −78° C. over five minutes, and the reaction solution was stirred at the same temperature for 20 minutes. 2,6-Difluoropyridine (0.388 mL) was added dropwise to the solution at −78° C., and the reaction solution was stirred at −78° C. for three hours. A solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1.0 g) in tetrahydrofuran (5.0 mL) was added dropwise to this solution at −78° C., and the reaction solution was stirred at 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.2 g of the title compound as a pale yellow oil. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:19]Br.C1(C)C=CC=CC=1>C(O)(=O)C>[Br:19][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen purge, a suspension or 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.6 g; 0.005 mol) in acetic acid (25 mL) is heated, all the material dissolving to a clear solution at about 60° C. A solution of bromine (0.8 mL; 0.015 mol) in acetic acid (10 mL) is added dropwise over 15 minutes to the refluxing solution. The solution is refluxed 6 hours then allowed to stir 18 hours at room temperature. The HPLC of the reaction mixture shows about 80% conversion to product. The mixture is heated back to reflux and more bromine (0.5 mL; 0.01 mol) in acetic acid (5 mL) is added dropwise. After refluxing another 3 hours, the aliquot shows >95% conversion to product. The reaction is cooled, and solvent removed under reduced pressure on a rotary evaporator to obtain a dark grey solid. Toluene is added to the mixture and removed under reduced pressure, but the odor of acetic acid still remains. The entire material is dissolved in hot toluene (75 mL) to a turbid solution which is treated with DARCO filter and filtered. The light pink solution deposits a white solid upon cooling to ambient. After cooling in the freezer, the solid is collected by filtration, washed with hexanes, and dried on the filter. Further drying in a vacuum oven at 45° C. provides the product (1.2 g; app. 60% theoretical); mp 247°-250° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([Cl:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[Cl:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCCCCC(Cl)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClCCCCCCCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of lithium tetrachlorocuprate [THF 33 L, lithium chloride (0.87 kg, 19.3 mol), cupric chloride (1.4 kg, 10.4 mol)] was added to a solution of benzylmagnesium chloride (160 L of 1.86M, 298 mol) in tetrahydrofuran at 15° C., and the mixture stirred for 30 min. Bromochlorohexane in toluene (85.5 kg of solution, 55% w/w by assay, 47.1 kg, 236 mol) was added over 3 h while maintaining the temperature between 15°-20° C. Stirring was continued for a further 1.25 h. 10% Ammonium chloride solution (263 L) was added over 1 h, maintaining the temperature below 30° C. The phases were separated and the organic phase further washed with ammonium chloride solution (170 L) and 20% sodium chloride solution (3×197 L). The organic solution was concentrated under vacuum to leave an oil (56.8 kg, 77% pure by HPLC assay, 88% corrected yield), which was distilled (b.p. 129°-132° C., 2 mbar) to yield the title compound (70%, 99% pure by GC assay).
Reaction SMILES: [C:1]([C:5]([Br:8])(Br)[Br:6])([F:4])([F:3])[F:2].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].O>CN(C=O)C.[Zn]>[Br:6][C:5]([Br:8])([C:1]([F:4])([F:3])[F:2])[CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[Cl:9])[OH:13]
Reactant: O=Cc1ccccc1Cl
Reactant: FC(F)(F)C(Br)(Br)Br
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: OC(c1ccccc1Cl)C(Br)(Br)C(F)(F)F
Reaction time: 6 h

Procedure:
83.5 g of CF3CBr3 in anhydrous DMF and 28 g of 2-chlorobenzaldehyde were reacted under a nitrogen atmosphere. The mixture was brought to 5° C. and zinc in powder (g. 16.0) was added to it slowly. Then the mixture was let reach the room temperature and kept under stirring for 6 hours. The mixture was poured into water and extracted three times with ethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH2:22])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][CH3:22])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(CC)cc1)C2=O
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccc(CN2Cc3cc(CC)cc(Cl)c3C2=O)cc1
Yield: 49.4 %

Procedure:
A mixture of 7-chloro-5-ethenyl-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.062 g, 0.2 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-chloro-5-ethyl-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.031 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.23 (t, 6H), 2.68 (q, 4H), 4.18 (s, 2H), 4.72 (s, 2H), 7.07 (s, 1H), 7.14-7.36 (m, 5H). GC-MS: m/z 313 (M)+, 284 (M−29)+.
Reaction SMILES: [N:1]1([CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S1C=CC=C1.N.[H][H]>CO.[Pt]>[N:1]1([CH:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Agent: N
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Yield: 99 %

Procedure:
(a-3) A mixture of 3.4 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzenamine, 1 part of a solution of thiophene in methanol 4%, 80 parts of methanol and 80 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 2.64 parts (99%) of 4-[(1H-imidazol-1-yl)-phenylmethyl]-1,2-benzenediamine as a residue (int. 126), or alternatively
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1>CCO>[Cl:4][C:5]1[N:6]=[C:7]([NH:2][NH2:3])[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1csc2c(NN)nc(Cl)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
Hydrazine monohydrate (2.21 mL; 45.6 mmol; 2.0 equiv) was added to a suspension of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (5 g; 22.8 mmol; 1.0 equiv) in 40 mL of EtOH. The reaction was stirred at ambient temperature for 2 days. The solid was filtered, washed with H2O and dried to give 2-chloro-4-hydrazino-7-methylthieno[3,2-d]pyrimidine as an off-white solid (4.4 g; 90% yield); MS (ES) 214.97 (M+H), 212.99 (M−H).
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:23][OH:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=O)C1C=CC=CC=1.O1CCOCC1.[C:31]1([S:41](Cl)(=[O:43])=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C.CN(C)C=O.[C].[Pd].O>[C:31]1([S:41]([NH:11][C@H:12]([CH2:23][OH:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:43])=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(N[C@H](CO)Cc1c[nH]c2ccccc12)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H](CO)Cc1c[nH]c2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-tryptophanol (1.0 g) in ethanol hydrogenation (20 ml)-dioxane (40 ml), palladium-carbon (5%, 0.5 g) was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. After the palladium-carbon was filtered off, the filtrate was concentrated under reduced pressure to yield an oily substance. This oily substance was dissolved in N,N-dimethylformamide (10 ml), and 1-naphthalenesulfonyl chloride (0.77 g) was added and then triethylamine (0.39 g) was added at 0° C. After overnight stirring at room temperature, the reaction mixture was poured over water and extracted with ether. The ether layer was washed by sequential additions of a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline and then dried (MgSO4). After the solvent was distilled off, the oily residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1) to yield a powder of N-(1-naphthylsulfonyl)-(L)-tryptophanol (0.8 g, 68%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17](OC)=[O:18])[CH:11]=1)([CH3:9])[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.CC(=O)OCC>C1COCC1.O>[OH:18][CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:4]([CH3:9])([CH2:3][OH:2])[CH2:5][OH:6])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1cccc(C(C)(C(=O)OC)C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(CO)(CO)c1cccc(CCO)c1
Temperature: 0 °C

Procedure:
The compound of step 2 (0.128 g, 0.435 mmol) was dissolved in 2 ml of THF and cautiously added to an ice-cold suspension of lithium aluminium hydride (174 mg, 4.35 mmol) in THF. After a few minutes, diethyl ether (12 ml) was added and thereafter 200 μl of EA. Subsequently, water was added slowly and cautiously until the alumina salts formed a light grey mass at the bottom of the flask. The supernatant was decanted and the residue washed with EA. The combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1.C1O[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:19](Cl)[CH2:20][CH3:21])[O:17]C1>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]([CH2:19][CH2:20][CH2:21][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][O:7]3)[CH2:3][CH2:2]2)=[O:17])=[CH:28][CH:27]=1
Reactant: CCC(Cl)C1(c2ccc(F)cc2)OCCO1
Reactant: c1ccc2c(c1)COC21CCNCC1
Product: O=C(CCCN1CCC2(CC1)OCc1ccccc12)c1ccc(F)cc1

Procedure:
Reaction of 1,3-dihydrospiro[isobenzofuran1,4'-piperidine] and α-chloro-p-fluorobutyrophenone ethylene ketal by the method described in Example 6 provides 1,3-dihydro-1'-[3-(4-fluorobenzoyl)propyl]spiro[isobenzofuran-1,4'-piperidine] as a solid, hydrochloride salt, m.p. 215°-217°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:22][CH:23]([OH:41])[CH2:24][NH:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:22][CH:23]([OH:41])[CH2:24][NH:25][C:26]1[CH:31]=[C:30]([C:2]2[N:7]=[C:6]3[N:8]([CH3:11])[CH:9]=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cn1cnc2ccc(Br)nc21
Reactant: CC1(C)OB(c2ccnc(NCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc2ccc(-c3ccnc(NCC(O)CN4CCc5ccccc5C4)c3)nc21
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromo-3-methyl-3H-imidazo[4,5-b]pyridine (100 mg, 0.47 mmol), 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)propan-2-ol (230 mg, 0.56 mmol), K2CO3 (195 mg, 1.41 mmol) and Pd(dppf)Cl2 (10 mg) in a solution of dioxane (4 mL) and H2O (1 mL). The mixture was stirred then 120° C. for 30 min under microwave mediated heating. After cooling, the catalyst was filtered and the filtrate concentrated and purified by Prep-HPLC to give the desired product 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((4-(3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)amino)propan-22-ol (52 mg, 26.7%). 1HNMR (CH3OD, 400 MHz) δ: 8.38-8.26 (m, 1H), 8.07-7.92 (m, 2H), 7.78-7.68 (m, 1H), 7.33-7.26 (m, 1H), 7.26-7.18 (m, 1H), 7.10-6.97 (m, 3H), 6.96-6.88 (m, 1H), 4.15-4.03 (m, 1H), 3.88 (s, 3H), 3.67 (s, 2H), 3.60-3.50 (m, 1H), 3.46-3.36 (m, 1H), 2.92-2.72 (m, 4H), 2.72-2.55 (m, 2H). LCMS (m/z): 415.2 [M+H]+