Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].B(F)(F)F.CCOCC.CSC>C(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CSC
Product: CS(=O)(=O)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
4-(Benzyloxy)phenyl methanesulfonate (5.31 g, 19.08 mmol) was dissolved in dry DCM (70 mL) under nitrogen atmosphere. Boron trifluoride diethyl etherate (10.83 g, 76.31 mmol) was added followed by dimethyl sulfide (4.74 g, 76.31 mmol) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was poured onto ice and the aqueous layer was extracted with DCM. The organic layers were combined, washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (2.96 g, 82.5%). 1H NMR (500 MHz, CDCl3): δ 3.14 (s, 3H), 5.51 (s, 1H), 6.83 (d, 2H), 7.14 (d, 2H); 13C NMR (125 MHz, CDCl3): δ 37.35, 116.74, 123.49, 142.68, 155.06.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([N+:12]([O-])=[O:13])([CH3:11])[CH3:10].C(O)(=O)C>C(O)C.[Zn]>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N+:12]([C:9]([CH3:11])([CH3:10])[CH3:8])[O-:13]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1ccc[nH]1

Procedure:
To a suspension of pyrrole-2-carbaldehyde (277.8 mg, 2.92 mmol), 1,1-dimethylnitroethane (601.1 mg, 5.83 mmol) and zinc (572.5 mg, 8.76 mmol) in ethanol (4.0 ml) was added acetic acid (1.05 g, 17.5 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=1/1-2/3).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][C:17]([F:34])=[CH:16][N:15]=1>C(#N)C>[F:34][C:17]1[CH:18]=[C:19]2[N:20]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)[C:1](=[O:2])[NH:13][C:14]2=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(F)cnc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncc(F)cc32)CC1
Yield: 39.1 %

Procedure:
Carbonyldiimidazole (1.53 g, 9.41 mmol) was added to a solution of tert-butyl 4-[(2-amino-5-fluoropyridin-3-yl)amino]piperidine-1-carboxylate (0.73 g, 2.35 mmol) in acetonitrile (10 mL) at room temperature. The reaction was stirred until all the starting material was consumed (approximately 2 h) and then the solvent was evaporated in vacuo. The residue was diluted with water, extracted with dichloromethane (3×), dried over magnesium sulfate and then concentrated. The crude product was purified by chromatography (silica gel, 1% to 10% methanol in methylene chloride gradient elution), which gave the title compound (0.309 g). MS 337.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]2=[N:34][C:35](=[O:37])[N:36]=[C:32]2[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:27])[F:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:29][C:30]3[CH:39]=[CH:38][C:33]4[NH:34][C:35](=[O:37])[NH:36][C:32]=4[CH:31]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Product: COCCC(C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
76 mg (purity 82%, 0.15 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoic acid (racemate) and 25 mg (0.17 μmol, 1.1 eq.) of 5-aminobenzimidazolone were reacted according to General Method 1. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 37 mg (45% of theory)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([NH:15][C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH3:22])[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].CN(C)C=O.C(N(CC)CC)C.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>O1CCCC1.O>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([NH:15][C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[S:7][C:8]=3[N:9]=2)[CH:17]=1)=[O:36])([CH3:32])[CH3:33])#[N:35]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CCl)sc2n1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CN3CCOCC3)sc2n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
To a solution of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}amino)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (152 mg, 292 μmol) in tetrahydrofuran (4 mL)/N,N-dimethylformamide (0.5 mL) were added triethylamine (121 μL, 876 μmol) and morpholine (76 μL, 876 μmol), and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added water (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→97/3), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and hexane to give the title compound (131 mg, 78%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]=[O:16]>Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:15][OH:16])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: O=c1ccc(-c2cccc(Br)c2)n[nH]1
Agent: Cl
Solvent: CO
Product: O=c1ccc(-c2cccc(Br)c2)nn1CO
Reaction time: 8 h
Yield: 40 %

Procedure:
2.51 g of 6-(3-bromophenyl)-3(2H)-pyridazinone, 5 ml of a 37% formalin and 2 drops of concentrated hydrochloric acid were dissolved in 50 ml of methanol, and then the solution was heated under reflux for about 7 hours. The mixture was then left to stand overnight, after which it was filtered and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was extracted with a 1:1 by volume mixture of ethyl acetate and acetone. After distilling the solvent from the extract, there were obtained 1.13 g (yield 40%) of the desired Compound No. 1 in the form of a white solid melting at 228°-229° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34]Cl.C(N(C(C)C)CC)(C)C.CCOCC>C(Cl)Cl>[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][O:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[O:6])[CH2:25]1
Reactant: COCCOCCl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCO[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC=O)CC[C@@H]32)C1
Reaction time: 4 h

Procedure:
Methyl lithocholate is dissolved in methylene chloride, and β-methoxyethoxymethyl chloride and diisopropylethylamine are added. The mixture is stirred for four hours, ether added and washed with water. After drying the solvents are evaporated, the residue dissolved in toluene and the 24-ester group reduced to the 24-alcohol group with Vitride. The 24-alcohol then is oxidized with chromium trioxide-pyridine and the 3α-(β-methoxyethoxymethoxy)-5β-cholane-24-aldehyde obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH:25]([CH2:38][C:39]3([OH:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:26][N:27](C)[C:28](OCC[Si](C)(C)C)=O)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[N+](CC)(CC)(CC)CC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH:25]([CH2:38][C:39]3([OH:45])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:26][NH:27][CH3:28])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)NC(CN(C)C(=O)OCC[Si](C)(C)C)CC2(O)CCCCC2)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Product: CNCC(CC1(O)CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(Cl)c2)C1
Temperature: 45 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (20 mg, 0.03 mmol) in anhydrous THF (1 mL) was added Et4NF (3 mg). The solution was stirred at 45° C. for 2 h and evaporated under reduced pressure. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide (13.2 mg, 71%) as its TFA salt. 1H NMR (400 MHz, CD3OD): 7.43 (t, 1H), 7.32-7.21 (m, 3H), 4.42 and 4.29 (two isomers on 1 to 1 ratio, d, 1H), 4.15 (m, 1H), 3.95 and 3.83 (two isomers on 1 to 1 ratio, d, 1H), 3.34 (m, 1H), 3.27 (s, 3H), 3.14 (m, 1H), 2.99 (m, 1H), 2.80 (s, 3H), 2.64-2.38 (m, 3H), 1.94 (t, 2H), 1.76 (m, 2H), 1.68-1.18 (m, 20H), 0.98 (m, 1H); MS m/z 524 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH:8](O)[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[C:7]([CH:8]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(OC)cc2)cc1C(O)CC(C)C
Product: CCc1nn(-c2ccc(OC)cc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 11.7 %

Procedure:
Using 1-[3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.5 g) synthesized in Example 48(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.44 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.1 g, 12%) was obtained as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:8]=[C:9]2[N:13]([CH:14]=1)[N:12]=[C:11]([CH2:15][O:16][CH3:17])[S:10]2.CN(C)[CH:20]=[O:21]>>[Cl:6][C:7]1[N:8]=[C:9]2[N:13]([C:14]=1[CH:20]=[O:21])[N:12]=[C:11]([CH2:15][O:16][CH3:17])[S:10]2
Reactant: CN(C)C=O
Reactant: COCc1nn2cc(Cl)nc2s1
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nn2c(C=O)c(Cl)nc2s1
Temperature: 0 °C
Yield: 79 %

Procedure:
Phosphorus oxychloride (2.75 ml, 3 eq) is added very slowly to dimethyl formamide (5 ml) cooled at 0° C. The temperature rises to 50° C. The reaction mixture is heated at 60° C., then 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole a15 (2 g, 9.82 mmol, 1 eq) is added portionwise for 2.5 h. The reaction mixture is poured on an ice/water mixture. The precipitate is filtered and washed with water. The residue is dried overnight at 40° C. under reduced pressure to afford 1.8 g of 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde a16 as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([CH3:1])[C:3]=1[F:13])[CH3:15]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(F)c(C)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
A solution of 3-methyl-2,4,5-trifluorobenzoic acid (Shimizu T., Asai T., Kumai S., Jpn. Kokai Tokkyo Koho (1997) Japanese Appl. JP 95-219069, 4.3 g, 22.6 mmol) in dichloromethane (100 mL) at 0° C. is treated with oxalyl chloride (4.2 g, 33 mmol) followed by N,N-dimethylformamide (2 drops). The mixture is stirred at room temperature for 3 hours, concentrated and dried in vacuo. The acid chloride is diluted with dichloromethane, cooled to 0° C., and treated with absolute ethanol (10 mL, 170 mmol). The resulting solution is stirred at room temperature for 20 hours, poured into saturated NaHCO3 solution and extracted with dichloromethane. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (3.8 g). 1H NMR (200 MHz, CDCl3): δ 7.67-7.26 (m, 1H), 4.44 (q, 2H), 2.27 (dd, 3H), 1.42 (t, 3H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.[Cu-]=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:5]3[CH:6]=[CH:7][N:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[N:12][CH:13]=1
Reactant: c1cc2nc[nH]c2cn1
Reactant: Fc1ccc(Br)nc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(-n2cnc3cnccc32)nc1
Yield: 25 %

Procedure:
A solution of 5-azabenzimidazole (1.00 g, 8.40 mmol), 2-bromo-5-fluoropyridine (1.48 g, 8.40 mmol), copper (I) oxide (0.13 g, 0.84 mmol), 8-hydroxyquinoline (0.24 g, 1.68 mmol), and Cs2CO3 (5.47 g, 16.8 mmol) in DMSO (4 mL) was irradiated in a microwave apparatus for 1 hour at 140° C. The reaction was diluted with H2O (100 mL) and extracted with EtOAc (75 mL×3). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.45 g, 25%). MS (ESI): mass calculated for C11H7FN4, 214.07. m/z found 215.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH3:21])[N:15]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>O1CCCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)=[N:15][C:16]=1[CH3:21]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(N)ccc1Br
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of p-trifluoromethylbenzaldehyde (16, 1.00 g, 5.74 mmol) in tetrahydrofuran (9 mL) was added 2-amino-5-bromo-6-methylpyridine (33, 1.08 g, 5.77 mmol), followed by dibutyltin dichloride (40 mg, 0.13 mmol). The mixture was stirred for 5 minutes at 25° C. and phenylsilane (0.69 g, 6.4 mmol) was added. The reaction was heated at 50° C. overnight, then the solvent was removed at reduced pressure. Ethyl acetate was added to the resulting solid which was washed with saturated sodium carbonate, dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded a light yellow solid (34, 1.7 g, 4.93 mmol). MS (ESI) [M+H+]+=345.1.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: O=C1CCC(c2ccccc2-c2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 411.89 g/mol.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Br:43][C:44]1[CH:45]=[C:46]([CH:51]=[C:52](I)[CH:53]=1)[C:47]([O:49]C)=[O:48].[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[Br:43][C:44]1[CH:45]=[C:46]([CH:51]=[C:52]([NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:53]=1)[C:47]([OH:49])=[O:48]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(O)c1cc(Br)cc(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of palladium(II) acetate (1.1 mg, 0.005 mmol) and xantphos (8.9 mg, 0.015 mmol) in toluene (8 ml) was stirred at room temperature for 5 min in a sealable tube purged with nitrogen, methyl 3-bromo-5-iodobenzoate (340 mg, 1.0 mmol) and aniline (111.8 mg, 1.2 mmol) were added and let stir for 5 more min, Sodium tert-butoxide (134.6 mg, 1.4 mmol) was then added and the mixture was stirred at room temperature for 5 min before heated up to 80° C. for 3 h. The reaction mixture was cooled down to RT and ether (containing 1% triethylamine) was added, passed through a celite column, dried over sodium sulfate and concentrated under vacuum to give the crude product which was used directly in the next reaction without further purification: HPLC retention time: 2.123 min (method A). MS (ESI) (M+H)+ 292.07.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:23](I)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C(O)CCC>CO>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCI
Reactant: CCCCCCC1Cc2ccc(-c3ccc(O)cn3)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: CCCCCCCCCCOc1ccc(-c2ccc3c(c2)CC(CCCCCC)C3)nc1
Yield: 39.2 %

Procedure:
0.045 g (0.15 mM) of 2-hexyl-5-(5-hydroxypyridine-2-yl)indan, 0.05 ml (0.23 mM) of decyl iodide, 0.013 g (0.20 mM) of 85%-KOH and 1 ml of n-butanol were mixed and heat-refluxed for 130 minutes under stirring. After the reaction, methanol was added to the reaction mixture, followed by filtration under cooling with ice to obtain an insoluble matter. The insoluble matter was dried and purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1), followed by recrystallization from acetone to obtain 0.026 g of 2-hexyl-5-(5-decyloxypyridine-2-yl)indan (Yield: 39.2%). ##STR308##
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]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:24][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:25]1[CH2:27][CH2:26]1)(=[O:30])[CH3:29]
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120.0 mg, 0.284 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.3 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (94.5 mg, 0.203 mmol, 72%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10](=[O:12])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27])=[O:17])[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][C:10]1=[O:12])=[O:27])=[O:17])[CH3:14]
Reactant: O=c1[nH]cc(-c2ccccc2)o1
Reactant: CCOC(=O)CCCCCCCN=C=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCNC(=O)n1cc(-c2ccccc2)oc1=O
Reaction time: 24 h

Procedure:
16.1 g (0.1 mol) of 5-phenyl-4-oxazolin-2-one are dissolved in 100 ml of absolute DMF and 25.6 g (0.12 mol) of ethoxycarbonylheptyl isocyanate are added. The mixture is stirred for 24 hours at 50°-60° C., water is added and the oily/crystalline precipitate which is formed is separated, washed with water and dried in vacuo at room temperature. The crude product is recrystallised from ethanol.
Reaction SMILES: O[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ncnc(Cl)c2CC1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl 4-hydroxy-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate (4.3 g, 16.2 mmol) and POCl3 (2.3 ml) in toluene (30 mL) is heated at 90° C. for 1 hr. The solvent is removed in vacuo and EtOAc (30 ml) and water (30 ml) are added to the residue. NaHCO3 is carefully added until the pH of the aqueous layer is greater than 7. The layers are separated and the aqueous layer is extracted with EtOAc (2×30 ml). The combined extracts are washed with brine (50 ml) and dried (Na2SO4), and the solvent is evaporated. Flash column purification of the residue with EtOAc/hexane (6:1) provides the title compound as a light yellow solid.