Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[NH:13][C:12]1=[O:21])[CH2:8]2.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH2:16][C:17]([F:20])([F:18])[F:19])[N:13]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:12]1=[O:21])[CH2:10]2
Reactant: O=c1[nH]c(CC(F)(F)F)cn1C1C2CC3CC(C2)CC1C3
Reactant: BrCC1CC1
Product: O=c1n(C2C3CC4CC(C3)CC2C4)cc(CC(F)(F)F)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-(2,2,2-trifluoro-ethyl)-1,3-dihydro-imidazol-2-one (obtained in example 16, 100 mg) by alkylation with bromomethylcyclopropane (67 mg). 1-Adamantan-2-yl-3-cyclopropylmethyl-4-(2,2,2-trifluoro-ethyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow solid (72 mg). MS (EI): 354.2 (M+).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH:23]([C:28](=O)[CH2:29][CH2:30][CH3:31])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1)#[N:9].C([O-])(=O)C.[NH4+:37].C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:37]/[C:28](/[CH2:29][CH2:30][CH3:31])=[C:23](/[CH2:22][C:19]1[CH:20]=[N:21][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]#[N:9])=[CH:17][CH:18]=1)\[C:24]([O:26][CH3:27])=[O:25]
Reactant: [NH4+]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC/C(N)=C(\Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Process 2: A toluene (45 mL)-acetic acid (5 mL) mixture containing methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.2 g, 3.6 mmol) and ammonium acetate (8.3 g, 108 mmol) was refluxed under heating for 1 hour. After cooling to room temperature, saturated aqueous solution of sodium hydrogen carbonate was added and extraction was carried out with toluene. After washing with brine, it was dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl (Z)-3-amino-2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-2-hexenoate (1.15 g) as brown oil crude product. It was used for the next process without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:11])(=[O:10])[NH2:9].Br[CH2:13][C:14]([NH:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:13][C:14]([NH:16][CH3:17])=[O:15])(=[O:11])(=[O:10])[NH2:9]
Reactant: CNC(=O)CBr
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)COc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
To a solution of crude 1-(hydroxy)-2-sulfamoylbenzene (400 mg, 2.4 mmol.) in 60 mL of acetonitrile was added 2-bromo-N-methylacetamide (332 mg, 2.4 mmol.), K2CO3 (662 mg, 4.8 mmol.) and KI (400 mg, 2.4 mmol.). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered, concentrated and purified by prep-TLC to afford 2-(2-sulfamoylphenoxy)-N-methylacetamide (260 mg, 47%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].C(C(C)=O)C(C)C>C(N(CC)CC)C>[C:8]([O:13][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: O=C1OCCC1Br
Reactant: C=C(C)C(=O)O
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
After charging 100 parts of α-bromo-γ-butyrolactone and 104.4 parts of methacrylic acid (2.0 times in mole based on α-bromo-γ-butyrolactone), a three times amount of methyl isobutyl ketone based on α-bromo-γ-butyrolactone was added thereto to form a solution. To this solution was added dropwise 183.6 parts of triethylamine (3.0 times in mole based on α-bromo-γ-butyrolactone). Then, the solution was stirred at room temperature for about 10 hours. After filtration, the organic layer was washed with 5% aqueous sodium hydrogen carbonate-solution and then washed twice with water. The organic layer was concentrated to give α-methacryloyloxy-γ-butyrolactone represented by the following formula in 85% yield:
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([C:12]2[O:5][C:3]([CH3:4])=[C:2]([CH3:1])[N+:6]=2[O-:7])[CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(=O)C(C)=NO
Solvent: CC(=O)O
Product: Cc1oc(-c2cccc(Br)c2)[n+]([O-])c1C
Yield: 74.1 %

Procedure:
A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and 3-bromobenzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooled to 0° C. and then gaseous HCl was bubbled through the solution for 35 min while the reaction was stirred in an ice bath. Diethyl ether (500 mL) was then added to the reaction to precipitate the product and the resultant slurry stirred 45 min at 0° C. before being filtered. The solids were rinsed with Et2O (50 mL), taken up in water (1 L) and concentrated NH4OH (60 mL) added to the slurry. This mixture was extracted with CHCl3, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give 97.4 g (74%) of 2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide as a white solid. The compound should be used directly with 24-48 h. 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 2.39 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[N:7]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:6]=2[CH:5]=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:13][CH2:12]4)[N:7]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:6]=3[CH:5]=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C1CCNCC1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(Br)cc(C(F)(F)F)cc21
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(N3CCCCC3)cc(C(F)(F)F)cc21

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole from step (a) above (160 mg, 0.26 mmol) and piperidine (84 mg, 1 mmol) reacted under the conditions of Example 127b to give the title compound as an oil. MS (ESI, pos. ion) m/z: 629 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][C:28]([NH:30][NH2:31])=[O:29].O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([NH:31][NH:30][C:28](=[O:29])[CH3:27])=[O:14])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(C(=O)O)cc12
Reactant: CC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2oc(C(=O)NNC(C)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution (700 ml) of 4-methoxybenzo(b)furan-2-carboxylic acid (43.4 g) in THF was added 1,1′-carbonylbis-1H-imidazole (CDI) (38.4 g) and the mixture was stirred at room temperature for 1 hr. Acetohydrazine (17.6 g) was added to this reaction mixture, and the mixture was stirred for 1 more hr. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and dried to give the title compound (38.4 g) as pale-brown crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[Cl:29])=[CH:21][C:20]=1[O:30][CH3:31]>C1COCC1.C1COCC1.CN(C=O)C>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[C:26]3[Cl:29])=[CH:21][C:20]=2[O:30][CH3:31])[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1cc2ccnc(Cl)c2cc1CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ccnc(Cl)c2cc1CN1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
Sodium hydride (0.057 g, 1.4 mmol, 60% mineral oil dispersion) is suspended in anhydrous THF (5 mL) and treated with a solution of (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (0.223 g, 1.1 mmol) and 7-bromomethyl-1-chloro-6-methoxy-isoquinoline (0.32 g, 1.1 mmol) in THF/DMF (10 mL, 6:1) at 0° C. The reaction mixture is warmed to ambient temperature, stirred for 3 hours, quenched by the addition of saturated NH4Cl and diluted with EtOAc. The layers are separated. The organic layer is washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated to give a white solid. The solid is collected, washed with a small amount of EtOAc and copious amounts of Et2O to yield the title compound (0.18 g, 0.47 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].ClC1C=CC(O[CH2:22][C:23]#[N:24])=CC=1.CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:12]([F:13])([F:14])[F:15])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:22][C:23]#[N:24])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: -10 °C
Yield: 77.7 %

Procedure:
A mixture of 1-methoxy-4-nitro-2-trifluoromethylbenzene (93 g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55 g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KOtBu (103.85 g, 0.927 mol) in dry DMF (400 ml) at −10° C. After complete addition the resulting purple solution was maintained at −10° C. for 1 h then poured into a mixture of ice/water (1.5 l) and 5 M aqueous HCl (1.5 l). The resulting mixture was extracted with dichloromethane (3×1 l). The combined extracts were washed with water (3 l), dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetate/petroleum ether to afford the title compound (85.13 g, 78%) as a white solid. Mp 103-104° C.
Reaction SMILES: N#N.[CH:3]1[C:20]2=[C:21]3[C:10]([C:11]4[C:22]5[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=5)[CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:30]([O:33]C(CCl)CCl)CCl.Cl>O.ClC1C=CC=CC=1Cl>[CH:18]1[C:19]2=[C:22]3[C:11]([C:10]4[C:21]5[C:6](=[CH:5][CH:4]=[CH:3][C:20]2=5)[CH:7]=[CH:8][CH:9]=4)=[CH:12][CH:13]=[CH:14][C:15]3=[C:16]([CH:30]=[O:33])[CH:17]=1
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reaction time: 16 h

Procedure:
A 3 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with perylene (Aldrich Chemical Co., Milwaukee, WI, 53201, 25 g, 99 mmol) and o-dichlorobenzene (500 mL). The liquid was warmed until all the large chunks of solid dissolved (80° ) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 51.2 g, 0.897 mol, 23 mL), was added in one portion. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 14.9 g, 0.13 mol, 11.7 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40° over 2 h and further stirred for 16 h. Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted perylene from the aldehyde and a more polar product. Fractions (5 L) containing the aldehyde were combined and the PhCH3 removed. The resulting oily solid was shaken with CH3OH (200 mL) and the orange-brown crystals which formed were collected by filtration to give after drying 23.2 g (83%) of 3-perylenecarbaldehyde mp 223°-233°, (C,H), (lit. mp 236°(darkens >230 °)), N. P. Buu-Hoi and C. T. Long, Recueil 75 1121 (1956).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][N:14](C=O)C>C(OCC)(=O)C.O>[C:13]([C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8])#[N:14]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(CC(=O)O)ccc1F
Temperature: 130 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
2-(3-Bromo-4-fluorophenyl)acetic acid (64 g, 275 mmol) was diluted with DMF (400 mL) followed by the addition of Cu(I)CN (49 g, 549 mmol). The reaction was heated to 130° C. and stirred for 12 hours. The reaction was allowed to cool and diluted with ethyl acetate and water, and the mixture was filtered. The organic layer was washed with water, 1N HCl, water and the brine. The organic layer was dried over MgSO4, filtered and concentrated to yield 2-(3-cyano-4-fluorophenyl)acetic acid (36 g, 73% yield) as light yellow oil that solidified to a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]OS(C)(=O)=O)=[CH:3][CH:2]=1.[CH3:15][S-:16].[Na+]>CO>[CH3:15][S:16][CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OCCCc1ccncc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCCCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a solution of methanesulfonic acid 3-pyridin-4-yl-propyl ester (6.5 g, 30.19 mmol) in methanol (150 mL) was added sodium thiomethoxide (6.35 g, 90.57 mmol, Aldrich). The mixture was stirred at room temperature for 1 h then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with water (2×), brine (1×), dried over anhydrous sodium sulfate and concentrated to give 4-(3-methylsulfanyl-propyl)-pyridine as dark brown oil (2.24 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH:15]3[NH:20][CH:21]=[O:22])[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:4].O.[CH3:24]I>C1(C)C(C)=CC=CC=1>[CH2:3]([N:5]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH:15]3[N:20]([CH3:24])[CH:21]=[O:22])[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:4]
Reactant: CCn1c2c(c3ccccc31)C1CCC2C(NC=O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCn1c2c(c3ccccc31)C1CCC2C(N(C)C=O)C1
Reaction time: 18 h

Procedure:
To a stirred suspension of sodium hydride (0.5 g of 57% oil dispersion, 0.011 mole) in dry xylene (15 ml), a solution of N-(9-ethyl-2,3,4,9-tetrahydro-1,4-ethano-1H-carbazol-2-yl)-formamide (0.9 g, 0.0034 mole, described in Example 6) in dry xylene (15 ml) was added dropwise under nitrogen. The suspension was refluxed with stirring for 18 hr. The reaction mixture was cooled. The water condenser was replaced by a dry ice/acetone condenser and methyl iodide (1.7 ml) was added. The reaction mixture was refluxed for 5 hr. Additional 1.7 ml of methyl iodide was added. The solution was refluxed for 4 hr and stirred at 20° C. for 18 hr. The reaction mixture was cooled in ice, and water was added dropwise to destroy the excess hydride. The compound was extracted with ethyl acetate and the organic layer was washed with water, dried and evaporated to afford the title compound as a yellow oil (ca. 1.2 g): IR (CHCl3) 1650 cm-1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[NH:13].C(N(CC)CC)C>C1COCC1>[C:2]1([C:1]2[O:8][N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]4[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=N)NO)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3noc(-c4ccccc4)n3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
0.019 mL (0.16 mmol) Benzoyl chloride are added to a mixture of 45.7 mg (0.15 mmol) (S)—N-(1-{4-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (XXVII.2) and 0.063 mL (0.45 mmol) triethylamine in 4 mL THF. The mixture is stirred for 12 h at 80° C. and is subsequently purified by HPLC (RP C18 Sunfire; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O>N1C=CC=CC=1>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNCC1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1c(N2CCCCC2)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (115 mg, 0.314 mmol, Eq: 1.00) and piperidine (150 mg, 174 μl, 1.76 mmol, Eq: 5.6) in pyridine (1.5 ml) was stirred at 135° C. for 3 h in a sealed tube. The solution was allowed to cool to RT and cold water and ice were added. A light yellow solid precipitated which was filtered off, washed with water and dried (42 mg, 6,8-dichloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid methyl ester, MS (ESI): 415.3 (M+H)). The mother liquor was evaporated, water was added to the remaining residue and the pH was adjusted to 2 with 0.1N HCl. The mixture was extracted with chloroform and the combined organic extracts were dried with Na2SO4 and evaporated to yield the title compound (64 mg, yellow solid). MS (ESI): 401.2 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[CH2:6]([O:8][C:9](=[O:22])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH3:7].[Li+].CC([N-]C(C)C)C.C(Br)C=C>C(OCC)C>[CH2:6]([O:8][C:9](=[O:22])[CH:10]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH2:5][CH:1]=[CH2:2])[CH3:7]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCC(C(=O)OCC)C(C)(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
Cool a THF solution of 1.0 equivalent of 3-(2,4-Dichloro-phenyl)-3-methyl-butyric acid ethyl ester, obtained above, to −78° C., treat with LDA (2.0 eq), followed by allyl bromide (1.1 eq), warm to room temperature and stir 17 h. Quench reaction with NH4Cl, dilute with diethyl ether, wash organics with 0.1 N HCl, brine, dry over sodium sulfate, filter and evaporate. Chromatography, (silica, hexanes/EtOAc, 98:2) provides 2-[1-(2,4-dichloro-phenyl)-1-methyl-ethyl]-pent-4-enoic acid ethyl ester in 52% yield.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].CN1CCNCC1.C[O:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][C:24]=1[Cl:32].O>C1(C)C=CC=CC=1>[Cl:32][C:24]1[CH:25]=[C:26]([CH:29]2[CH2:30][CH2:31]2)[CH:27]=[CH:28][C:23]=1[CH:22]=[O:21]
Reactant: COC(=O)c1ccc(C2CC2)cc1Cl
Agent: CN1CCNCC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C2CC2)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.01 ml Red-Al 13.5 M (24.54 mmol) in toluene was added at 0° C. a solution of 3.0 ml 1-methylpiperazine (26.89 mmol) in 16 ml toluene over 30 min. The resulting solution was then added dropwise over 40 min to 1.1 g of 2-chloro-4-cyclopropyl-benzoic acid methyl ester (5.2 mmol) in 32 ml toluene between −5° C. and 0° C. After stirring for 30 min at this temperature, the reaction mixture was cooled to −10° C. and treated dropwise with 30 ml water. The mixture was then filtered, diluted with ethylacetate, washed with 1N—HCl, brine, dried over magnesium sulfate, filtered again and concentrated in vacuo, leading to 0.98 g of 2-chloro-4-cyclopropyl-benzaldehyde as a brown oil (100%). MS (+cEI): 180.1 (M).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C=O)C>[CH2:38]([O:30][C:22]1[C:21](=[O:31])[N:14]2[CH2:15][CH:16]3[CH2:17][CH2:18][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])([C:13]2=[N:24][C:23]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]3)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Yield: 42 %

Procedure:
To a solution of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (prepared according to the procedure in WO2009117540) (500 mg, 1.170 mmol) in DMF (20 mL) was added K2CO3 (323 mg, 2.339 mmol) followed by benzyl bromide (0.208 mL, 1.755 mmol) and the resulting mixture was heated at 50° C. for 16 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane to afford the title compound (250 mg, 42% yield) as a light yellow liquid. 1H NMR (500 MHz, CDCl3) δ: 7.47 (d, 2H, J=7.02 Hz), 7.32-7.39 (m, 8H), 7.19 (brs, 1H), 5.26 (s, 2H), 5.08 (s, 2H), 4.31 (q, 2H, J=7.02 Hz), 4.13 (d, 2H, J=3.97 Hz), 2.87-2.96 (m, 2H), 2.46 (brs, 1H), 1.94-2.03 (m, 2H), 1.80-1.89 (m, 2H), 1.65-1.75 (m, 2H), 1.29 (t, 3H, J=7.32 Hz). LCMS (M+H)=518.28.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([F:30])=[C:23]([Cl:22])[CH:24]=3)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NCC1CCCCC1)c1cnc(Nc2ccc(F)c(Cl)c2)nc1C(F)(F)F
Yield: 79.9 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (100 mg) in 1,4-dioxan (1 ml) was added 3-chloro-4-fluoroaniline (228 mg, ex Lancaster) and the solution stirred at reflux for 4 hours. Dioxan was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 2N hydrochloric acid (2×3 ml) and water (3×3 ml), dried MgSO4), evaporated and triturated with isohexane to afford the title compound (107 mg).