Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])[CH:16]=1)C(O)=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[C:49]1[C:55]([N:56]2[C:63]3[N:59]([N:60]=[C:61]([C:64]4[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=4)[CH:62]=3)[CH:58]=[CH:57]2)=[C:54]([CH3:70])[CH:53]=[CH:52][C:50]=1N.O.[CH3:72][N:73]([CH:75]=[O:76])C>>[CH3:50][C:52]1[CH:53]=[C:54]([CH3:70])[C:55]([N:56]2[C:63]3[N:59]([N:60]=[C:61]([C:64]4[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=4)[CH:62]=3)[CH:58]=[CH:57]2)=[CH:49][C:72]=1[NH:73][C:75]([C:10]1[CH:9]=[C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[CH:16]=[C:15]([S:17]([F:20])([F:22])([F:21])([F:18])[F:19])[CH:14]=1)=[O:76]
Reactant: CC(C)(C)OC(=O)Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)c(C)c1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(CC(=O)OC(C)(C)C)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
836 mg (2.31 mmol) of the compound of Example 97A and 1.05 g (2.77 mmol) of HATU were dissolved in 14 ml of DMF, and 338 mg (2.77 mmol) of 4-N,N-dimethylaminopyridine (DMAP) were added slowly. 700 mg (2.31 mmol) of the compound of Example 11A were then added. The reaction mixture was stirred at RT for 3 h. About 200 ml of water were then added, and the mixture was extracted three times with in each case about 200 ml of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness. The crude product obtained in this manner was purified by MPLC on about 100 g of silica gel with cyclohexane/ethyl acetate 50:50→0:100 as mobile phase. Evaporation of the product fractions and drying of the residue under high vacuum gave 966 mg (64% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Solvent: ClCCl
Product: Clc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-bromo-3-chlorophenol (2.0 g, 0.0096 mol), phenylboronic acid (3.5 g, 0.029 mol), TEA (8.1 mL, 0.058 mol), cupric acetate (3.2 g, 0.017 mol) and DCM (40 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 24 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=6.74 (dd, J=8.84, 2.78 Hz, 1H), 6.94-7.02 (m, 2H), 7.06 (d, J=2.78 Hz, 1H), 7.14 (t, J=7.33 Hz, 1H), 7.29-7.38 (m, 2H), 7.48 (d, J=8.84 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To 4-hydroxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (1.25 g, 5.45 mmol) and pyridine (0.661 mL, 8.18 mmol) in dichloromethane (10 mL) at 0° C. is added methanesulfonyl chloride (0.593 mL, 7.63 mmol). After 3 hours, one additional equivalent of methanesulfonylchloride and pyridine are added. After 1 hour the reaction mixture is concentrated, then EtOAc and water are added. The organic layer is concentrated and chromatographed on silica gel eluting with MeOH in dichloromethane 0-3% to give the title compound as a yellow oil (1.60 g, 95% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:13]=1[CH2:14][OH:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: OCc1cc(Cl)c(F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(F)cc1Cl
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a solution of oxalyl chloride (1.72 mL, 19.74 mmol) in 20 mL methylene chloride at -78° C. was added a solution DMSO (2.8 mL, 39.5 mL) in 3 mL methylene chloride. The mixture was stirred for 5 minutes at -78° C. followed by the addition of a solution of Part A 2,5-dichloro-4-fluorobenzyl alcohol (3.5 g, 17.95 mmol) from above in 15 mL methylene chloride. The mixture was stirred at -40° C. for 15 min., cooled to -78° C. followed by the addition of triethylamine (8.26 mL, 59.2 mmol). The mixture was allowed to come to RT, washed sequentially with 10% HCl, saturated sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate and concentrated to afford the title compound 3.39 g as a white solid. ##STR266##
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](OCC)=[O:11])=[N:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([N:4]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][OH:11])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)nn1C(C)C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To ethyl 1-isopropyl-5-methyl-1H-pyrazole-3-carboxylate (7.68 g, 39.1 mmol) in THF (50 mL) at 0° C. was added LAH (1.49 g, 39.1 mmol). The cold bath was removed, and the reaction mixture was stirred for 2 hours, and then quenched carefully with sodium sulfate decahydrate. The reaction mixture was filtered through Celite and washed with Et2O. The filtrate was concentrated under reduced pressure to give 5.3 g (88%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[C:45](Cl)(=[O:48])[CH2:46][CH3:47].CO>ClCCl>[C:45]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:48])[CH2:46][CH3:47]
Reactant: CCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CO
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reaction time: 2 h

Procedure:
4-(5-Cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride from example A138 (472 mg; 1.0 mmol) and DBU (2.5 mmol) is dissolved in dry dichloromethane (5 mL). Propionyl chloride (1.1 mmol) is syringed into the reaction mixture at ice bath temperature. After complete addition stirring is continued at ambient temperature over night. Methanol (1 mL) is added and stirring is continued for two hours. The volatiles are evaporated. The residue is purified by reversed phase preparative HPLC. The collected product fraction is freeze-dried to yield 375 mg of the title compound as colorless solid.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[C@@H:16]2[CH2:20][NH:19][C:18](=[O:21])[CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:23]>O=[Pt]=O>[ClH:15].[NH2:19][CH2:20][C@@H:16]([C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:17][C:18]([OH:21])=[O:23]
Reactant: CO
Reactant: O=C1C[C@H](c2ccc(Cl)cc2/C=C/c2ccccc2)CN1
Agent: O=[Pt]=O
Product: Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)cc1CCc1ccccc1

Procedure:
Crude 4-[2-((1E)-2-phenylvinyl)-4-chlorophenyl](4R)pyrrolidin-2-one (3a) was then stirred overnight with 5% PtO2 in methanol under a hydrogen atmosphere (1 atm). The catalyst was filtered using Celite and filtrate concentrated to dryness. The crude product was treated overnight with 6N HCl aqueous solution at 90° C. and the title compound (3) purified by HPLC. 1H-NMR (400 MHz, CD3OD): δ 2.36-2.41 (dd, J=16.0, 4.0 Hz, 1H), 2.69-2.75 (dd, J=16.0, 8.0 Hz, 1H), 2.88-3.00 (m, 4H), 3.05-3.12 (m, 1H), 3.17-3.24 (m, 1H), 3.65-3.69 (m, 1H), 7.14-7.22 (m, 8H); MS (ESI) m/z 318.09 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])([C:10]#[N:11])[C:12]#[N:13])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: N#CC(C#N)Cc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc([N+](=O)[O-])cc1
Yield: 10.8 %

Procedure:
Using 5.00 g of (4-nitrobenzyl)malononitrile, 60 ml of N,N-dimethylformamide, 1.10 g of sodium hydride (60% in oil), and 4.85 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.80 g of 2-(4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (18)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O[N:51]1[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[N:52]1>ClCCl>[N:51]1([O:27][C:26](=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([C:19]3[N:18]=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:12][CH:13]=4)[O:21][N:20]=3)=[CH:30][CH:29]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[N:52]1
Reactant: On1nnc2ccccc21
Reactant: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a mixture of 4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid (2.0 g) and triethylamine (1.1 g) in dichloromethane (60 ml) was added 3-(3-dimethylaminopropyl)-1-ethylcarbodimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (0.8 g). The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was triturated with isopropyl ether. The precipitates were collected by filtration, washed with isopropyl ether and dried to give 4-[5-(4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid benzotriazol-1-yl ester (2.1 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1C=C)=[CH2:2].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(CC(C)(C)C)=C.C1(O)C=CC=CC=1.CC(CC(C)(C)C)=C>O>[CH2:2]([C:14]1[CH:15]=[CH:16][C:11]([OH:17])=[CH:12][CH:13]=1)[CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1ccccc1
Reactant: C=Cc1ccccc1C=C
Agent: C=C(C)CC(C)(C)C
Solvent: O
Product: CCCCCCCCc1ccc(O)cc1

Procedure:
The reaction is performed discontinuously in a stirred flask equipped with contact thermometer and reflux condenser, under the conditions indicated in Table 1. The flask is charged with 90 g of a sulfonated polystyrene ion exchange resin in the H-form, crosslinked with divinylbenzene to an extent of 8% by weight and having an activity of 4.6 meg/g catalyst, and 282 g of phenol and 168 g of diisobutene (molar ratio phenol: diisobutene=2:1) and 9 g of water (2% by weight, based on the mixture of phenol-diisobutene) is added thereto. After a reaction period of 15 minutes, the crude product is separated from the catalyst by filtration and worked up by distillation in a manner known per se without any pretreatment, thus obtaining a p-octyl phenol having a very high degree of purity (setting point 80.2° C.).
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:48][C:49]1[N:50]=[CH:51][C:52]([CH2:55][NH:56][C:21]([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=2)=[O:22])=[CH:53][CH:54]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(Cl)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (21 mg, 0.064 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol), 1-hydroxybenzotriazole hydrate (9.9 mg, 0.064 mmol), and CH2Cl2 (3 mL) were added 2-chloro-5-aminomethylpyridine (14 mg, 0.097 mmol) and N,N-diisopropylethylamine (17 μL, 0.097 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-80% MeCN/water[10 mM Et2NH]) to yield a white foam.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:6]1([CH3:20])[N:10]2[C:11](=[O:18])[C:12]3[C:17]([C:9]2=[N:8][C:7]1=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:5])[CH3:4].Cl>C(O)C.O1CCCC1>[CH:3]([C:6]1([CH3:20])[N:10]2[C:11](=[O:18])[C:12]3[C:17]([CH:9]2[NH:8][C:7]1=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:5])[CH3:4]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C1(C)C(=O)NC2c3ccccc3C(=O)N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a stirred suspension of 10.4 g (0.274 mole) sodium borohydride in 164 ml absolute ethanol under nitrogen was added dropwise at 5° C a solution of 133.9 g (0.548 mole) of 2,5-dihydro-3-isopropyl-3-methyl-3H-imidazo[2,1-a]isoindole-2,5-dione in 155 ml tetrahydrofuran. After the addition, the mixture is stirred a further 3 hours at room temperature and then poured over 1070 g ice with stirring. The mixture is acidified with concentrated HCl and after stirring for 1.5 hours, the precipitate removed by filtration, washed with water and air-dried to give 118.7 g of 1,9b-dihydro-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole2(3H),5-dione, melting point 178°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](=[N:16][NH2:17])[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14][CH3:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:26])[O:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:22]([O:21][C:20]([NH:17][N:16]=[C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14][CH3:15])=[CH:9][CH:8]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1)=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)COC(=O)Cl
Reactant: CSCc1ccc(C(=NN)c2ccc(Cl)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSCc1ccc(C(=NNC(=O)OCC(C)C)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.8 %

Procedure:
To a dichloromethane solution (30 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone hydrazone (1.5 g) and 4-(N,N-dimethylamino)pyridine (1.2 g), isobutyl chlorocarbonate (0.8 g) was dropwise added under cooling with ice and subsequently stirred at a room temperature for 20 hours. The reaction mixture was then successively washed with 2N hydrochloric acid, water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:4) to obtain 4-chloro-4'-methylmercaptomethylbenzophenone isobutoxycarbonyl hydrazone (0.5 g) as an isomer mixture.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17]C(C(F)(F)F)=[CH:15][C:3]=1[C:4](N[C@H]1CC[C@H:10]([CH:13]=[O:14])CC1)=O.NC1C=NC=C(C)C=1.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=[O:33])[CH3:32].[Na+]>C(Cl)Cl>[CH3:32][CH2:31][O:33][C:13]([CH3:10])=[O:14].[CH3:17][CH2:18][CH2:2][CH:3]([CH3:15])[CH3:4]
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1cncc(N)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
To a 50 mL round-bottomed flask containing trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) (100 mg, 0.3 mmol) and 3-amino-5-methylpyridine (36 mg, 0.3 mmol) in dry DCM (5 mL) is added sodium triacetoxyborohydride (106 mg, 0.45 mmol) in one portion. The suspension is stirred at RT for 4 hours. The mixture is partitioned between DCM and saturated sodium bicarbonate, passed through a phase separator to recover the DCM layer and evaporated to give a colourless solid. The crude product is redissolved in DCM, absorbed directly onto silica gel and columned on silica gel using a 12 g pre-packed column and isohexane/EtOAc gradient elution (0% to 100% EtOAc). Product-containing fractions are combined and evaporated and the product is isolated as a colourless solid after trituration with 20% EtOAc/isohexane, 55 mg, [MH+426.40].
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C([N:25]4[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])CC4)C=CN=3)=C(C3C=CC=CC=3)N=2)C=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52](Cl)[N:51]=2)=[CH:36][CH:35]=1.N1CCC(O)C1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[N:51]=[C:52]([N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:32]3)[CH:53]=[N:54][CH:55]=2)=[CH:36][CH:35]=1
Reactant: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(Cl)n2)cc1
Agent: OC1CCNC1
Product: OC1CCN(c2cncc(Cc3c(-c4ccc(Cl)cc4)nc4ccccn34)n2)C1

Procedure:
The title compound was prepared according to the experimental for compound 187 from 2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridine and pyrrolidin-3-ol. M/e+ 406 for C22H21ClN5O (M+H)−; 1H-NMR (400 MHz, CDCl3) δ 8.20 (d, J=6.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.71 (d, J=10.6 Hz, 2H), 7.59 (dd, J=9.1, 0.7 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.16 (m, 1H), 6.77 (t, J=6.9 Hz, 1H), 4.56 (s, 1H), 4.32 (s, 2H), 4.06 (m, 1H), 3.53 (m, 3H), 3.00 (bs, 1H), 2.04 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl[CH2:36][C:37](Cl)=[O:38].[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CC#N>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:37](=[O:38])[CH2:36][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Reactant: O=C(Cl)CCl
Reactant: C1CCNCC1
Solvent: CC#N
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(=O)CN1CCCCC1
Reaction time: 7 h
Yield: 9.6 %

Procedure:
To the product from step (v) (180 mg) in MeCN (5 mL), 2-chloroacetyl chloride (44.0 mg) was added at 0° C. and stirred for 7 h. Piperidine (332 mg) was added and stirred at rt for 15 h. The solvent was removed and the crude product was purified by RPHPLC. The resulting residue was triturated with diethyl ether to afford the title compound as a white solid (22 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[CH2:13]([O:15][C:16](=[O:24])[CH2:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1)[CH3:14].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[NH2:8][CH2:9][C:10]([NH:23][C:20]1[S:21][CH:22]=[C:18]([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24])[N:19]=1)=[O:11]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)CN)n1

Procedure:
A mixture of N-(tert-butoxycarbonyl)glycine (3.1 g), 2-amino-4-thiazoleacetic acid ethyl ester (3 g) and bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (7.54 g) in dimethylformamide (20 ml) was treated with N,N-diisopropylethylamine (6 ml). After 25 minutes N,N-dimethyl-4-aminopyridine (1.96 g) was added. After 24 hours the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, IN HCl and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 50% ethyl acetate in isohexane. The product (0.77 g) was dissolved in dichloromethane (25 ml) and trifluoroacetic acid (10 ml). After 2 hours the mixture was evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase was repeatedly extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. Yield 0.41 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Yield: 76.2 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 4-chloro-3-nitroquinoline (109.70 g, 525.87 mmol) and dichloromethane (500 mL). To the solution was added triethylamine (79.82 g, 788.81 mmol) and 4-amino-1-butanol (46.87 g,525.87 mmol) to give a homogeneous, dark yellow solution. The reaction was judged to be complete after heating at reflux for 30 minutes. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with chloroform (1×). The organic layers were combined and then concentrated under reduced pressure to afford 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (104.67 g, 400.60 mmol) as a dark yellow solid. This material was used without further purification.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)([OH:3])=[O:2].[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]O)([O-:29])=[O:28]>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:25])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([O:3][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[N+:27]([O-:29])=[O:28])=[O:2])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)OCc3ccccc3[N+](=O)[O-])coc12
Yield: 37.2 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and 2-nitrobenzyl alcohol (0.12 g) to give Compound 154 (0.15 g, 38%) as white crystals.