Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21](O)=[O:22]>ClCCl.CO>[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)C(C)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine (as prepared in example 1b) and 2-methyl-malonic acid monomethyl ester (Nader et al., Chem. Ber. 1986, 119, 1196). Yield after flash-chromatography with dichloromethane/methanol 98:2: 40%. Colorless solid. Mp=119° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH:7]=[O:8]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A 20 g portion of sodium borohydride was suspended (partially dissolved) in 90 ml of ethanol, and 380 ml of ethanol solution containing 125 g of 3,5-difluorobenzaldehyde to the suspension which was cooled in an ice bath. After the dropwise addition, this was stirred for 1 hour, the solvent was evaporated and the resulting residue was mixed with 400 ml of water. This was extracted with 700 ml of ethyl acetate, washed with water and saturated brine in that order and then dried with anhydrous sodium sulfate. By evaporating the solvent, 120 g of 3,5-difluorobenzyl alcohol was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:14]I>C1COCC1>[CH3:14][N:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc(C)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)cn1C
Reaction time: 0.17 h

Procedure:
To a solution of 4-methyl-2-pyrrolecarboxylic acid ethyl ester (100 mg, 0.653 mmol) in THF (2.5 mL), was added NaH (31.3 mg, 0.783 mmol). The mixture was stirred for 10 min and then MeI (0.061 mL, 0.979 mmol) was added dropwise. The resulting mixture was stirred overnight. The reaction was quenched with sat. NH4Cl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (1000 μm, hexanes/EtOAc (9:1)) to give ethyl 1,4-dimethyl-1H-pyrrole-2-carboxylate. 1H NMR (500 MHz, CDCl3): δ 6.77 (s, 1H); 6.58 (s, 1H); 4.28 (q, J=7.1 Hz, 2H); 3.88 (s, 3H); 2.08 (s, 3H); 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:19].[Na+]>CO.O1CCCC1.[Ag]=O>[C:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]2[O:7][C:3]([C:1]([OH:19])=[O:2])=[CH:4][CH:5]=2)[CH:9]=1)#[N:18]
Reactant: N#Cc1cn(-c2ccc(C=O)o2)c2ccccc12
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cn(-c2ccc(C(=O)O)o2)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 1-(5-formylfuran-2-yl)-1H-indole-3-carbonitrile (0.085 g) in methanol (4 mL) and tetrahydrofuran (4 mL) were added silver oxide (0.1 g) and 2 mol/L aqueous sodium hydroxide solution (0.27 mL), this mixture was stirred at room temperature for 6 hours. The insoluble material of reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. To this residue were added water (15 mL) and 2 mol/L hydrochloric acid solution (2 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.023 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:23].[CH2:24]([CH:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)[CH2:25][CH2:26][CH2:27][CH3:28].C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:24]([CH:29]1[CH2:30][CH2:31][CH:32]([C:35]([O:23][C:3]2[C:4]3[CH2:5][CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([F:13])([F:14])[C:9]=3[CH:10]=[C:11]([F:12])[C:2]=2[F:1])=[O:36])[CH2:33][CH2:34]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC1CCC(C(=O)O)CC1
Reactant: CCCCCCCCC1CCc2c(cc(F)c(F)c2O)C1(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCCCC1CCc2c(cc(F)c(F)c2OC(=O)C2CCC(CCCCC)CC2)C1(F)F

Procedure:
From 2,3,5,5-tetrafluoro-6-octyl-5,6,7,8-tetrahydronaphthalen-1-ol and 4-pentylcyclohexanecarboxylic acid by means of DCC esterification.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].ClS([N:20]=[C:21]=[O:22])(=O)=O>ClCCl>[C:21]([O:1][CH:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:22])[NH2:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)C#CC(O)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C#CC(OC(N)=O)c1ccccc1
Yield: 98 %

Procedure:
To 100 ml of a dichloromethane solution containing 8 g (39.2 millimoles) of ethyl 4-hydroxy-4-phenyl-2-butynoate, 3.5 ml (40.2 millimoles) of chlorosulfonyl isocyanate was added at a temperature of -20° C., and the mixture was reacted for 30 minutes at -10° C. under stirring. Then, hydrolysis and purification treatment were conducted in the same manner as in Example VI-38, whereby 9.5 g (yield: 98%) of ethyl 4-carbamoyloxy-4-phenyl-2-butynoate in crystal form was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[O:13]=[C:14]1[NH:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15]1>C(OCC)(=O)C>[F:1][C:2]1[C:7]([O:8][C:19]([CH:16]2[CH2:15][C:14](=[O:13])[NH:18][CH2:17]2)=[O:20])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C1CC(C(=O)O)CN1
Solvent: CCOC(C)=O
Product: O=C1CC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 212.3 %

Procedure:
To a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (18.5 mg, 0.096 mmol) in 2 mL ethyl acetate was added pentafluorophenol (35.6 mg, 0.193 mmol) at 0° C. After 10 minutes, 5-oxo-pyrrolidine-3-carboxylic acid 16 (33.9 mg, 0.064 mmol) was added at 0° C. and the reaction mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (ethyl acetate:hexane=1:2) to yield the corresponding 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 17 as a colourless oil (40.1 mg, 89.80%).
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([CH3:20])[CH3:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH2:1]([S:7][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([CH3:20])[CH3:19])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCS
Reactant: COC(=O)NC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCSCc1ccc(C(C)(C)NC(=O)OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 1-hexanethiol (4.89 g) in DMF (15 ml) was added to a suspension of sodium hydride (1.66 g, 60% dispersion in mineral oil) in DMF (35 ml) over 15 minutes with stirring under nitrogen. The mixture was stirred at ambient temperature for 3 hours and then heated on a steam bath for 15 minutes. A solution of methyl N-[1-(4-bromomethylphenyl)-1- methylethyl]-carbamate (11.85 g) in DMF (50 ml) was added to this mixture, dropwise, over 10 minutes, at 20° C., with stirring. The mixture was stirred at ambient temperature for 18 hours and then quenched with saturated potassium carbonate solution (100 ml). The mixture was diluted with water and extracted with ether to give methyl N-[1-(4-hexylthiomethylphenyl)-1-methylethyl]carbamate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH:27]1([C:30]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[N:10][N:11]([C:13]4[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccccc2F)ccn1
Reactant: O=C(Cl)C1CC1
Product: O=C1CCC(n2cc(-c3ccnc(NC(=O)C4CC4)c3)c(-c3ccccc3F)n2)=NN1
Yield: 71.5 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 50.0 mg (0.14 mmol) of 4-(2-aminopyridin-4-yl)-3-(2-fluorophenyl)-1-(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 55 in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 15.7 mg (0.15 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 41.9 mg of the title compound as a white powder. (Yield: 70%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:32][OH:33]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=[N:32][OH:33])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Reactant: NO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CO
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-morpholin-4-ylpropyl)-1,2,5-oxadiazole-3-carboxamide (10.0 mg, 27 μmol) was suspended in benzene (0.4 mL) under an atmosphere of nitrogen and phosphorus pentachloride (6.2 mg, 29.8 μmol) was added. The solution was heated at reflux for 2.5 h. The volatiles were evaporated in vacuo. The reaction was dissolved in EtOH (0.3 mL) and hydroxylamine (40 μL, 0.7 mmol) (50% solution in water) was added to the reaction. After stirring for 1 h, the reaction solution was diluted with MeOH and purified by preparative LCMS to give the desired product (5.2 mg, 50%). LCMS for C16H20ClFN5O3 (M+H)+: m/z=384.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][C:31]([C:34](=[O:39])[NH:35][CH2:36][CH2:37][OH:38])([CH3:33])[CH3:32])=[CH:19][CH:18]=1)#[N:2].CCN(C(C)C)C(C)C.[CH3:49][C:50]([Si:53](Cl)([CH3:55])[CH3:54])([CH3:52])[CH3:51].[OH-].[Na+]>CN(C1C=CN=CC=1)C.C1COCC1>[C:50]([Si:53]([CH3:55])([CH3:54])[O:38][CH2:37][CH2:36][NH:35][C:34]([C:31]([CH3:33])([O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:4]2[C:5]3[N:6]([CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11]=3[CH3:12])[N:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)[CH3:32])=[O:39])([CH3:52])([CH3:51])[CH3:49]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c12
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO[Si](C)(C)C(C)(C)C)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A solution of 433F (164 mg, 0.31 mmol), DIEA (0.27 ml, 1.55 mmol), DMAP (7.6 mg, 0.062 mmol) and TBSCl (140 mg, 0.93 mmol) in THF (4 ml) was stirred under argon at rt for 2 h. 1N NaOH (0.70 ml, 0.70 mmol) was added. The resulting mixture was stirred at rt for 1 h. Removal of the solvent followed by flash chromatography of the residue of silica gel (2%-5% MeOH—CH2Cl2) gave 433G (75 mg, 38%) as a yellow oil. It has a retention time of 7.43 min (standard LC1 method, 8 min run). MS Found: (M+H)+=644.0
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][C@@:8]2([CH3:28])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:9]2=[O:27])=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([C:38]1([NH2:41])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[C:31]([O:35][C:36]([C:38]1([NH:41][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=4)([CH3:28])[C:9](=[O:27])[N:10]([C:19]4[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=4)[C:11]3=[N:15][CH:14]=2)=[O:17])[CH2:39][CH2:40]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)C1(N)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (3.3 g, 7.48 mmol), 1-amino-cyclopropane-carboxylic acid tert-butyl ester (1.8 g, 11.4 mmol) and HATU (4.27 g, 11.2 mmol) were dissolved in anhydrous DMF (20 mL). The mixture was stirred for 15 min. Et3N (2.95 mL, 20.4 mmol) was then added to the reaction. After 30 min, the crude reaction was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10% to 30% EtOAc/Hexanes) to give 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid tert-butyl ester (3.8 g, 6.55 mmol, 87.5%) as a white solid, m/z 580.5 [M+1]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:10]1([C:13]([C:32]2[CH:33]=[CH:34][C:29]([NH:28]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:30][CH:31]=2)=[O:14])[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C(=O)C2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4cyclohexyl-carbonyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C30H28N2O4
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:26])[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:2]([CH:4]1[C:13]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:26])(=[O:1])[CH3:3]
Reactant: CC(O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture of tert-butyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (600 mg, 1.66 mmol) and Dess-Martin periodinane (8.3 mL of 0.30 M, 2.5 mmol) was stirred at 25° C. for 5 h. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3 (2×), 5% Na2S2O3 (2×), brine, dried over MgSO4, filtered and concentrated to dryness. Purification by silica gel chromatography provided tert-butyl 3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (435 mg, 73%). ESI-MS m/z calc. 359.2, found 360.4 (M+1)+; Retention time: 2.84 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J=7.8, 1.5 Hz, 1H), 7.60-7.52 (m, 1H), 7.07-7.01 (m, 2H), 4.10-3.79 (m, 2H), 3.76 (s, 1H), 3.29-3.03 (m, 2H), 2.27 (s, 3H), 2.10-1.85 (m, 3H), 1.68-1.58 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:16]=1[C:17](O)=[O:18]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[CH2:7]1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1ccc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)c1

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 2,5-dimethoxybenzoic acid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCN(C2CCNCC2)CCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was coupled with 1-piperidin-4-yl-[1,4]diazepan-5-one (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3243.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([CH:21]=1)[O:7][C@@H:8]([CH2:19][OH:20])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].I[CH3:25]>C(#N)C.[Ag]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([CH:21]=1)[O:7][C@@H:8]([CH2:19][O:20][CH3:25])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCC[C@H](CO)Oc1cc(Cl)ccc1C#N
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COC[C@@H](CCNC(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.7 %

Procedure:
The product from step (d) (380 mg, 1.12 mmol) was dissolved in acetonitrile (40 ml) and silver oxide (1.292 g, 5.58 mmol) and iodomethane (1.589 g, 11.2 mmol) added. The reaction was stirred at room temperature for 20 h, then at 60° C. for 3 days. The reaction was cooled and filtered. The filtrate was evaporated in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (3:1, then 2:1), to afford the title compound as a colourless oil (146 mg, 37%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].Br[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>O1CCCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of diethyl malonate (320 mg, 2 mmol) in tetrahydrofuran (15 ml) was added a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 2.2 ml, 2.2 mmol). After stirring for 10 minutes, 4-bromonitrobenzene (404 mg, 2 mmol) was added. After stirring for 12 hours, the reaction was quenched by addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide crude 2-(4-nitro-phenyl)-malonic acid diethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(O)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccc3ccc(N)nc3n2)cc1
Yield: 99.3 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-napthyridine (35.8 g), 4-methoxyphenol (99.2 g) and potassium hydroxide pellets (22.4 g; 85% purity). After treatment with caustic soda and washing, 2-amino-7-(4-methoxyphenoxy)-1,8-naphthyridine (52.9 g) is produced, m.p. 200° C. EXAMPLE 13
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]([CH:22]=O)=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH:25][CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]([CH2:22][N:25]([CH3:26])[CH3:24])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A mixture of 2-anilino 4-(2-formyl-1-propylimidazol-5-yl)pyrimidine (Method 118; 200 mg, 0.65 mmol) and dimethylamine (391 μl of 2M solution in THF, 0.78 mmol) in MeOH (6 ml) stirred for 3 hours at ambient temperature. Acetic acid (41 mg, 0.716 mmol) and sodium cyanoborohydride (45 mg, 0.716 mmol) were added and the mixture stirred for a further 18 hours. The volatiles were removed by evaporation and residue dissolved in EtOAc (7 ml). This solution was washed with saturated aqueous sodium hydrogen carbonate solution, water, and brine, then dried and the solvent removed by evaporation to give the title compound (210 mg, 96%) as a yellow foam. NMR: 0.62 (t, 6H), 1.50 (m, 2H), 2.23 (s, 6H), 3.60 (s, 2H), 4.56 (m, 2H), 6.98 (t, 1H), 7.10 (d, 1H), 7.28 (t, 2H), 7.62 (m, 3H), 8.39 (d, 1H), 9.39 (s, 1H); m/z 337.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>>[CH3:25][C:21]1[N:22]=[CH:23][NH:24][C:20]=1[CH2:19][S:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOc1cc(Cl)nc2ccccc12
Reactant: Cc1nc[nH]c1CSCCN
Product: CCOc1cc(NCCSCc2[nH]cnc2C)nc2ccccc12
Yield: 30.3 %

Procedure:
2-Chloro-4-ethoxyquinoline (3.72 gms) and 5-(2-aminoethyl)thiomethyl-4-methylimidazole (3.1 g.) were heated together at 150°-160° C. (oil-bath temperature) for three hours. The residue, on colling, was washed with water and dried. Purification was effected by column chromatography (silica gel column, ethyl acetate-5% methanol eluant) and crystallisation from acetone to give 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline (1.86 gms) m.p. 152.5°-153.5° C.