Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])[N:5]=[CH:4][C:3]=1C#N>Cl>[F:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([F:14])[C:7]=1[N:6]1[C:2]([NH2:1])=[CH:3][CH:4]=[N:5]1
Reactant: N#Cc1cnn(-c2c(F)cccc2F)c1N
Agent: Cl
Product: Nc1ccnn1-c1c(F)cccc1F

Procedure:
To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride (12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added 2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed by triethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for 10 min and then heated to reflux for 1.5 h. The contents were cooled to RT and solvents removed under reduced pressure. The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAc layer was separated, washed with 50 mL of brine, dried and concentrated. The concentrated solid was stirred in 50 mL of hexanes for 5 min, filtered through a flitted funnel, and dried in a vacuum oven at 45° C. for 2 h to afford 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brown solid. This material was used without further purification. MS (ES+): 221.1 (M+H)+. (B): A mixture of 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64 mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reaction mixture was concentrated to half of its volume, cooled with an ice bath, pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL of EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as a brown amorphous solid. This material was used without further purification. MS (ES+): 196.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[N:22]([CH:24]=[CH:25][CH:26]=3)[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[N:22]([CH:24]=[CH:25][CH:26]=3)[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)ON=c1cc(-c2cn3cccc3cn2)oc2ccc(O)cc12
Agent: Cl
Product: CC(C)(C)ON=c1cc(-c2cn3cccc3cn2)oc2ccc(OCCN3CCOCC3)cc12
Yield: 68 %

Procedure:
6-(2-Morpholin-4-yl-ethoxy)-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 68% yield using the procedure described in example 85A, starting from 6-Hydroxy-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one O-tert-butyl-oxime (example 123B) and 4-(2-chloroethyl) morpholine hydrochloride. The title compound was isolated as a beige solid.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:16][C:15]3[CH:17]=[CH:18][C:19]4[C:24]([C:14]=3[CH:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CO>[CH:13]1[C:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:15]=2[O:16][C:12]=1[CH:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCC(c2cc3c(ccc4ccccc43)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: c1ccc2c(c1)ccc1oc(C3CCNCC3)cc12

Procedure:
7.8 g of 4-(naphtho[2,1-b]furan-2-yl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 60 ml of ethylene glycol. After the addition of 40 ml of a 50% aqueous potassium hydroxide solution, the formed cloudy solution is heated, with vigorous stirring, for 15 hours at 160°. The reaction solution is thereupon cooled to 20° and extracted twice with 500 ml of ethyl acetate. The organic phases are washed five times with 1 liter of water each time, dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 400 ml of 2N hydrochloric acid, and the acid solution extracted with toluene. The aqueous solution is then adjusted by addition of 10% sodium hydroxide solution to have a pH value of 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 4-(naphtho[2,1-b]furan-2-yl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 225°.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:13][CH2:12][CH2:11]1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[C:20]1([C:18]2[N:19]=[C:15]([CH2:14][C:10]3([CH2:9][OH:8])[CH2:13][CH2:12][CH2:11]3)[S:16][CH:17]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(COCC2(Cc3nc(-c4ccccc4)cs3)CCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCC1(Cc2nc(-c3ccccc3)cs2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a solution of 0.7 g (2.0 mmol) of 2-({1-[(benzyloxy)methyl]cyclobutyl}methyl)-4-phenyl-1,3-thiazole in 15 mL of dichloromethane was added a 1.0 M solution of 2.2 mL (2.2 mmol) of boron tribromide and the contents stirred at room temperature for 16 h. After quenching with 10 mL of methanol, the contents were concentrated under vacuum and the residue was purified by silica gel chromatography using ethyl acetate:hexane (1:9) as the eluent to afford 0.16 g (31%) of {1-[(4-phenyl-1,3-thiazol-2-yl)methyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.13 (t, J=7 Hz, 1H), 3.66 (d, J=6 Hz, 2H), 3.3 (s, 2H), 2.08-1.94 (m, 6H). GC-MS m/z 260 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([NH2:9])[CH:3]=1.[CH2:10](Cl)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C1C=CC=CC=1.C(Cl)Cl>[CH2:11]([C:10]1[S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=C(CCl)c1ccccc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: Clc1ccc2sc(Cc3ccccc3)nc2c1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
A round bottom flask fitted with a Dean-Stark trap was charged with 4-Chloro-2-aminobenzenethiol (3.47 g, 21.7 mmol) and phenacyl chloride (3.0 mL, 22.7 mmol) in benzene (40 mL), and the mixture heated 18 h in an 80° C. oil bath. The reaction mixture was diluted with CH2Cl2, and the organics washed sequentially with aqueous Na2CO3, brine, then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel chromatography eluting with 35-100% CH2Cl2/hexanes to provide the title compound as a white solid (1.94 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(=O)=O>CO>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([C@@H:15]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[CH:20][N:19]=3)[CH3:16])[CH2:13][CH2:14]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(C(C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Agent: O=C=O
Solvent: CO
Product: CC(C)c1noc(N2CCC([C@H](C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1

Procedure:
The racemic 2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (prepared as in Example 156) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 70% CO2: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 25.83 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:22]=[CH:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:23]3[N:22]=[CH:21][S:20][CH:24]=3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2cscn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2cscn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(thiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 409.07 g/mol.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[C:7]([C:8]#[N:9])=[N:6][N:5]([CH3:10])[C:4]=1[CH2:11][C:12]1([F:25])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1>C(O)C>[ClH:1].[Br:2][C:3]1[C:7]([C:8]#[N:9])=[N:6][N:5]([CH3:10])[C:4]=1[CH2:11][C:12]1([F:25])[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: Cn1nc(C#N)c(Br)c1CC1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: Cn1nc(C#N)c(Br)c1CC1(F)CCNCC1
Temperature: 70 °C

Procedure:
Hydrochloric acid (0.55 mL of 6 M) was added to a suspension of tert-butyl 4-[(4-bromo-5-cyano-2-methyl-2H-pyrazol-3-yl)methyl]-4-fluoropiperidine-1-carboxylate (446 mg, 1.11 mmol) in ethanol (10 mL), and the reaction was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide 4-bromo-5-[(4-fluoropiperidin-4-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile hydrochloride as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]C)=[O:24])=[CH:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl>COCCOC>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OC(C)C)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a solution of methyl 7-(4-isopropoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (250 mg) in 1,2-dimethoxyethane (10 ml) was added 6N hydrochloric acid (3 ml), and the mixture was stirred at 70° C. for 18 hours. To the mixture were added 1,2-dimethoxyethane (10 ml) and 6N hydrochloric acid (5 ml), and the mixture was stirred at 70° C. for 4 days, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine; dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with hexane to give colorless crystals of 7-(4-isopropoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (230.3 mg).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH:8]=[CH:2][C:3]1=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN1CCCCC(Br)C1=O
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCCCCCCCCCCCN1CCCC=CC1=O
Temperature: 25 °C

Procedure:
A solution of 10.0 g (28 mmol) of 3-bromo-1-dodecylazacycloheptan-2-one and 5.1 g (47 mmol) of 2,6-lutidine was refluxed for 3 hours, then cooled to room temperature. 100 ml of toluene was added, the mixture was filtered, and the filtrate was concentrated in vacuo to yield a crude oil. Purification by flash chromatography (silica gel; 7:3 petroleum ether/ether V/V) gave the product as a colorless oil, Rf =0.38; Kuglerohr distilled at 165°-170° C./0.2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16](Cl)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonyl chloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) was added 1 drop of DMF followed by cyclohexylamine (306 μL, 2.68 mmol). The reaction mixture was stirred at room temperature for two hours then stopped.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:21])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[CH3:18][O:17][C:15]([C:14]1[CH:19]=[CH:20][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:12][C:13]=1[O:21][CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:16]
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CCOC(=O)CCC(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A stirred suspension of sodium hydride (340 mg) in dry dimethylformamide (100 mL) is treated portionwise with methyl 4-benzyloxy-2-hydroxybenzoate (2 g). After stirring at ambient temperature for 30 minutes, it is treated with ethyl (RS)-4-chloro-4-phenylbutanoate (1.9 g) in one portion and stirred for 16 hours at ambient temperature, and then for two hours at 80° C. The reaction mixture is then concentrated in vacuo and the residue is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography of the resulting oil, eluting with 5-10% ethyl acetate/cyclohexane, affords ethyl (RS)-4-(2-methoxycarbonyl-5-benzyloxyphenoxy)-4-phenylbutanoate (2 g), in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(CCl)ccn1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
(2-Methyl-pyridin-4-yl)-methanol (40 mg, 0.33 mmol) described in Manufacturing Example 47-1-1, thionyl chloride (0.047 ml, 0.65 mmol) and methylene chloride (4.0 ml) were stirred for 5 minutes at 60° C. Sodium bicarbonate solution and ethyl acetate were added to separate the reaction solution, and the ethyl acetate layer was dried over sodium sulfate. The solvent was evaporated under a reduced pressure to obtain 4-chloromethyl-2-methyl-pyridine as a crude product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:16])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OCc1ccc(C(=O)O)cc1

Procedure:
4-[acetyloxy-methyl]benzaldehyde (15.3 g, 86.5 mmol) in acetone (250 ml) was then reacted with Jones reagent (33.0 ml, a three-fold excess) while stirring (exothermal reaction). This was stirred for 2 h before filtering out the green solid. The green solid was then dried under reduced pressure and dissolved in ethyl acetate (400 ml) and washed with sodium carbonate solution and water until neutral. After removal of solvent, a crop of yellow crystals (13.3 g) was obtained which was then recrystallised in chloroform-hexane to give a white crystal (3) (12.62 g, 76%). m.p. 120-123° C.; Rf 0.29 (1:1 Hexane-ether v/v).
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([N:11]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]1[C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:32]([CH:34]1[O:36][CH2:35]1)Cl>O1CCOCC1>[O:36]1[CH2:35][CH:34]1[CH2:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[O:21][C:20]([C:12]3[N:11]([CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=3)=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: Oc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3Cc3ccccc3)o2)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cn(Cc2ccccc2)c(-c2ccc(-c3ccc(OCC4CO4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 48.1 ml of 1N sodium hydroxide solution and 18.5 ml of water is added to a solution of 18.5 g of 2-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-5-(4-hydroxyphenyl)-furan in 160 ml of dioxan and the mixture is stirred for 10 minutes at room temperature. After the addition of 13.3 g of epichlorohydrin, the mixture is stirred for a further 48 hours at room temperature, then filtered and the filter residue is washed with dioxan/water 1:1 and then with ether. After drying, 2-[4-(2,3-epoxypropoxy)-phenyl]-5-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-furan is obtained in the form of a white crystallisate.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=2)[CH3:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.B(Br)(Br)Br>ClCCl>[ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH3:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: COc1ccc(N(C)c2nc(Nc3ccccc3C)nc3ccccc23)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1Nc1nc(N(C)c2ccc(O)cc2)c2ccccc2n1
Reaction time: 3 h
Yield: 23.7 %

Procedure:
2-(2-Methylphenylamino)-4-(N-methyl-4-methoxyphenylamino)quinazoline hydrochloride (1.6 g, 0.0043 mol) was stirred in dry dichloromethane (50 ml) at 0°-5° under nitrogen. To this solution was added boron tribromide (2.0 ml, 0.0216 mol) dropwise at 0°-5° over 10 minutes. The mixture was stirred for 3 hours at 0°-5° and then allowed to reach room temperature over 16 hours. After pouring onto ice, basifying and neutralising the aqueous phase was extracted with dichloromethane, the organic extracts which dried and evaporated to dryness. The residue afforded crystals of 2-(2-methylphenylamino)-4-(n-methyl-4-hydroxyphenylamino)quinazoline hydrochloride (0.4 g, 23.7%) from ethanolic hydrogen chloride m.p. 317°-319°.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([OH:8])[C@@H:6]2[CH2:9][CH2:10][C@H:3]1[C@@H:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]2[C@@H](C1C=CC=CC=1)C>CO>[OH:1][C@@H:2]1[C@H:7]([OH:8])[C@@H:6]2[CH2:9][CH2:10][C@H:3]1[C@@H:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:5]2
Reactant: CCOC(=O)[C@@H]1[C@@H]2CC[C@@H]([C@@H](O)[C@H]2O)N1[C@H](C)c1ccccc1
Solvent: CO
Product: CCOC(=O)[C@H]1N[C@H]2CC[C@@H]1[C@H](O)[C@@H]2O
Reaction time: 2 h

Procedure:
Ethyl (1S,3S,4S,5S,6R)-5,6-dihydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate obtained in Example 1-1 (4.2 g) was dissolved in methanol (10 mL), and 10% Pd(OH)2—C (800 mg) was added to the solution. The mixture was hydrogenated under H2 (4.0 atm) at room temperature for 2 hrs.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:47])[CH2:43][CH2:44][CH2:45]I)=[CH:38][CH:37]=1>CN(C)C=O.C(OCC)(=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42](=[O:47])[CH2:43][CH2:44][CH2:45][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:22][CH:23]=4)[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:40][CH:41]=1
Reactant: CS(=O)(=O)Nc1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Reactant: O=C(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a solution of N-(4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide (0.2 g, 0.46 mmol) and potassium carbonate (0.191 g, 1.38 mmol) in N,N-dimethylformamide (5 mL), was added 1-(4-fluorophenyl)-4-iodobutan-1-one (0.134 g, 0.46 mmol). After stirring at 65° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by pTLC (10% methanol/dichloromethane) to obtain the product (0.03 g, 12%); 1H NMR (DMSO-d6): δ 1.70-1.90 (m, 4H), 2.40-2.49 (m, 2H), 2.66-2.84 (m, 6H), 2.97 (s, 3H), 3.05 (br, 2H), 5.12 (s, 2H), 6.88 (t, 1H, J=7.6 Hz) 6.99-7.03 (m, 2H), 7.26 (d, 4H, J=9.2 Hz), 7.34 (t, 2H, J=8.4 Hz), 7.76 (d, 2H, J=8.8 Hz), 8.04-8.07 (m, 2H), 9.73 (s, 1H); MS for C30H33FN4O4S m/z 565.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[NH:23][C:22]1=[O:32])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([CH2:11][N:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][CH:21]([NH:20][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:22]1=[O:32])=[O:10])[CH3:2]
Reactant: O=C1Nc2ccccc2CCC1NC(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (5.0 g) in dry dimethylformamide was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [from the 60% mineral oil dispersion (0.5 g) washed with petroleum ether (3×80 ml)] in dry dimethylformamide (100 ml) at room temperature. Stirring was continued for an additional 30 minutes at room temperature, when a solution of ethyl bromoacetate (2.0 g) in dry dimethylformamide (10 ml) was added. After an additional 30 minutes at room temperature the reaction mixture was heated to 50°, and maintained at that temperature for 18 hours. The reaction mixture was cooled to room temperature and the solvent removed under high vacuum. Water (150 ml) was added and the solution extracted with ethyl acetate (2×300 ml). The combined ethyl acetate solutions were washed with water (100 ml), dried over MgSO4, and the solvent removed under reduced pressure to give a brown oil which was chromatographed on silica gel (250 g). Elution with toluene/ethyl acetate (9:1; 600 ml) gave an oil, characterized as isomer A of the title compound. Elution with an additional 1000 ml of the solvent mixture gave an oil characterized as isomer B of the title compound.