Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=O)=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[O:63]=[C:61]1[CH2:62][N:58]([C:22]([C:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[C:16]([C:20]#[N:21])[CH:17]=[CH:18][CH:19]=3)[N:9]([C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][CH:6]=3)[N:10]=2)=[O:24])[CH2:59][NH:60]1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2cccc(C#N)c2)c1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(C#N)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 111A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 16 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].Br[CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:15][CH2:16][O:17][CH3:18])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COCCBr
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(C#N)cc1C(=O)OC
Temperature: 60 °C

Procedure:
Methyl 5-cyano-2-hydroxybenzoate (Astatech, 3.0 g, 16.9 mmol), 1-bromo-2-methoxyethane (2.6 g, 18.6 mmol), and K2CO3 (2.3 g, 16.9 mmol) were mixed in 25 mL of DMF and heated at 60° C. for 48 hours. The reaction was diluted with 100 mL of EtOAc washed with water, brine, dried with MgSO4 and the solvent removed to provide the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.46 (s, 3H) 3.79-3.84 (m, 2H) 3.90 (s, 3H) 4.23-4.28 (m, 2H) 7.07 (d, J=8.82 Hz, 1H) 7.72 (dd, J=8.65, 2.20 Hz, 1H) 8.11 (d, J=2.37 Hz, 1H). MS (DCI/NH3) m/z 236.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)C1CCCCC1
Temperature: 2 °C
Reaction time: 12 h

Procedure:
A solution of cyclohexanecarbonyl chloride (9.1 ml) in CH2Cl2 (25 ml) was added slowly under nitrogen atmosphere at 0-4° C. to a stirred mixture of AlCl3 (9.1 g), CH2Cl2 (25 ml) and benzene (50 ml). The resulting mixture was stirred for 1 hour at 0-4° C. and 12 hours at the room temperature. The mixture was poured into ice-water (200 ml, contains 1 ml of concentrated HCl) and stirred for 5 minutes. The phases were separated and the aqueous phase was washed with CH2CO2 (2×20 ml). The organic phases were combined and extracted with water (2×20 ml), 2.5% NaOH solution (2×30 ml) and water (2×20 ml). The organic phase was dried over Na2SO4 and evaporated. Yield was 12.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:2]([NH:1][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=2)=[C:3]([CH:21]=1)[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccc(F)cc2)c1
Yield: 86.3 %

Procedure:
In methanol (10 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example (1) (0.5 g) and 4-fluorobenzaldehyde (0.2 g). To the solution were added acetic acid (0.1 g) and cyano sodium borohydride (0.1 g). The mixture was concentrated, to which were added water (60 ml) and ethyl acetate (50 ml), followed by extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to leave 5-chloro-2-(4-fluorobenzylamino)-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.56 g) as a colorless oily product.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([O:7][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[CH3:9])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(OC(C)c2ccc(C(=O)O)cc2)cc1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 4-(1-(p-tolyloxy)ethyl)benzoate (50 mg, 0.19 mmol), lithium hydroxide monohydrate (39 mg, 0.92 mmol), tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL) were stirred at 20° C. for 12 hours. The reaction mixture was concentrated, acidified with concentrated hydrochloric acid to pH=1, extracted with ethyl acetate (20 mL×3). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give 4-(1-(p-tolyloxy)ethyl)benzoic acid used in next step without further purification (42 mg, 86%). LRMS (M+H)− m/z: calcd 256.11. found 256.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[Br:10]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:10][C:8]1[C:2]([F:1])=[C:3]([OH:9])[C:4](=[CH:6][CH:7]=1)[OH:5]
Reactant: Oc1cccc(F)c1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Br)c(F)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
3-Fluorocatechol (7.2 g) in 50 ml of carbon tetrachloride and 40 ml of chloroform are treated at -10° C. within 10 minutes with a solution of 2.88 ml of bromine in 30 ml of carbon tetrachloride. After stirring at -10° C. for 1 hour the reaction mixture is filtered. The residual solid is washed with a small amount of cold carbon tetrachloride and dried. There are obtained 6.30 g of 4-bromo-3-fluorocatechol as a white powder. This is treated with 6.0 ml of diphenylchloromethane and heated to 130° C. within 1 hour. Subsequently, the product is distilled at 135° C./0.05 Torr and recrystallized from ethanol. There are obtained 6.40 g of 5-bromo-4-fluoro-2,2-diphenyl-1,3-benzodioxol as a white crystalline powder of m.p. 61.5°-63° C.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[CH2:8]([C:15]1([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:20][CH2:19][C:18]([NH:23][CH3:24])([C:21]#N)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)C>[CH2:8]([C:15]1([CH2:25][N:26]([CH3:27])[CH3:28])[CH2:16][CH2:17][C:18]([C:21]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)([NH:23][CH3:24])[CH2:19][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNC1(C#N)CCC(Cc2ccccc2)(CN(C)C)CC1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: CNC1(c2ccccc2)CCC(Cc2ccccc2)(CN(C)C)CC1

Procedure:
Phenyl lithium (33 mL, 60 mmol, 1.8 M solution in dibutyl ether) was mixed in drops with a solution of the title compound from step 1 (5.70 g, 20 mmol) in diethyl ether (60 mL) in argon and at room temperature. During this, the temperature of the reaction solution rose to 35° C. and a solid separated out. The reaction mixture was stirred with reflux for 30 min, then hydrolysed in an ice bath with 20% NH4Cl solution (40 mL) and the organic phase was separated. The aqueous phase was extracted with ether (3×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (20:1→9:1→1:1→1% TEA). The polar diastereomer was obtained in clean form. The non-polar diastereomer was isolated in impure state.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.BrC1C=CC(F)=CC=1C(O)=O.B.O1CCCC1.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10]
Reactant: COCOCc1cc(F)ccc1Br
Agent: B
Agent: O=C(O)c1cc(F)ccc1Br
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene: To a solution of 2-bromo-5-fluorobenzoic acid (10.3 g, 45.3 g) in tetrahydrofuran (50 mL) was added borane-tetrahydrofuran complex (1M in tetrahydrofuran; 92 mL) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature overnight. Water was carefully added, and the mixture was concentrated under reduced pressure to about 50 mL. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-bromo-5-fluorobenzyl alcohol, which was converted into its methoxymethyl ether in a similar manner to Example 11, step (a) to afford 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene (9.64 g, 85% in 2 steps): 1H NMR (300 MHz, CDCl3) δ 3.43 (s, 3H), 4.62 (s, 2H), 4.78 (s, 2H), 6.88 (td, J=8.5, 3.2 Hz, 1H), 7.25 (dd, J=9.6, 3.1 Hz, 1H), 7.48 (dd, J=8.8, 5.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[O:13])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][OH:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:31][CH2:30][CH2:29][C:21]1[N:20]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH:12]=[O:13])[N:8]3[CH3:11])=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: OCCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21
Yield: 67.2 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (500 mg, 1.78 mmol), 2-(1H-benzoimidazol-2-yl)ethanol (335 mg, 2.06 mmol), Pd2dba3 (40 mg, 0.043 mmol), Xphos (85 mg, 0.18 mmol) and cesium carbonate (840 mg, 2.58 mmol) in 1,4-dioxane (10 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 98:2 to 95:5 to 90:10) to afford 2-[2-(2-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde as a yellow solid (487 mg, 67%). 1H NMR (CDCl3, 400 MHz) δ 9.93 (s, 1 H); 8.16-8.12 (m, 1 H); 7.76-7.72 (m, 1 H); 7.35-7.29 (m, 2 H); 4.52 (m, 4 H); 4.20 (t, J=5.3 Hz, 2 H); 4.14 (s, 3 H); 3.91 (m, 5 H) and 3.57 (t, J=5.3 Hz, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][C@@H:15]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.Cl[C:42](Cl)([O:44]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.CCOCC>C1COCC1.C(Cl)Cl.CCOC(C)=O>[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:17]1[CH2:16][C@H:15]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[N:14]([CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=[N:10][CH:11]=2)[C:42]1=[O:44]
Reactant: CS(=O)(=O)CC[C@@H](CNCc1cccc(Cl)c1)NCc1cncn1Cc1ccc(C#N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CS(=O)(=O)CC[C@H]1CN(Cc2cccc(Cl)c2)C(=O)N1Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19.9 %

Procedure:
To a solution of the product from Step G (63 mg, 0.17 mmol) in 2.5 mL of THF at 0° C. was added triethylamine (0.15 mL, 1.0 mmol), followed by triphosgene (31 mg, 0.10 mmol). The reaction was stirred at 0° C. for 1.5 hour, then poured into EtOAc and washed with sat. aq. NaHCO3 and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo. The product was taken up in methanol and injected onto a preparative HPLC column and purified with a mixed gradient of 25%-55% acetonitrile/0.1% TFA; 75%-45% 0.1% aqueous TFA over 50 minutes. After concentration in vacuo, the resultant product was partitioned between dichloromethane and aq. NaHCO3 soln., and the aqueous phase was extracted with CH2Cl2. The organic solution was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to provide the product free base, which was taken up in CH2Cl2 and treated with excess 1M HCl/ether solution. After concentrated in vacuo, the titled product (9.3 mg) was isolated as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:20]3[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: OCc1c(F)cccc1F
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cccc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 28b), the alkylation of the (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 28a)] with 2,6-difluorobenzylalcohol yields the (R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=362 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[S:13][CH2:12][C:11]1([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH3:22].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[S:13][CH2:12][C:11]1([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH3:22])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
(3RS,4RS)-4-(8-hydroxyoctyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (3.25 g, 7.58 mmol) was dissolved in dichloromethane (100 ml), to which were added triethylamine (1.59 ml, 11.37 mmol) and methanesulfonyl chloride (0.88 ml, 11 37 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with methylene chloride. The organic layer was washed with 1M HCl solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The product was purified by column chromatography on silica gel, eluting with 30% ethyl acetate in n-hexane to afford 3.75 g of the title compound as a pale yellow oil. (yield: 97.7%)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([S:15]([NH2:18])(=[O:17])=[O:16])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:5]1([S:15]([NH2:18])(=[O:16])=[O:17])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: NS(=O)(=O)C1c2ccccc2-c2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(S(N)(=O)=O)c2ccccc2-c2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
Under nitrogen, (21) (2.6 g, 9.3 mmoL) was added portionwise to a stirred suspension of sodium hydride (465 mg of a 60% mineral oil dispersion, 1.25 eq) in dry dimethylformamide (60 mL , from CaH2). After 30 minutes, ethyl bromoacetate (1.3 g, 11.6mmoL, 1.25 eq) was added and stirring was continued overnight. The reaction was then diluted with water (200 mL), neutralized, and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (3×200 mL), dried (MgSO4), and concentrated. The crude solid was recrystallized twice from ethyl acetate/hexane to provide 1.7 g(50%) of product (22): mp 189°-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[N:9]=1)[C:5]#[N:6].ClC1C=C(C=C(Cl)N=1)C(N)=[O:22].OC1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[N:9]=1)[C:5]([NH2:6])=[O:22]
Reactant: NC(=O)c1cc(Cl)nc(Cl)c1
Reactant: N#Cc1cc(Cl)nc(N2CCC(O)CC2)c1
Agent: OC1CCNCC1
Product: NC(=O)c1cc(Cl)nc(N2CCC(O)CC2)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 26 starting from 2,6-dichloroisonicotinamide and 4-hydroxypiperidine (both commercially available).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]([C:18]([OH:20])=[O:19])=[C:8]([CH2:9][N:10]([CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH3:11])[C:4]=2[CH:3]=1.[N+](=[CH2:25])=[N-]>C(Cl)Cl.O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]([C:18]([O:20][CH3:25])=[O:19])=[C:8]([CH2:9][N:10]([CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH3:11])[C:4]=2[CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: COC(CN(C)Cc1c(C(=O)O)sc2ccc(Cl)cc12)OC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1sc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Temperature: 0 °C
Yield: 96 %

Procedure:
A suspension of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylic acid (5.0 g, 14.5 mmol) in methylene chloride-tetrahydrofuran was stirred at 0° C. and treated with excess diazomethane in ethyl ether. The mixture was stirred for 2 hours at 0° C., treated with a stream of argon and concentrated to give 5.0 g (96%) of methyl 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[C-]#N.[K+].[CH3:30][N:31](C)C=O>CO>[C:30]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH2:4]1)#[N:31]
Reactant: CN(C)C=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)c(F)c2)C(=O)O1
Yield: 51 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (18.0 mmol) and potassium cyanide (22.0 mmol) in methanol: dimethylformamide mixture (1:5, 20 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 51% yield.
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([NH2:11])=[O:10])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH2:28]([O:27][C:25]([N:5]1[CH2:6][CH2:7][CH2:8][C:3]([C:9](=[O:10])[NH2:11])([CH3:2])[CH2:4]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C(N)=O)CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C(N)=O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 409.7 %

Procedure:
To a solution of 3-Methyl-piperidine-3-carboxylic acid amide hydrochloride (740 mg, 4.1 mmol) in a cosolvent of 1,4-dioxane and water (12 mL, v:v=5:1) was added sodium carbonate (1.6 g, 15 mmol). The mixture was cooled to 0° C., benzyl chloroformate (900 mg, 0.53 mmol) was added, and the mixture was allowed to stir at room temperature for 3 h. LCMS showed starting material was consumed. The volatile components were removed, and the residue was extracted with ethyl acetate, purified by column chromatography (eluting with 10% methanol in dichloromethane) to give 600 mg (53%) of 3-Carbamoyl-3-methyl-piperidine-1-carboxylic acid benzyl ester. LCMS (Method K, ESI): RT=1.18 min, m+Na=298.8; 1H NMR (400 MHz, CDCl3) δ: 7.32-7.23 (m, 5H), 5.07-5.03 (m, 2H), 4.30-4.10 (m, 1H), 4.10-3.90 (m, 1H), 3.10-2.40 (m, 2H), 1.65-1.75 (m, 2H), 1.60-1.30 (m, 2H), 1.25-1.15 (m, 1H), 1.09 (s, 3H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1>O.C(O)(=O)C>[OH:3][N:1]=[C:15]([C:14](=[O:21])[CH2:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH3:5])[CH:7]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CCc1cccc(C)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(C)c1
Reaction time: 1 h

Procedure:
Sodium nitrite (32 g) in water (60 ml) was added dropwise over 1 hour to a stirred solution of the product from example 13 step (i) (99.4 g) in acetic acid (200 ml) at a rate such that the internal temperature did not rise above 30° C. The solution was allowed to stir a further 1 hour before adding water (500 ml). After stirring for a further 24 h the reaction mixture was extracted with diethyl ether (×4). The combined ether extracts were washed with saturated sodium bicarbonate solution, and finally water before collecting the organic layer and drying over magnesium sulphate. The solution was filtered and the solvent evaporated under reduced pressure to leave the subtitle product.
Reaction SMILES: [ClH:1].C1(C2CCN(C[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[C:28]4[CH:31]=[CH:32][CH:33]=[C:26]5[C:27]=4[C:22](=[CH:23][CH:24]=[CH:25]5)[C:21]3=[O:34])CC=2)C=CC=CC=1.BrCCCCC[N:41]1[C:50](=O)[C:49]2[CH:52]=[CH:53][CH:54]=[C:47]3[C:48]=2[C:43](=C[CH:45]=[CH:46]3)[C:42]1=O.BrCCCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[C:47]1([C:48]2[CH2:49][CH2:50][N:41]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:21](=[O:34])[C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:27]=4[C:28](=[CH:31][CH:32]=[CH:33]5)[C:29]3=[O:30])[CH2:42][CH:43]=2)[CH:46]=[CH:45][CH:52]=[CH:53][CH:54]=1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CC=C(c2ccccc2)CC1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCN1CC=C(c2ccccc2)CC1

Procedure:
Following the procedure of part (b) of Example 56 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1). The product is purified by recrystallization from n-butanol; m.p. 207°-210°.