Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1cccc(Cl)c1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4cccc(Cl)c4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 45.8 mg (0.269 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 73.3 mg (55% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:10]#[N:11])([CH3:13])[CH3:12])[CH:5]=[C:6]([F:8])[C:7]=1[C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C#N)c1cc(F)cc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1c(F)cc(C(C)(C)C#N)cc1Br
Temperature: -76 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 2-(3-bromo-5-fluorophenyl)-2-methylpropanenitrile (30 g, 124 mmol, 1.0 equiv.) in 180 mL THF was added lithium diisopropylamide (82.6 ml of 1.8 M, 149 mmol, 1.2 equiv.) dropwise at −75° C. The reaction mixture was stirred at −76° C. for 2 hr. The tert-butylisocyanate (18.4 g, 21.8 ml, 186 mmol, 1.5 equiv.) was added dropwise at −75° C. and stirring was continued for 2 hr. An additional 0.5 equiv. of tert-butylisocyanate was added and the reaction mixture was allowed to warm gradually to room temperature and stirred overnight. The reaction mixture was quenched with 180 mL water and the THF was then removed under reduced pressure at 60° C. IPA was added at 60° C. and the product was crystallized out from 180 mL H2O and 120 mL IPA at 60° C. The mixture was cooled to room temperature slowly overnight. The crystals were collected by filtration, washed with H2O, H2O/IPA (1/1), and heptane, and dried overnight to afford 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (34.7 g, 102 mmol, 82.1% yield) as white crystalline solid with >99% HPLC purity. 1H NMR (300 MHz, DMSO-d6) 8 ppm 1.34 (s, 9 H) 1.70 (s, 6 H) 7.47 (dd, J=10.01, 1.70 Hz, 1 H) 7.60 (s, 1 H) 8.34 (s, 1 H).
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[CH:6]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[CH3:11][C:9]1[CH:10]=[C:5]([C:4](=[O:13])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([CH3:12])[N:8]=1
Reactant: CON(C)C(=O)c1cc(C)nc(C)c1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Cc2ccccc2)cc(C)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
At −78° C., to a solution of N-methoxy-2,6,N-trimethyl-isonicotinamide (1 g) and benzyl bromide (0.73 mL) in THF (30 mL) was added n-BuLi (1.6M in hexane, 6.6 mL) dropwise. The reaction was stirred at −78° C. for 3 hours. A saturated aqueous solution of NH4Cl (200 mL) was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (EtOAc/n-heptane 1:2) yielded the title compound (1.8 g, 99%) as a colorless liquid, MS (ESI+): m/z=226.1 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1.[S:32]([C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=1)(=[O:35])(=[O:34])[NH2:33]>>[S:32]([C:36]1[CH:37]=[C:38]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:31])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:28])([F:30])[F:29])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:39]=[CH:40][CH:41]=1)(=[O:34])(=[O:35])[NH2:33]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.13) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Light yellow solid. MS (ISP) 607.9 [(M−H)−]; mp 241° C.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[N:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:10]=1.CC(O)C.C1COCC1>Cl>[OH:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[N:7][C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(CC(C)(C)C)nc1C(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)c1nc(CC(C)(C)C)ccc1O
Yield: 63.7 %

Procedure:
A solution of 1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone (3.75 g, 15 mmol) in (2:1:1) 5 M HCl: i-PrOH:THF (100 mL) was stirred 16 h at rt. The mixture was concentrated to remove the THF and i-PrOH. The resulting solution consisting of the product in aqueous HCl was quenched by slow addition to a solution of saturated aqueous NaHCO3 (500 mL) containing excess solid NaHCO3 (28 g). The aqueous layer was extracted with CH2Cl2 (3×100 mL), the organic layers combined and washed with saturated aqueous NaCl (100 mL), dried (MgSO4), and concentrated to give the crude product as a brown oil. The product was purified by ISCO (0-10% EtOAc/Hexanes) to give 1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone (1.98 g, 64% yield) as a clear, colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH:5]1[C:13]2[C:8](=[C:9]([C:14]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([O:27]C(C)C)=[C:23]([CH:26]=4)[C:24]#[N:25])[O:16][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.B(Cl)(Cl)Cl>ClCCCl>[OH:27][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[O:16][N:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:8]=3[CH2:7][CH2:6][CH:5]4[NH:4][CH2:3][CH2:2][OH:1])[N:18]=2)=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4NCCO)no2)cc1C#N
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Product: N#Cc1cc(-c2nc(-c3cccc4c3CCC4NCCO)no2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 671.2 %

Procedure:
To 5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (15.0 mg, 0.37 mmol) in DCE (3 mL) was added BCl3 (1.85 mL of 1M DCM solution). The reaction mixture was stirred at room temperature for 18 hrs. The solvent was evaporated, and the residue purified by chromatography (DCM/MeOH) to give 900.0 mg (67%) of 2-hydroxy-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 102 as white solid. LCMS-ESI (m/z) calculated for C20H18N4O3: 362.4; found 363.1 [M+H]+, tR=2.13 min. Enantiomerically pure materials can be obtained in an analogous fashion from (R)- or (S)-5-(3-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([O:15]CC)=O)=[C:5]2[OH:18].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:15])=[C:5]2[OH:18]
Reactant: CCOC(=O)c1cnc2c(C)cc(Cl)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: Cc1cc(Cl)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 190 °C
Reaction time: 3 h

Procedure:
A mixture of 3.0 g of ethyl 6-chloro-4-hydroxy-8-methyl-3-quinolinecarboxylate (Maybridge Chemical Co.) and 7.0 mL of 4-chlorobenzylamine is stirred 3 h at 190° C. The mixture is cooled to 25° C. and is diluted with 35 mL of hexanes. The precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it was recrystallized from 30 mL of glacial acetic acid. It was dried at 20 torr and 100° C. for 20 h. The yield is 1.6 g (40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].Cl.[OH-].[Na+]>COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1N
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(N3CCOCC3)cc2OC)ncc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-(2,5-dichloro-pyrimidin-4-yl-amino)-N-methyl-benzamide (5.05 g, 17.0 mmol) in 90 mL of 2-methoxyethanol are added 2-methoxy-4-morpholinoaniline dihydrochloride (4.56 g, 16.2 mmol) and 17.0 mL of 1N ethanolic solution of hydrogen chloride (17.0 mmol). After the reaction mixture is stirred at 110° C. for 4 hours and cooled to room temperature, the mixture is neutralized with 1N aqueous NaOH solution and extracted with EtOAc (100 mL×3). The organic layer is washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting black solid is washed with EtOH (90 mL), then purified with silica gel column chromatography (CH2Cl2 to CH2Cl2:AcOEt=1:2) to give 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a pale yellow solid.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=2[N:11]=[CH:10]1.[Na]>CO.O>[Br:1][CH2:22][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=2[N:11]=[CH:10]1
Reactant: BrBr
Reactant: CC(=O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCCCC(=O)CBr)n(C)c1=O
Reaction time: 0.5 h
Yield: 40 %

Procedure:
9.7 Grams (0.06 moles) of bromine were added to a solution of 15 g (0.054 moles) of 7-(5-keto-hexyl)-1,3-dimethylxanthine in 100 ml of anhydrous methanol, at 10° C. with stirring. After 30 minutes at the same temperature, stirring was continued for 7 more hours at room temperature. The mixture was then concentrated under reduced pressure till a residual volume of 30 ml, diluted with 30 ml of water, added with 3 drops of 96% sulphuric acid and stirred for 4 hours at room temperature, to hydrolyze any dimethylketal formed, then diluted with 100 ml of water and alkalized with a 10% sodium bicarbonte aqueous solution. The mixture was extracted with 2×80 ml of methylene chloride, the organic phase was washed with water, dried and evaporated under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate, cooled and crystallized at 5°-10° C. 7.5 Grams (40%) of the title compound were obtained, melting at 106°-109° C., which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])=[N:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)=[O:12])=[N:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
(5-Chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)(4-methylsulfonylpiperazin-1-yl)methanone, 1H-indazol-4-yl-4-boronic acid (2.5 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 140° C. for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was washed with methylene chloride and the organic layer was purified by silica gel chromatography followed by reverse phase silica gel chromatography to give the product 141.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2(O)[CH2:10][CH2:9][CH2:8]2)=[CH:5][N:6]=1>FC(F)(F)C(O)=O.[OH-].[OH-].[Pd+2]>[CH:7]1([C:4]2[S:3][C:2]([NH2:1])=[N:6][CH:5]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ncc(C2(O)CCC2)s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2CCC2)s1
Reaction time: 24 h
Yield: 79 %

Procedure:
A solution of 1-(2-amino-thiazol-5-yl)cyclobutanol (Preparation 1; 6.6 g, 39 mmol) in trifluoroacetic acid (150 mL) was treated with 20% palladium hydroxide on carbon (2.3 g). The mixture was evacuated and purged with nitrogen (3 times), then was evacuated and purged with hydrogen gas (50 psi). The mixture was shaken for 24 hours and was evacuated and purged with nitrogen. The mixture was then filtered through Celite which was rinsed with methanol. The organic solvent was removed in vacuo, ethylacetate was added, followed by 29% ammonium hydroxide solution. The aqueous and organic layers were separated and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with brine, were dried (MgSO4), were filtered, and the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography (40:1:1 CHCl3—MeOH—NH4OH) to afford 4.75 g of 5-cyclobutyl-thiazol-2-ylamine, the title compound. 1HNMR (400 MHz, DMSO-d6): 6.66(s,2H), 6.57(s, 2H), 3.43 (m,1H), 2.20 (m,2H), 1.98-1.7 (m,4H).
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12.[CH3:19][S:20]S(C)(=O)=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:19][S:20][C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12
Reactant: Ic1ncn2ccsc12
Reactant: CSS(C)(=O)=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncn2ccsc12
Reaction time: 1 h

Procedure:
A 1 M ethylmagnesium bromide/THF solution (1.4 ml) was added under ice cooling to a solution of 0.31 g of 7-iodoimidazo[5,1-b]thiazole in 3 ml of dry THF in an argon atmosphere. The mixture was stirred at the same temperature for one hr. Methyl methanethiolsulfonate (0.15 ml) was added thereto. The mixture was stirred at room temperature for 12 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution. Ethyl acetate was added thereto. The mixture was washed with a dilute aqueous sodium thiosulfate solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 0.15 g of 7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [OH-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[NH:21][C:22]=2[CH:23]=1>O.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[N:21]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:22]=2[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]c3cc(Br)ccc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CCC3)cc1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
6 N NaOH (10 mL), TsCl (0.48 g, 2.5 mmol) and (Bu4NH)2SO4 (50% solution in water, 0.17 mL) were added to a solution of tert-butyl 8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.76 g, 2.1 mmol) in toluene (17 mL), and the resulting solution was stirred for 18 h. Additional TsCl (55 mg, 0.29 mmol) was added, and the reaction was stirred for 18 h. The solution was partitioned with H2O and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO hexanes/EtOAC, 90:10 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes) provided the title compound (0.54 g, 50%) as a white foam: 1H NMR (500 MHz, DMSO-d6) δ 8.24-8.20 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H) 4.44-4.40 (m, 2H), 3.56 (t, J=5.5 Hz, 2H), 3.20-3.18 (m, 2H), 2.31 (s, 3H), 1.86-1.84 (m, 2H), 1.29-1.03 (m, 9H).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:23][C@@H:22]([CH2:24][C:25]([O:27]CC)=[O:26])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[CH2:19][C:18]=2[CH:34]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:23][C@@H:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[CH2:19][C:18]=2[CH:34]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCc3ccc4c(n3)NCCC4)cc2Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1Cc2ccc(OCCc3ccc4c(n3)NCCC4)cc2Cc2ccccc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
To a solution of ethyl (S)-10,11-dihydro-3-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (131 mg, 0.29 mmole) in THF/H2O (2 mL) was added 1.0 N LiOH (0.43 mL, 0.43 mmole), and the mixture was heated to 50° C. After 18 hr, the mixture was cooled to RT and washed with Et2O (2×2 mL). The aqueous layer was acidified to pH 6 using 10% HCl. The resulting milky solution was passed through a C-18 bond-elute column (gradient elution: H2O, then 20% CH3CN/H2O, then CHCl3 as eluent). Fractions containing the product were concentrated under reduced pressure to give the title compound (30 mg, 24%) as a white powder: MS (ES) m/e 429 (M+H)+. Anal. Calcd for C27H28N2O3.0.95 HCl: C, 70.02; H, 6.30; N, 6.05. Found: C, 70.01; H, 6.33; N, 5.71.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6]
Reactant: CN(C)C=Nc1c(C(=O)CN=[N+]=[N-])ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Yield: 91.6 %

Procedure:
The compound (40) (35 mg) obtained in item (7) above was dissolved in methanol (3.5 ml) and the resulting solution was subjected to catalytical reduction by blowing hydrogen therein in the presence of palladium black as catalyst at room temperature for 30 minutes. The reaction solution was filtered and the filtrate was concentrated. The resulting solid was washed with ethyl acetate to yield the titled compound (41) (29.7 mg) as an insoluble solid. Yield: 92%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([N:8]([CH3:14])[S:9]([CH3:12])(=[O:10])=[O:11])=[N:6][CH:7]=1
Reactant: Cc1cc(NS(C)(=O)=O)ncc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(N(C)S(C)(=O)=O)ncc1Br

Procedure:
The product from step (i) (2.23 g), potassium carbonate (2.33 g) and methyl iodide (0.7 ml) were stirred in DMF (20 ml) for 20 h. The reaction was quenched with water, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 30% EtOAc/isohexane. Yield 1.5 g. Carried forward to step (ii) without characterisation.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20](O)=[C:21]([C:23](=[O:25])[CH3:24])[CH:22]=1>N1C=CC=CC=1.C(OCC)C>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:20]1[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=1[C:23](=[O:25])[CH3:24])(=[O:8])=[O:9]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)c1cc(F)ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 101.4 %

Procedure:
Trifluoromethanesulfonic anhydride (8.6 mL, 51 mmol) was added dropwise at 0° C. to a stirring solution of 5′-fluoro-2′-hydroxy-acetophenone (6.4 g, 41 mmol) in pyridine (62 mL). The reaction was stirred overnight from 0° C. to ambient temperature. The reaction solution was diluted with diethyl ether (500 mL). The organic layer was washed with 1 N aqueous hydrochloric acid (1×300 mL), followed by a saturated, aqueous sodium chloride solution (2×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a maroon-colored liquid (11.9 g, 100% ). The product was further purified by Kugel-Rohr distillation to afford a yellow oil that solidified upon standing.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N:20]1([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][O:30][C:29]4=[O:33])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: COc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(CCN3CCOC3=O)CC1)C2

Procedure:
15.4 g. of 10-chloro-8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin are treated with 41 g. of 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone and stirred at 120°-130° C. (internal temperature) for 10 minutes. The cooled mixture is treated with 2N sodium hydroxide and extracted with chloroform. The chloroform solution is washed to neutrality with water and shaken out with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and the base extracted with chloroform. The organic solution is washed with water, dried over magnesium sulfate and concentrated. The residue is recrystallized from acetone, whereby there is obtained 3-{2-[4-(8-fluoro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone of melting point 177°-179° C. The corresponding maleate melts at 212°-214° C.