Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:33])(=[O:32])[N:17]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]([CH3:27])[CH3:26])=[CH:20][N:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.ClCCl>FC(F)(F)C(O)=O>[F:1][C@H:2]1[C@@H:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:17]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]([CH3:26])[CH3:27])=[CH:20][N:19]=3)(=[O:32])=[O:33])=[CH:14][CH:15]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OC[C@H]2CCNC[C@H]2F)cc1
Yield: 51.2 %

Procedure:
tert-Butyl cis-3-fluoro-4-((4-(N-isobutyl-N-(5-isopropyl-3-methylpyridin-2-yl)sulfamoyl)phenoxy)methyl)piperidine-1-carboxylate (53 mg, 0.09 mmol) was dissolved in trifluoroacetic acid (TFA) (1 mL) and dichloromethane (DCM) (1 mL) and stirred under nitrogen, at room temperature for 30 minutes. The reaction was concentrated under a stream of nitrogen, then purified by mass directed autoprep (ammonium carbonate modifier) to give the title compound (22 mg). LCMS (2 min, formic) Rt 1.06 min, m/z (ES+) 478 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([CH:21]=O)[CH:15]=[CH:14]2.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([N:8]=[CH:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2cc(C=O)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc2cc(C=NCc3ccccc3)ccc2c1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of benzylamine (0.57 mL, 5.37 mmol) in 5 mL of methylene chloride was added dropwise under nitrogen over 5 minutes to a mixture of 6-methoxy-naphthalene-2-carbaldehyde (1.0 g, 5.37 mmol) and anhydrous MgSO4 (3 g) in 20 mL of methylene chloride. The reaction stirred under nitrogen for 24 h (overnight). The MgSO4 was removed by filtration and the solvent removed under reduced pressure to give benzyl-(6-methoxy-naphthalen-2-ylmethylene)-amine (1.455 g, 98%) as an off-white solid, mp 115-117° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Oc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 2,4-dichloro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (150 mg, 0.4 mmol, 1.0 eq) in DMF (50 mL), was added K2CO3 (220 mg, 0.6 mmol, 1.5 eq) and the solution was stirred at room temperature for 30 min. BrCH2CO2Et (100 mg, 1.6 mmol, 4.0 eq) was added dropwise and the reaction was stirred overnight. The reaction was quenched by addition of water (200 mL) and extracted with EtOAc. The combined organic extracts were dried (Mg2SO4), filtered and evaporated under reduced pressure and the residue obtained purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound (130 mg, 70%).
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].[CH3:16][O:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.CO>CN(C)C=O>[CH3:16][O:17][C:18]1[O:22][C:21](/[CH:23]=[CH:5]/[C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)=[O:6])=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(C(N)=O)cc1
Reactant: COc1ccc(C=O)o1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2ccc(C(N)=O)cc2)o1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (in portions) was added, over a time interval of about three minutes, to 4-acetyl-benzamide (1.38 g, 8.5 mmol) and 5-methoxy-furan-2-carbaldehyde (1.31 g, 10.6 mmol) in a 1:1 mixture of methanol and dimethylformamide (16 mL). The resulting solution was placed under N2 and stirred overnight at 45° C. The reaction mixture was then evaporated to dryness under vacuum, followed by the addition of water and brine (100 mL) to the resulting residue. The aqueous solution was extracted with ethyl acetate (125 mL×3) and the combined organic layers were washed with brine (100 mL) and dried over MgSO4. The crude reaction mixture of 4-[(E)-3-(5-methoxy-furan-2-yl)-acryloyl]-benzamide and unreacted 4-acetyl acetamide is used without purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([CH3:2])=[C:4]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:21][CH:22]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(S(C)(=O)=O)cc2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and 1-bromomethyl-4-methanesulfonyl-benzene are processed according to the method described in Example 11 to give 1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 2.33 (s, 3H), 3.08 (s, 3H), 5.46 (s, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.55 (dd, J=7.8, 4.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.85 (dt, J=7.8, 1.9 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.59 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 377.1318 [(M+H)+ Calcd for C22H21N2O2S: 377.1324].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[C:9](=[O:18])[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.F[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:31]#[N:32].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:31]([C:30]1[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:28]([NH:1][C:2]2[N:7]=[C:6]3[N:8]([C@@H:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH3:20])[C:9](=[O:18])[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:5]3=[CH:4][CH:3]=2)[CH:29]=1)#[N:32]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Nc3cc(C#N)ccc3[N+](=O)[O-])nc21
Temperature: -15 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
A solution of (R)-tert-butyl 5-amino-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (94 mg) and 3-fluoro-4-nitrobenzonitrile (225 mg) in DMF (6 mL) was cooled to −25° C. and treated with NaH (60% w/w in mineral oil, 75 mg) and slowly allowed to warm to −15° C. The mixture was stirred for four hours between −20° C. and −15° C., then diluted with EtOAc and quenched with saturated ammonium chloride solution. The organic phase was washed three times with brine, separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (2% MeOH in methylene chloride) provided 100 mg (R)-tert-Butyl 5-(5-cyano-2-nitrophenylamino)-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (70).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH2:11][CH3:12])[C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:24][CH:25]1[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1>C1(C)C=CC=CC=1>[C:25]1([CH2:24][N:1]2[CH2:6][CH2:5][CH:4]([N:7]([CH2:11][CH3:12])[C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=1
Reactant: CCN(C(C)=O)C1CCNCC1
Reactant: CC1Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCN(C(C)=O)C1CCN(CC2=Cc3ccccc32)CC1

Procedure:
3.3 g of N-piperid-4-yl-N-ethylacetamide and 2.8 g of 1-methylbenzocyclobutene tosylate (prepared in accordance with the process described in J.A.C.S., (1975), 154, p. 347) are refluxed under nitrogen for 20 hours in 16 ml of toluene. After cooling, the reaction mixture is evaporated to dryness and taken up in diethyl ether. After extraction with N hydrochloric acid, the extract is rendered basic in the presence of diethyl ether and the organic phase is washed with water, dried over magnesium sulphate and evaporated in vacuo to yield N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylacetamide. The corresponding hydrochloride is obtained in ethyl acetate in the presence of ethereal hydrogen chloride.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:8]=[C:9]([Cl:14])[C:10]=1[CH:11]([OH:13])[CH3:12].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CCOCC>[C:11]([C:10]1[C:9]([Cl:14])=[CH:8][C:7]([C:15]([F:18])([F:16])[F:17])=[CH:6][C:5]=1[Cl:4])(=[O:13])[CH3:12]
Reactant: CC(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 80.2 %

Procedure:
An anhydrous methylene chloride solution (50 ml) of 23.5 g of 3,5-dichloro-4-(1-hydroxyethyl)benzotrifluoride (9) was added at a time to 100 ml of an anhydrous methylene chloride suspension of 30.0 g of pyridinium chlorochromate and 20 g of Celite at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with 100 ml of ether and thereafter applied to a column packed with 100 g of silica gel. Ether was used for elution, and the eluent was concentrated under reduced pressure to obtain 18.7 g of the desired compound in the form of a yellow oil (crude yield 72.8%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[CH:5].[Li]CCCC.[CH2:11]([N:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](N(OC)C)=[O:26])[CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:31]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:19]1[CH2:20][CH2:21][C@H:22]([C:25](=[O:26])[C:5]#[C:4][CH2:3][O:2][CH3:1])[CH2:23][CH2:24]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C#CCOC
Reactant: CON(C)C(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC#CC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 3-methoxyprop-1-yne (0.207 ml, 2.456 mmol) in THF (2 mL) was treated with BuLi (1.535 ml, 2.456 mmol) dropwise at −78° C. After stirring for 15 min, 13D (300 mg, 0.819 mmol) in THF (2 mL) was added and reaction mixture was warmed to room temperature over 30 min. The reaction was quenched with aq. HOAc and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was purified by Isco silica column (12 g), eluted with ethyl acetate:hexane, 0-70%. Concentration of the appropriate fractions provided 13E (300 mg, 98% yield). This material was taken without characterization to the next step.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2OCCN1Cc1ccccc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To a solution of N-benzyl-4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (14.5 g, 41.2 mmol) in N,N-dimethylformamide (200 ml) was added under ice-cooling sodium hydride (60%, 2.14 g, 53.5 mmol), and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (10.1 g, 73.7%) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:37])/[CH:12]=[CH:13]/[C:14]1[CH:15]=[C:16]2[C:33](=[N:34][CH:35]=1)[NH:32][C:31](=[O:36])[C:18]1([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[CH2:17]2)[CH3:9]>ClCCl>[O:36]=[C:31]1[C:18]2([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH2:17][C:16]2[C:33](=[N:34][CH:35]=[C:14](/[CH:13]=[CH:12]/[C:11]([O:10][CH2:8][CH3:9])=[O:37])[CH:15]=2)[NH:32]1
Reactant: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a suspension of (E)-tert-butyl 6-(3-ethoxy-3-oxoprop-1-enyl)-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (1.52 g, 3.66 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was partitioned between an aqueous solution of sodium hydroxide (1N, 60 mL) and dichloromethane (40 mL). The aqueous layer was separated and extracted with dichloromethane (2×70 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The title product was obtained as a pale yellow solid (904 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[F:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH:16]2[CH2:19][NH:18][CH2:17]2)=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:19][CH:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:21][CH:20]=3)[CH2:17]2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Fc1ccnc(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CN(c3ccnc(Cl)c3)C2)cc1
Temperature: 84 °C
Yield: 90.3 %

Procedure:
To 2-chloro-4-fluoropyridine (160.0 mg, 1.216 mmol) and 3-(4-fluoro-phenoxy)-azetidine hydrochloride (248 mg, 1.216 mmol) in 2-propanol (3.0 mL) in a disposable sealed tube at RT was added N-ethyl-N-isopropylpropan-2-amine (0.530 mL, 3.04 mmol). The resulting reaction mixture was heated at 84° C. for 18 h, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 60% EtOAc-hexanes) giving 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (306.1 mg).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][C:26]1[S:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[CH3:25][C:26]1[S:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:33])=[O:32]
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCN(C(=O)OC(C)(C)C)C4C)c(C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,5-dimethyl-3-thienyl sulfonyl chloride (24 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,5-dimethyl-3-thienyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (4 mg). MS m/z 377 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:25][CH2:24][CH2:23][CH2:22][C:17]=3[C:18]=2[C:19]([OH:21])=[O:20])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:11]3[O:20][C:19](=[O:21])[C:18]4[C:17]5[CH2:22][CH2:23][CH2:24][CH2:25][C:16]=5[S:15][C:14]=4[N:13]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1sc2c(c1C(=O)O)CCCC2)c1cccc(CN2CCOCC2)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=c1oc(-c2cccc(CN3CCOCC3)c2)nc2sc3c(c12)CCCC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A mixture of 22.2 g of 2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid and 230 mL of toluene was heated at 60° C., and 20 mL of thionyl chloride was added thereto, followed by stirring for 1 hour at 60° C. The insoluble material was collected by filtration and washed with toluene. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the material collected by filtration, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was washed with ethanol, thereby obtaining 18.9 g of 2-[3-(morpholin-4-ylmethyl)phenyl]-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13](Cl)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)CCc1ccc(Cl)cc1
Yield: 100 %

Procedure:
To a stirred solution of 3-(4-chlorophenyl)propanoic acid (commercially available from Maybridge) (14.5 g, 77.1 mmol) in methanol (400 ml) was added acetyl chloride (50 ml) and the reaction mixture was refluxed for 20 h. After this time the reaction mixture was left to cool before being concentrated under reduced pressure. The residue was then dissolved in DCM (200 ml) and washed with 1M sodium hydroxide solution (100 ml). The organic layer was dried with magnesium sulphate and concentrated in vacuo to give the title product as a brown oil (15.7 g, 77 mmol, 100%); 1HNMR (400 MHz, CDCl3) δ: 2.55 (t, 2H), 2.9 (t, 2H), 3.6 (s, 3H), 7.1 (d, 2H), 7.2 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[S:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)c1ccc(Cl)s1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Clc1ccc(-c2cc(Cl)c3c(n2)CCC3)s1
Yield: 14.3 %

Procedure:
Following general procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with (5-chlorothiophen-2-yl)boronic acid (0.142 g, 0.88 mmol) to afford the title compound (0.031 g, 14%) as a white solid. MW=270.18. 1H NMR (CDCl3, 500 MHz) δ 7.32 (s, 1H), 7.27 (d, J=4.0 Hz, 1H), 6.89 (d, J=4.0 Hz, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.16 (quin, J=7.5 Hz, 2H); APCI MS m/z 270 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:10]=1)[NH:7][N:6]=[CH:5]2>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c2[nH]ncc2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 4-(((5-methyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (12 mg, 0.028 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 4 mL) and stirred at room temperature for 45 min. The reaction was concentrated, and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol to give 9.4 mg (quant.) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 9.43 (bs, 1H), 7.85 (s, 1H), 7.47 (m, 2H), 7.39 (m, 4H), 7.25 (s, 1H), 6.89 (s, 1H), 4.65 (s, 2H), 3.56 (s, 2H), 2.91 (m, 2H), 2.77 (m, 2H), 2.38 (s, 3H), 2.21 (m, 2H), 1.99 (bs, 1H), 1.86 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 144.2, 137.3, 133.8, 129.9, 128.9, 127.1, 126.8, 126.0, 124.1, 120.5, 119.1, 80.6, 72.4, 42.7, 41.7, 33.9, 21.3. Mass spec.: 336.13 (MH)+. Accurate mass spec.: m/z 336.2066 [MH]+, Δ=2.9 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.O>C(O)(=O)C>[Cl:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([N:1]2[C:14](=[O:15])[C:13]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]3[C:11]2=[O:16])=[CH:7][C:6]=1[OH:8]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)c(Cl)cc1F
Yield: 92.9 %

Procedure:
5-Amino-2-chloro-4-fluorophenol (3.0 g, 18.6 mmol) and phthalic anhydride (3.3 g, 22.3 mmol) were dissolved in glacial acetic acid (60 ml) and the solution refluxed for 2 hr. Water was added and the resultant precipitate was separated by filtration. The residue was washed with water and dried to afford the title compound (5.04 g); 1H NMR (CDCl3+CD3OD, 300 MHz) 3.68 (1H, s), 6.93 (1H, d, J=6.6 Hz), 7.27 (1H, d, J=9.1 Hz), 7.84 (2H, dd, J=3.0, 5.5 Hz), dd, J=3.0, 5.5 Hz) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(CC)CC>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:9]([C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:10])[CH2:28][CH2:27]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 18.9 mg (0.07 mmol) 2-Morpholin-4-yl-5-nitro-benzoyl chloride, 16.5 mg (0.084 mmol) 1-(2-Chloro-phenyl)-piperazine and 34 ul (0.245 mmol) NEt3 in 2 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 2 ml CH3CN/MeOH/HCOOH 2/2/1 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 23.2 mg (77%) of the title compound. MS (m/e): 431.2 (MH+, 100%)