Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[O:8]1[CH2:13][CH2:12][O:11][C:10]2C(C(O)=O)=C[CH:16]=[CH:17][C:9]1=2.C(Cl)(=O)OCC.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[O:8]1[CH2:13][CH2:12][O:11][C:10]2[C:6]([NH2:3])=[CH:7][CH:16]=[CH:17][C:9]1=2
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc2c1OCCO2
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cccc2c1OCCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Triethylamine in acetone was added dropwise to the solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (360 mg, 2 mmol) in water and acetone at 0° C. To the mixture was added ethyl carbonochloridate in acetone slowly. The mixture was stirred for 4 h then a solution of NaN3 (196 mg, 3.02 mmol) in water was added dropwise. The reaction mixture was stirred for 1 h then it was poured into ice water and extracted with Et2O. The combined organic extracts were washed with brine, dried with MgSO4, and concentrated in vacuo. The residue was dissolved in anhydrous toluene and the mixture was heated on a steam bath until nitrogen evolution had ceased. The toluene was then removed in vacuo and 20% aq HCl (4 mL) was added and the solution was heated to reflux and stirred overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in water, made strongly alkaline by the addition of 40% aq NaOH, then extracted with Et2O. The combined organic extracts were washed with brine, dried by MgSO4, and purified by flash chromatography on silica gel column (PE:EtOAc=5:1) to give 2,3-dihydrobenzo[b][1,4]dioxin-5-amine (intermediate 60) (270 mg, 70%). HPLC: 99%, RT 1.214 min. MS (ESI) m/z 152.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:4]=1.Cl.Cl[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]Cl.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:5]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:4]=1
Reactant: ClCCNCCCl
Reactant: COc1ccc(N)c(C2CC(C)(C)CC(C)(C)C2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 220 °C
Reaction time: 2 h

Procedure:
A mixture of the crude product of 4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine produced in Example (85b), bis(2-chloroethyl)amine hydrochloride (770 mg, 4.33 mmol) and 1,2-dichlorobenzene (10 ml) was stirred for 2 hours at an external temperature of 220° C. During the reaction, the excess hydrogen chloride gas in the reactor was removed several times with nitrogen gas. Bis(2-chloroethyl)amine hydrochloride (180 mg, 1.01 mmol) was then added and the mixture was stirred for 1 hour under the same conditions. The reaction mixture was cooled to room temperature, saturated aqueous solution of sodium hydrogencarbonate was added and extraction was performed with chloroform. The aqueous layer was again extracted with chloroform, and the organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 660 mg of the title compound as a brown solid.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH2:13])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>[N+](C1C=CC=CC=1)([O-])=O.C(#N)C.O>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)n1c(N)cc(=O)n1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CC#N
Product: C=C(C)C(=O)Nc1cc(=O)n(-c2ccccc2)n1C(=O)OCC

Procedure:
123.5 g (0.5 mole) of 1-phenyl-2-ethoxycarbonyl-3-amino-3-pyrazolin-5-one (compound 2) are dissolved at room temperature in a solution of 133.5 g (1 mole) of anhydrous aluminium chloride and 15 ml of nitrobenzene in 500 ml of acetonitrile. The resulting solution is mixed with 57.5 g (0.55 mole) of methacryloyl chloride and is then refluxed for 3 h. The reaction mixture is poured out in 1 l of water and the precipitate formed is separated. The product is recrystallized from benzene/hexane (1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][C:24]=2[CH3:32])[CH:19]=[N:20][C:21]=1[Cl:22]>N1C=CC=CC=1>[Cl:22][C:21]1[N:20]=[CH:19][C:18]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][C:24]=2[CH3:32])=[CH:17][C:16]=1[NH:15][S:11]([C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3sc(NC(C)=O)nc3C)cnc2Cl)c(OC)c1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2,4-Dimethoxyphenylsulfonyl chloride (J. Med. Chem., 1977, 20, 1235; 376 mg) was added to a stirred solution of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (150 mg) in pyridine (1.5 mL) and the resultant solution was heated at 50° C. for 16 hours. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by preparative HPLC on Kromasil C18 reversed-phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent at a flow rate of about 10 mL/minute. The material so obtained was triturated under diethyl ether to give the title compound as a white solid (70 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.29 (s, 3H), 3.76 (s, 3H), 3.83 (s, 3H), 6.60 (m, 1H), 6.69 (d, 1H), 9.64 (d, 1H), 6.75 (d, 1H), 8.25 (br s, 1H), 9.80 (s, 1H); Mass Spectrum: M+H+ 483.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([N:6]1[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of (R)-2-methylpiperazine (10 g, 100 mmol) in ethanol at room temperature was added K2CO3 (27.6 g, 200 mmol). The reaction mixture was cooled to 0° C., benzyl bromide (15.3 g, 89.5 mmol) was added and the reaction mixture was heated to 60° C. and stirred for 8 h. The reaction mixture was allowed to cool to room temperature, filtered through a filtration funnel and the filtrate was concentrated under reduced pressure to remove ethanol. The residue was washed with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 5% methanol in chloroform to afford pure 12.0 g of (R)-1-benzyl-3-methylpiperazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[C:11]([N+:18]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:18])=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1cc(C2=CCN(C)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1cc(C2CCN(C)CC2)ncc1N
Temperature: 80 °C
Yield: 105.7 %

Procedure:
In a microwave tube, 400 mg of 1′-methyl-5-nitro-4-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine are introduced into 30 ml of methanol. 546 mg of ammonium formate and 333 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to give 380 mg of 6-(1-methylpiperidin-4-yl)-4-(propan-2-yloxy)pyridin-3-amine in the form of a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:6](=[CH:12][C:13]([OH:19])=[C:14]([N+:16]([O-])=O)[CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]>C(O)C.[Pd]>[NH2:16][C:14]1[CH:15]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:6](=[CH:12][C:13]=1[OH:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(O)c([N+](=O)[O-])cc1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(O)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diethyl-4-hydroxy-5-nitrophthalate (16.0 g, 56.7 mmol) in ethanol is treated with 10% palladium on carbon (1.6 g) and shaken overnight at room temperature on a Parr hydrogenator. After evacuation of hydrogen, the reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to afford the title product as a yellow oil, 14.3 g (100%) identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[C:4]([CH3:10])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12]([S-:14])#[N:13].[K+].C(Cl)(=O)C1C=CC=CC=1.[OH-].[K+]>C(O)C.O.CC(C)=O>[CH3:1][N:2]([CH3:11])[C:3]1[C:4]([CH3:10])=[C:5]([NH:6][C:12]([NH2:13])=[S:14])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(N)cccc1N(C)C
Reactant: N#C[S-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: Cc1c(NC(N)=S)cccc1N(C)C
Temperature: 25 °C
Yield: 91.3 %

Procedure:
57 g of 3-dimethylamino-2-methyl-aniline, 1.15 litres of acetone, 36.6 g of KSCN and 43.8 ml of benzoylchloride are refluxed together for 3 hours. After cooling to ambient temperature the reaction mixture is poured onto 2.4 kg of crushed ice. The precipitate obtained is heated to 60° C. for 2 hours together with 85 g of KOH, 85 ml of water and 255 ml of ethanol. After the addition of 850 ml of water the ethanol is distilled off under reduced pressure. After the resulting precipitate has been worked up, 72 g of N-(3-dimethylamino-2-methylphenyl)-thiourea are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:22])=[O:29])=[CH:17][CH:16]=2)[O:3]1
Reactant: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1
Yield: 62 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylthio)phenyl}-3(2H)-furanone (2.0 g, Example 166) in 50 ml dichloromethane, was added 1.5 g of m-chloroperoxybenzoic acid at 0° C. The reaction solution was stirred at the same temperature for one and half hours, after which 30 ml 5% aqueous sodium bicarbonate was added and the solution was stirred for another 10 minutes. Then the reaction mixture was concentrated in vacuo, and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=1:1) to give 1.3 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. mp: 143-144° C. NMR: δ1.58 (s, 6H), 2.76(s, 3H), 7.26-7.08 (m, 3H), 7.30-7.38 (m, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Br[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(O)c1ccccc1Br
Reactant: Cc1cc(N)cnc1Br
Product: Cc1cc(Nc2ccccc2C(=O)O)cnc1Br
Yield: 14 %

Procedure:
Obtained (0.17 g, yield 14%) following the procedure described in Intermediate 13 starting with 6-bromo-5-methylpyridin-3-amine (2.70 mmol, 0.5 g) and 2-bromobenzoic acid (4.03 mmol, 0.81 g).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc(F)c1
Yield: 37 %

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (3-fluoro-phenyl)-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 37% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[N:11][N:10](C2CCCCO2)[C:9](=[O:19])[C:8]=1[Cl:20])(=[O:3])[CH3:2].Cl.O>CO>[C:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:19])[C:8]=1[Cl:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1Oc1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1Cl
Yield: 79.1 %

Procedure:
A solution of 5-(2-acetyl-phenoxy)-4-chloro-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (15.0 g, 0.043 mol), concentrated hydrochloric acid (30 mL), water (45 mL) and methanol (130 mL) was heated at reflux for 2 h. At this time, the reaction was concentrated in vacuo. The residue was charged with water (200 mL) and then basified with a saturated aqueous sodium bicarbonate solution. The resulting material was collected by filtration, rinsed with water and petroleum ether, and dried to afford 5-(2-acetyl-phenoxy)-4-chloro-2H-pyridazin-3-one (9.0 g, 79%); ESI-MS 265 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5](O)=[O:6].C1[CH2:16][N:15]([P+](Br)(N2CCCC2)N2CCCC2)[CH2:14]C1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNC>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([N:15]([CH3:16])[CH3:14])=[O:6]
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1cc(O)cc(Br)c1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
To a solution of 3-bromo-5-hydroxy-benzoic acid (2.0 g, 9.25 mmol), PyBroP (7.7 g, 18.5 mmol) and diisopropylethylamine (6.4 mL, 37 mmol) in DMF (50 mL) was added dimethylamine hydrochloride (1.51 g, 18.5 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) using ethyl acetate as eluting solvent to give the title compound (1.5 g, 67%) as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:25]2[C:16]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])([C:17]3[C:22]([O:23][CH2:24]2)=[C:21]([F:26])[CH:20]=[CH:19][C:18]=3[F:27])[CH2:15][CH2:14][CH2:13]1)C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:16]23[C:17]4[C:22](=[C:21]([F:26])[CH:20]=[CH:19][C:18]=4[F:27])[O:23][CH2:24][CH:25]2[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:13][CH2:14][CH2:15]3)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCCN(CCCOCc3ccccc3)C1COc1c(F)ccc(F)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCCN(CCCO)C1COc1c(F)ccc(F)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(3-Benzyloxy-propyl)-4a-(4-chloro-benzenesulfonyl)-5,8-difluoro-2,3,4,4a,10,10a-hexahydro-1H-9-oxa-1-aza-phenanthrene (399.1 mg, 0.728 mmol) was dissolved in 20 ml of ethyl acetate. Palladium hydroxide (20% on carbon, 105 mg) was added and the system was purged with hydrogen gas. The reaction was stirred at room temperature for 1.5 h. More palladium hydroxide on carbon was added (203 mg) The reaction was stirred at room temperature for 3.5 h. Palladium hydroxide (307 mg) was added again and stirred for 1 h. The reaction was filter through a celite cake and concentrated. The product was purified by column using Hex./EtOAc as the eluent (gradient from 100/0 to 50/50 in 35 minutes, then to 0/100). This resulted in three products the desired product and two dechloronation products.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cccnc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of t-butyl bromoacetate (2 g, 10 mmol), 3-hydroxypyridine (1.5 g, 15 mmol), and K2CO3 (2.9 g, 21 mmol) in THF (20 mL) is stirred at 60° C. After 0.5 h, the reaction mixture is cooled down at room temperature and diluted with H2O, then extracted with EtOAc. The organic phase is washed with H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give the title compound MS: 210 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 1.85 min.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20](=[O:22])[CH3:21])(=O)C.P(=O)(O)(O)O>C(O)(=O)C>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:1]2[CH2:6][CH2:5][CH:21]([C:20]([OH:19])=[O:22])[CH2:3][CH:2]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: O=C(O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
A mixture of 100 g (0.52 mol) of 2-phenylindole, 80.8 g (0.57 mol) of 4-cyclohexanonecarboxylic acid, 518 mL of acetic acid, 103.6 mL of acetic anhydride and 25.9 mL of 85% phosphoric acid was stirred at room temperature for 3 days and then chilled in an ice bath to 20° C. The precipitate that resulted was collected, washed with water, pressed dry, taken up in ether, and this solution was washed with water three times and with brine one time, dried over magnesium sulfate, charcoaled, evaporated at 200 mL, and let stand for 2 days to give a precipitate. This precipitate was collected and combined with a second crop to give 72.7 g (44%) of 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylic acid, m.p. 178°-179° C. A small portion was recrystallized from acetonitrile, m.p. 180°-183° C.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([N:10]2[C@@H:14]([CH3:15])[CH2:13][CH2:12][C@H:11]2[CH3:16])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:32]2[C@@H:31]3[CH2:33][C@@H:30]3[CH2:29][C:28]=2[C:27]([C:34](O)=[O:35])=[N:26]1>>[CH3:16][C@H:11]1[CH2:12][CH2:13][C@@H:14]([CH3:15])[N:10]1[C:8]([C:3]1([NH:2][C:34]([C:27]2[C:28]3[CH2:29][C@H:30]4[CH2:33][C@H:31]4[C:32]=3[N:25]([C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[N:26]=2)=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:9]
Reactant: C[C@@H]1CC[C@H](C)N1C(=O)C1(N)CCCC1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: Cl
Product: C[C@@H]1CC[C@H](C)N1C(=O)C1(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)CCCC1

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1-aminocyclopentyl)((2R,5S)-2,5-dimethylpyrrolidin-1-yl)methanone hydrochloride and (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid. LCMS m/z=469.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 0.39-0.43 (m, 1H), 0.89-1.27 (m, 8H), 1.57-1.69 (m, 7H), 1.96-2.11 (m, 1H), 2.13-2.18 (m, 3H), 2.23-2.30 (m, 1H), 2.52-2.70 (m, 1H), 2.80 (d, J=17.2 Hz, 1H), 2.91 (dd, J=16.6, 6.6 Hz, 1H), 3.93-4.39 (m, 2H), 7.13-7.25 (m, 3H), 7.72 (td, J=8.8, 5.9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Br
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: OCc1cccnc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a solution of 2-bromonicotinic acid (4.0 g, 20 mmol) and triethylamine (3.34 mL, 24 mmol, 1.2 eq.) in THF (100 mL) was added i-butyl chloroformate (3.12 mL, 24 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (1.52 g, 40 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred for 30 min, added water (3 mL), continued to stir for 2 h, and concentrated to dryness. The crude was purified on silica gel using a mixture of ethylacetate and hexanes as eluent to give (2-bromopyridin-3-yl)methanol (3.4 g, 90%) as a white solid. LRMS (M+H+) m/z 188.0.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:20][CH2:21][F:22])[CH2:15][CH2:14]2)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:20][CH2:21][F:22])[CH2:15][CH2:14]2
Reactant: O=C1c2c(cccc2N(Cc2ccccc2)Cc2ccccc2)CCN1CCF
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc2c1C(=O)N(CCF)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
830 mg (2.136 mmol) 8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 50 ml of methanol and combined with 80 mg palladium hydroxide. The reaction mixture is stirred for 48 h at ambient temperature and 4.5 bar H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][S:11]1(=[O:20])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:20]=[S:11]1(=[O:19])[N:12]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH2:44]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]1[C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccc(F)c(F)c3F)S2(=O)=O)CC1
Yield: 61.3 %

Procedure:
In an analogous manner as general VI, a solution of 1-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.21 g, 0.7 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.27 g, 1.0 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.38 g, 1.4 mmol) were added followed by diisopropylazodicarboxylate (0.2 mL, 1.0 mmol to provide tert-butyl 4-{2-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.22 g, 625) as white solid: