Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34].O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-:34])=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of tert-butyl 2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (13.78 g 35.8 mmol) in 175 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 70%, 10.28 g, 41.7 mmol). After stirring for 3 h, the reaction mixture was treated with water (100 mL) and CHCl3 (50 mL) and the layers were separated. The organic portion was washed with 1% Na2CO3 solution (2×), water and brine then dried over Na2SO4 and concentrated to give 14.35 g tert-butyl 2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a sticky tan solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[N:21]=[CH:20]4)[CH3:16])=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])C.Cl>>[CH3:26][N:22]1[C:23]2[C:19](=[CH:18][C:17]([CH:15]([C:12]3[N:10]4[N:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)[CH3:16])=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Agent: Cl
Product: CC(=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 84.8 %

Procedure:
The title compound (325.0 mg, 75%, 88% pure) was synthesized from 6-(1-ethoxy-vinyl)-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (415.0 mg, 1.20 mmol) and HCl (1.20 mL, 1.20 mmol) using the same procedure as described in the synthesis of compound 69.4. LCMS (method A): [MH]+=320, tR=5.21 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:21][CH3:22])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC1CCOCC1)c1cc(Cl)cc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoate (0.40 g, 1.35 mmol) and acetaldehyde (0.120 g, 2.71 mmol) in dichloroethane (5 mL), acetic acid (0.48 g, 8.1 mmol) was added and the reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (0.663 g, 4.05 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure and the crude material purified by column chromatography to the title compound (0.38 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][CH:25]=1)[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(Cl)cc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 89 from 1.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-dimethylaminoindol-2-one and 1.40 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using a gradient of an AcOEt/hexane mixture (from 10/90; v/v to 20/80; v/v) as the eluent gives the expected product. m=1.5 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[C:12]1[C:17]([N+:18]([O-])=O)=[C:16]([NH2:21])[CH:15]=[C:14]([CH3:22])[N:13]=1.[NH4+].[OH-].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O.CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH:23]([CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH3:29])[C:12]1[C:17]([NH2:18])=[C:16]([NH2:21])[CH:15]=[C:14]([CH3:22])[N:13]=1
Reactant: CCCC(CCC)N(c1ccc(C(C)C)cc1Br)c1nc(C)cc(N)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CCC)N(c1ccc(C(C)C)cc1Br)c1nc(C)cc(N)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
N-[2-Bromo-4-(1-methylethyl)phenyl]-6-methyl-3-nitro-N-(1-propyl-butyl)pyridin-2,4-diamine (0.7 g, 1.51 mmol), was suspended between dioxane (30 mL) and water (30 mL) containing conc.NH4OH (1.2 mL). To that Na2S2O4 was added (2.1 g, 12.06 mmol) and the mixture was stirred at 25° C. for 2h. Then an additional 1 g Na2S2O4 was added followd by 10 mL dioxane and 10 mL water. After stirring for 1 h at 25° C. the mixture was patritioned between EtOAc (120 mL) and water (20 mL). The EtOAc was washed with water (100 mL), brine, dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel (20% EtOAc/hexanes eluting solvent) to give the product (0.5 g).
Reaction SMILES: C(O)(=O)C(O)=O.C(N(CC)C[C:11]#[C:12][CH2:13][C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:19][CH2:18][CH2:17][CH2:16][S:15]1)C.C(O)(=O)C(O)=O.COC1C=C(CCC(NC)C#CCC2(C3C=CC=CC=3)SCCCS2)C=CC=1OC>>[CH2:13]([C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:19][CH2:18][CH2:17][CH2:16][S:15]1)[C:12]#[CH:11]
Reactant: CCN(CC)CC#CCC1(c2ccccc2)SCCCS1
Agent: CNC(C#CCC1(c2ccccc2)SCCCS1)CCc1ccc(OC)c(OC)c1
Agent: O=C(O)C(=O)O
Product: C#CCC1(c2ccccc2)SCCCS1

Procedure:
Also prepared by this general method were: 2-(4-diethylaminobut-2-ynyl)-2-phenyl-1,3-dithiane oxalate, mp 144°-146° C., and 2-[4-[2-(3,4-dimethoxyphenyl)ethyl]methylaminobut-2-ynyl]-2-phenyl-1,3-dithiane oxalate, mp 144°-146° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 1-bromo-4-fluorobenzene
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:25])C.O>C(O)C>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:25]
Reactant: CC(=O)O
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound was synthesized by referring to Org. Synth., 1963, IV, 690. A suspension of (4-bromomethylphenyl)acetic acid (6.0 g) and hexamethylenetetramine (11.1 g) in ethanol (80 ml) was stirred for 2 hours at 100° C., then acetic acid (20 ml) and water (20 ml) were sequentially added thereto followed by stirring for 1.5 hours at 100° C. The solvent was evaporated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. A solution of the residue in tetrahydrofuran was filtered through silica gel, then the solvent was evaporated in vacuo, and the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (2.0 g).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19](CCCCCCCO)[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(N(CC)C(C)C)(C)C.CS(C)=O.O>ClCCl>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCCCCCO)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Reaction time: 0.67 h
Yield: 149.9 %

Procedure:
To a stirred solution of (S)-3-(1-carbamoyl-1,1-diphenylmethyl)-1-(7-hydroxyhept-1-yl)pyrrolidine (31.00 g, 78.57 mmol); N,N-diisopropylethylamine (68.4 mL, 392.8 mmol); and methyl sulfoxide (60.7 mL, 785.7 mmol) in dichloromethane (780 mL) under an atmosphere of nitrogen at −15° C., was added sulfur trioxide pyridine complex (37.5 g, 235.71 mmol) portion-wise over a 40 min. period. The reaction mixture was maintained between −10° C. and −20° C. during the addition. The reaction was then stirred in this temperature range for 40±10 min. Deionized water (300 mL) was added and the mixture was stirred for 10 minutes. The organic layer was separated and washed with deionized water (200 mL), followed by saturated aqueous sodium chloride (200 mL) and the organic layer was then dried with magnesium sulfate (10 g). The magnesium sulfate was filtered off and washed with dichloromethane (50 mL) and the solvent was reduced in vacuo. The resultant syrup was washed with petroleum ether (2×200 mL) to remove the remaining pyridine and DMSO and the resulting white solid was dried in vacuo to give 33.02 g of the title intermediate (98% yield; >93% purity by chiral HPLC Method A).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Iodo-1H-pyrazole (2 g, 10.3 mmol), ethyl bromoacetate (2.3 mL, 20.6 mmol) and cesium carbonate (5 g, 15.5 mmol) were combined in DMF (20 mL). After stirring at room temperature for 30 minutes the reaction was diluted with EtOAc/hexanes (1:1) and washed with H2O/brine, with back-extraction. The organic layer was dried over MgSO4, concentrated and filtered via silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH3:7][NH:8][C@@H:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C@H:12]([C:19]2[CH:20]=[CH:21][C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=2)[CH2:11][CH2:10]1>>[CH3:7][NH:8][C@@H:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C@H:12]([C:19]2[CH:20]=[CH:21][C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=2)[CH2:11][CH2:10]1.[C:1]([O-:6])(=[O:5])[C@H:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Product: C[C@H](O)C(=O)[O-]
Reaction time: 8 h

Procedure:
Sertraline hydrochloride (300 g) was slurried in a 3:1 mixture of water (3 liters) and ethyl acetate (1 liter). The pH of the slurry was adjusted to 8.0 by the addition approximately 1 liter of 1N sodium hydroxide solution. The free base of sertraline partitioned into the ethyl acetate phase. The two phases were allowed to separate completely by allowing the biphasic solution to stand overnight without agitation. The ethyl acetate layer was then separated and washed twice with 3 liters of deionized water to remove chloride ions. The final ethyl acetate layer containing sertraline base was concentrated to 300 mL under vacuum to remove residual water. The ethyl acetate solution containing sertraline base was heated to 40° C. L-lactic acid was dissolved in ethyl acetate to form a 7.5 M solution. The lactic acid solution was added to the sertraline base solution in small portions with constant agitation. The mixture was allowed to stir and granulate overnight (16-20 hours). The crystals were filtered and washed 4 times with an equal volume (200 mL each) of ethyl acetate. The crystals were dried overnight in a vacuum oven at 40° C. The yield was 97%. mp 153° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[S:51][CH:52]=[C:53]([C:55]2[CH:66]=[CH:65][C:58]([C:59]([NH:61][CH:62]3[CH2:64][CH2:63]3)=[O:60])=[CH:57][CH:56]=2)[N:54]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][C@H:9]1[C:13](=[O:15])[NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55]2[CH:56]=[CH:57][C:58]([C:59](=[O:60])[NH:61][CH:62]3[CH2:64][CH2:63]3)=[CH:65][CH:66]=2)[N:54]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)O
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-Thiazolidine-2,3-dicarboxylic acid 3-tert-butyl ester (49.4 mg, 0.21 mmol) was dissolved in DMF (2 mL). DIEA (74 μL, 0.42 mmol) was added followed by HATU (80.7 mg, 0.21 mmol). The reaction was stirred at ambient temperature for 15 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide (54.6 mg, 0.21 mmol) was added. The reaction was stirred at ambient temperature overnight and then heated to 50° C. for 7 hours. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 30.5 mg. MS: 475.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.54-0.75 (m, 4H), 1.22-1.47 (m, 9H), 2.79-2.90 (m, 1H), 3.05-3.25 (m, 2H), 3.55-3.75 (m, 1H), 5.33-5.50 (m, 2H), 7.78-7.98 (m, 5H), 8.40-8.48 (d, 1H), 12.50-12.59 (s, 1H).
Reaction SMILES: [CH:1]1(N)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[O:8]1[CH:13]=[CH:12][CH2:11][C:10](=[O:14])[CH2:9]1.[Li]CCCC.BrCCCC=C>C1C=CC=CC=1.C1COCC1>[CH2:5]([CH:11]1[CH2:12][CH2:13][O:8][CH2:9][C:10]1=[O:14])[CH2:6][CH2:1][CH:2]=[CH2:3]
Reactant: O=C1CC=COC1
Reactant: NC1CCCCC1
Agent: C=CCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=CCCCC1CCOCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclohexylamine (3.43 ml, 30.0 mmol) was added to pyran-3-one (3000 mg, 30.0 mmol) in benzene (20 mL). The reaction mixture was stirred at RT for 30 min and then refluxed for 2 hr with a dean-stark trap. The benzene was then distilled off and the residue was redissolved in THF (2 mL) and added to BuLi (13.18 ml, 33.0 mmol) in THF (Volume: 30.000 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 h before 5-bromo-1-pentene (5582 mg, 37.5 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hr. The mixture was cooled and quenched with water. The reaction mixture was extracted with diethyl ether (3×20 mL). The combined organic fractions were washed with water and brine (saturated, 100 mL), dried, filtered and the solvent was evaporated under reduced pressure (400 mmhg). The residue was purified by column chromatography on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 5.74-5.86 (m, 1H), 4.92-5.06 (m, 2H), 3.90-4.06 (m, 3H), 3.77-3.85 (m, 1H), 2.41-2.49 (m, 1H), 2.16-2.24 (m, 1H), 2.01-2.12 (m, 2H), 1.72-1.97 (m, 2H), 1.31-1.49 (m, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[CH:36])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]>CN(C=O)C.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.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[C:36][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Reactant: FC(F)(F)c1ccccc1I
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (64.5 mg, 0.03 eq.), 2-iodobenzotrifluoride (321 μL, 1.1 eq.), triethylamine (869 μL, 3.0 eq.), and copper (I) iodide (23.7 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (489 mg, 2.08 mmol, 1.0 eq.) in DMF (10.6 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 3/97 methanol/chloroform) to provide 0.13 g of 2-ethyl-1-[3-(2-trifluoromethylphenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline as a light yellow solid.
Reaction SMILES: [ClH:1].[I:2][C:3]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:11]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[ClH:1].[F:10][C:9]1[C:3]([I:2])=[C:4]([NH:5][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(F)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cccc(F)c1I
Temperature: -10 °C
Reaction time: 4 h

Procedure:
2-Iodo-3-fluoroaniline hydrochloride (5.7 g, 0.021 mol) was stirred in 7.4 mL of concentrated HCl and cooled to -10° C. An aqueous solution of sodium nitrite (1.63 g, 0.024 mL) in 5 mL water was added dropwise over a 20 minute period, stannous chloride (9.95 g, 0.044 mol) in 12 mL of 6N HCl added at -5° C., warmed to room temperature and stirring continued for 4 hours. The reaction mixture was cooled to 0° C., and made basic with 50% NaOH (pH 10-11), extracted with ether, washed with water, brine, dried (MgSO4), filtered and concentrated to give the hydrazine. Addition of ethereal HCl (pH 1-2) gave 4.6 g of the title compound, m.p. 165°-167° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Product: Fc1ccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)cc1

Procedure:
The title compound was prepared from the product of Example 105A and 4-fluorophenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 330.0 (M+H)+, retention time 1.51 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[CH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-:17].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([O:17][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2

Procedure:
In analogy to example 11 step 1 with 4-methylene-azepane-1-carboxylic acid tert-butyl ester (MW: 211.307, 1.73 mmol), 1.16 g sodium bicarbonate (MW: 84.01 13.8 mmol) and 1.36 g of 80% m-chloroperbenzoic acid (MW 172.57, 6.05 mmol) in 5 ml of dichloromethane. Yield: 250 mg, 63%. MS: 228.8 (M+H)+, 127.8 (M−(CH3)3COCO) method ESI+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][OH:13])[C:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1.[C:32]([O-])(O)=O.[Na+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][OH:13])[C:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:32])=[O:27])=[CH:21][C:20]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
Concentrated HCl (1 mL) was added to a solution of the product from step (i) (0.1 g) in MeOH (2 mL). The mixture was heated at 70° C. for 2 h, poured into saturated aqueous NaHCO3 solution (10 mL) and the aqueous was adjusted to pH ˜7 by adding NaHCO3. The aqueous was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.018 g.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][CH3:12].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+].C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[O:11][CH3:12])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc(CBr)c1CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc2c1CN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
The 2,3-bis-(bromomethyl)anisole prepared above and 1.5 g of benzyltriethylammonium chloride were dissolved in a mixture of 80 ml of aqueous 50% sodium hydroxide and 350 ml of toluene. To the solution was dropwise added 21.6 g of benzylamine over 15 minutes while stirring at room temperature. After stirring for one day for one day, the organic layer was separated and washed with brine. After concentration, the residue was purified by chromatography on silica gel (benzene/ethyl acetate=15/1) to give 15.2 g of 2-benzyl-4-methoxyisoindoline as an oily substance.
Reaction SMILES: BrC([CH:7](Br)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15])CC(O)=O.CC(C)([O-])C.[K+].Cl.[C:24]([O:27]CC)(=[O:26])[CH3:25]>C(O)(C)(C)C>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:7]#[C:25][C:24]([OH:27])=[O:26]
Reactant: CCOC(C)=O
Reactant: O=C(O)CC(Br)C(Br)c1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)C#Cc1ccc(Cl)cc1Cl
Reaction time: 1.5 h

Procedure:
A solution of 19.2 g (50.94 mmol) of 2,3-dibromo-3-(2,4-dichlorophenyl)propanecarboxylic acid in 130 mL of tert-butanol is combined batchwise with a total of 22.86 (203.78 mmol) of potassium tert-butoxide, so that the temperature does not exceed 40° C. Then the mixture is stirred for another 90 minutes at this temperature. The reaction mixture is poured into 2N hydrochloric acid and the precipitate is taken up in ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The desiccant is filtered off and the solvent is distilled off. The residue is dried in the circulating air dryer at 80° C. Yield: 9.73 g (88.8% of theory); melting point: 168° C.-171° C.; C9H4Cl2O2 (M=215.03); Rf value: 0.5 (silica gel, dichloromethane/ethanol/glacial acetic acid (10:1:0.1)).