Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:21]3[CH2:27][CH:26]4[N:28]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([Br:20])[CH:12]=3)=[O:5])[CH3:2].C(N(CC)C(C1C=CC2C(=C3CC4N(C(=O)C(F)(F)F)C(CC4)C3)C3C(OC=2C=1)=C(OC)C=CC=3)=[O:41])C.C(N(CC)C(C1C=CC2C(=C3CC4NC(CC4)C3)C3C(OC=2C=1)=C(Br)C=CC=3)=O)C>>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:21]3[CH2:27][CH:26]4[NH:28][CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([Br:20])[CH:12]=3)=[O:5])[CH3:36].[C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:41]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(Br)cc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(Br)cccc1C2=C1CC2CCC(C1)N2
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(Br)cc1C2=C1CC2CCC(C1)N2
Product: O=C(O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 17, substituting 7-bromo-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxylic acid diethylamide, 5f for 5-methoxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxylic acid diethylamide, 5d, the title compound 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-7-bromo-9H-xanthene-3-carboxylic acid diethylamide, 6f was obtained as a TFA salt after reverse phase HPLC purification (eluent gradient: CH3CN in H2O containing 0.1% TFA). MS m/z (MH+) 467/468.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N:8]([O-])=O.[Na+].[Sn](Cl)[Cl:13]>Cl>[ClH:13].[ClH:13].[NH:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: Nc1cccnc1
Agent: Cl
Agent: [Na+]
Product: NNc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
3-Aminopyridine (20 g) was dissolved in concentrated hydrochloric acid (125 mL), and an a aqueous solution (40 mL) of sodium nitrite (15 g) was added at −10° C. over 20 min. The mixture was stirred at 0° C. for 2 hr. This solution was added to a solution (200 mL) of tin(II) chloride (80 g) in concentrated hydrochloric acid at −2° C. over 20 min. The mixture was stirred for 14 hr. The precipitate was filtered off and ice was added. The mixture was made strongly-basic with a 50% a aqueous potassium hydroxide solution and extracted with dichloromethane. The extract solution was dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 mL) and 4 mol/L of hydrochloric acid-ethyl acetate (55 mL) was added under ice-cooling. The precipitate was collected by filtration to give 3-hydrazinopyridine dihydrochloride (18 g) as a pale-yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:1](=[O:4])[CH3:2])=[CH:8][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Acetic acid (1.321 g, 22.000 mmol) was dissolved in DMF (10 ml), 1-(4-fluorophenyl)methanamine (2.478 g, 19.800 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (7.770 g, 24.200 mmol) and N-ethyl-N,N-diisopropylamine (5.971 g, 46.200 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporations. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation and gave 1.344 g of N-(4-fluorobenzyl)acetamide (yield 36.5%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A mixture of ethyl 1H-imidazole-4-carboxylate (8 g, 57.1 mmol), 4-fluoro-1-nitrobenzene (8.05 g, 57.1 mmol) and potassium carbonate (8.68 g, 62.8 mmol) in acetonitrile (100 mL) was stirred at 60° C. for 16 h then cooled to room temperature and most the solvent was removed in vacuo. The residue was partitioned between AcOEt (200 mL) and water (150 mL) and the layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave ethyl 1-(4-nitrophenyl)-1H-imidazole-4-carboxylate (12.53 g, 48.0 mmol, 84%) as a yellow oil.
Reaction SMILES: [O:1]=[O:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(C)=O>O>[N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:1][OH:2]
Reactant: O=O
Reactant: Nc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: OO
Product: c1ccc(N=Nc2ccccc2)cc1

Procedure:
The excess hydroxide ion (OH-), dissolved dioxygen (O2), and aniline (PhNH2) reacted in the dimethyl sulfoxide solution to form superoxide ion (O2-.), azobenzene (PhN=NPh), hydrogen peroxide (HOOH), and water (H2O). The dioxygen was introduced by bubbling gaseous dioxygen through the solution of other reactants for 20 minutes, and then purging with argon. The reaction yielded concentrations of 1.4 mM of superoxide ion and 2.5 mM of azobenzene.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)[CH3:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCC1.Cl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNC1
Solvent: c1ccncc1
Product: CCc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
A solution of 4-ethylbenzaldehyde (26.0 g, 0.2 mol), malonic acid (41.6 g, 0.4 mol), pyrrolidine (3 ml), and pyridine (80 ml) was heated in an 85° C. oil bath for 16 hr. The reaction mixture was poured over crushed ice (800 ml), and then made acidic with 12N HCl (100 ml). The white precipitate was filtered, suspended in 1N HCl, and filtered again. The white precipitate was washed with water and air dried to give 4-ethyl cinnamic acid (34.0 g, 96.6).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:5][CH:4]([C:6]([CH:8]2[C:13](=[O:14])[O:12][C:11]([CH3:16])([CH3:15])[O:10][C:9]2=[O:17])=O)[CH2:3]1.C(O)(=O)C.[BH4-].[Na+]>C1COCC1>[F:18][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][CH:8]2[C:9](=[O:17])[O:10][C:11]([CH3:16])([CH3:15])[O:12][C:13]2=[O:14])[CH2:3]1
Reactant: CC1(C)OC(=O)C(C(=O)C2CC(F)(F)C2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)OC(=O)C(CC2CC(F)(F)C2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
A solution of 5-(3,3-difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (15.0 g, 57.3 mmol) in THF (200 mL) was cooled to −5° C. and acetic acid (38 g, 0.63 mol) was added. The mixture was stirred for 5 min and sodium borohydride (6.5 g, 0.17 mol) was added in portions. The reaction mixture was stirred for 2 h at −5° C. and then poured into ice water (200 mL). The resulting mixture was extracted with EtOAc (300 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 30:1) to afford 5-((3,3-difluorocyclobutyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.2 g, 58% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:13]([NH2:18])[C:14]([NH2:17])=[N:15][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.O=[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:22]=O>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:13]4[N:18]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][C:14]4=[N:15][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: COc1ccc(C2(c3nnc(N)n3N)CC2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C2(c3nnc4nc(-c5ccccc5)cnn34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[1-(4-methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine (70.2 mg, 0.286 mmol) and oxo(phenyl)acetaldehyde hydrate (0.0435 g, 0.286 mmol) in acetic acid (1.2 mL) was stirred at RT overnight. The mixture was diluted with methanol (3.0 mL) and subject to preparative RP-HPLC to afford the two regioisomers.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:37][C:38]1[N:39]=[C:40]([CH3:43])[S:41][CH:42]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:37][C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Product: Cc1nc(CN2CN(c3ccccc3Cl)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)cs1

Procedure:
The title compound, MS: m/e=617.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 4-chloromethyl-2-methylthiazole hydrochloride.
Reaction SMILES: [C:1]([C:4]([C:21]([O:23][CH3:24])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11](OC)[O:12]C)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([C:4]([C:21]([O:23][CH3:24])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11]=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC)C(CC(=O)OC)C(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: CCC#CCC(C(C)=O)(C(=O)OC)C(C=O)CC(=O)OC
Reaction time: 12 h

Procedure:
Methyl 4-acetyl-4-methoxycarbonyl-3-dimethoxymethyl-6-nonynoate (530 mg) is dissolved in 20 ml of tetrahydrofuran, and 25 ml of 1% aqueous solution of perchloric acid is added to the solution. The mixture is stirred at 26° to 28° C. for 12 hours. Subsequently the reaction mixture is neutralized with sodium bicarbonate and concentrated in a vacuum. The residue is extracted with ethyl acetate. The extract is dried and then concentrated to give methyl 4-acetyl-4-methoxycarbonyl-3-formyl-6-nonynoate (compound (3), R1 =R2 =CH3) in a yield of 98.3%.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:7]([CH3:16])[C:6]1=[O:17]>CCOCC>[CH3:2][C:6]1([OH:17])[CH:7]([CH3:16])[CH2:8][CH:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH:5]1[CH3:4]
Reactant: CI
Reactant: CC(C)CCC1CC(C)C(=O)C(C)C1
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC1CC(C)C(C)(O)C(C)C1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a Grignard solution prepared from magnesium (14.5 g, 0.6 g-atom) and methyl iodide (85.2 g, 0.6 mol) in anhydrous ether (500 mL) was added 2,6-dimethyl-4-(3-methylbutyl)cyclohexanone (59 g, 0.3 mol, produced according to Example 8) over 1 h at 15°-20° C. The mixture was stirred for an additional 1 h and then quenched into saturated ammonium chloride solution. The layers were separated and the aqueous solution was extracted with ether. The combined extracts were washed with 5% sodium bicarbonate solution, brine and then dried. Solvent removal and distillation gave 40 g of the alcohol, bp 92° C. (1 mm). NMR (CDCl3) δ0.8-1.1 (12H, m), 1.1-2.2 (16H, complex pattern with a singlet at 1.2). IR (film) 3550, 1025, 920, 890 cm-1. MS (m/e) 212 (M+), 85, 43, 57, 86.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[Cl:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]Cl)=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)=[CH:45][CH:44]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 97.6 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride were reacted to yield the title compound as yellow needles (yield: 97.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([O:14][CH:15](O)[CH3:16])=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[Na].[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>>[ClH:1].[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([O:14][CH2:15][CH2:16][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:4][CH:3]=1
Reactant: CC(O)Oc1ccc(Cl)c2c1CCN(C)CC2
Reactant: c1nc[nH]n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na]
Product: CN1CCc2c(Cl)ccc(OCCn3cncn3)c2CC1
Product: Cl

Procedure:
Following the general procedure of Example 2, [(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl) oxy]ethanol 4-methylbenzenesulfonate was heated with one equivalent of 1H-1,2,4-triazole sodium salt (prepared from 1H-1,2,4-triazole and sodium hydride in dimethylformamide) at 65° C. for 30 minutes to give 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-1H-3-benzazepine hydrochloride; mp 204°-211° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33]([Cl:36])(=[O:35])=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[ClH:36].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:34])=[O:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Product: COc1ccc(S(=O)(=O)n2ccc3c(N4CCNCC4)cccc32)cc1OC
Product: Cl

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 3,4-dimethoxyphenylsulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.00 (br, 1 H), 7.82 (d, J=5 Hz, 1 H), 7.66 (d, J=8 Hz, 1 H), 7.57 (m, 1 H), 7.40 (d, J=3 Hz, 1 H), 7.24 (t, J=8 Hz, 1 H), 7.10 (d, J=8 Hz, 1 H), 6.90 (d, J=5 Hz, 1 H), 6.78 (d, J=8 Hz, 1 H), 3.78 (s, 6 H), 3.24 (m, 8 H); MS (ESI+) for m/z 402 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH3:23])=[C:10]2[C:15]=1[O:14][CH2:13][C@H:12]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH2:11]2.[CH:24](=O)[CH2:25][CH3:26].C(O)(=O)C>CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH3:23])=[C:10]2[C:15]=1[O:14][CH2:13][C@H:12]([N:16]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH2:24][CH2:25][CH3:26])[CH2:11]2
Reactant: CCC(CC)N[C@H]1COc2c(F)ccc(OC)c2C1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(OC)c2C1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Sodiumcyanoborohydride (1.3 g, 20.7 mmol) was added during 10 min. to a stirred solution of (R)-8-fluoro-5-methoxy-3-(N-3-pentylamino)chroman (3.69 g, 13.8 mmol) and propionaldehyde (5 ml, 69.3 mmol) in 100 ml dry MeOH. The pH was adjusted with acetic acid to pH 6. The solution was stirred in room temp. for 18 hours and propionaldehyde (1 ml, 13.7 mmol) was added. After stirring at room temp. for 3.5 hours the solution was concentrated, and the residue was partitionated between 100 ml 2M NH3 and 200 ml ether. Extraction with 2×200 ml ether and drying of the combined organic layers (Na2SO4) gave after evaporation a crude product. Purification by flash chromatography on silica with hexane:acetone 20:1 gave 4.03 g of (R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman as an uncolored oil. [α]D&gt; -83° (c 1.08 in MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:24]=[CH2:25])=[C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) and vinyltributylstannane. White solid. MS (m/e): 272.4 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:17]([NH:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[CH2:17]([N:24]([CH3:25])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CNCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)Cc3ccccc3)nc2c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, 2.10 mmol) in DMSO (6 mL) was added benzyl(methyl)amine (305 mg, 2.52 mmol), and DIEA (542 mg, 4.19 mmol). The resulting solution was stirred for 2 h at 85° C., then water (50 mL) was added, causing a precipitate to form which was collected by filtration to afford methyl 3-(benzyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (0.55 g, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:13][CH3:14])[CH3:12].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:13][CH3:14])[CH3:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC1(C)C(=O)Nc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC1(C)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.52 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol) was dissolved in dimethoxyethane (22 cm3). After 15 min., 3-chlorophenylboronic acid (0.63 g, 4.1 mmol) and sodium carbonate (1.0 g) in water (10 cm3) was added and the reaction was heated under reflux. After 2 h the mixture was cooled, poured into water and extracted with EtOAc (×2), the combined organic extracts were washed with sodium hydroxide solution (1N, ×2) water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc:hexane, 5:1) to afford 5-(3-chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.17 g, 0.58 mmol, 29%): 1H NMR (CDCl3) δ 1.65 (s, 3H), 2.91 (s, 1H), 3.24 (s, 3H), 6.92 (d, 1H, J=8.1 Hz), 7.26-7.38 (m, 2H), 7.43-7.46 (m, 1H), 7.52-7.55 (m, 1H), 7.62 (d, 1H, J=1.8 Hz); MS ((+) APCI) m/z 288 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Br:17][C:18]1[CH:19]=[C:20](O)C=[CH:22][CH:23]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:17][C:18]1[CH:19]=[CH:20][C:25]([O:28][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(Br)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2nccc(Oc3ccc(Br)cc3)c2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (30 mg, 0.13 mmol), 3-bromophenol (68 mg, 0.39 mmol), and potassium carbonate (90 mg, 0.65 mmol) were suspended in DMF (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with H2O, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified via Biotage eluting with a gradient of 25 to 75% EtOAc in hexanes to provide 130 (5 mg, 11% yield) as a solid. LC-MS (M+H=367, obsd.=367). 1H NMR (400 MHz, d6-DMSO): δ 12.15 (s, 1H), 8.99 (d, 1H), 8.42 (dd, 1H), 8.33 (d, 1H), 7.87 (dt, 1H), 7.71 (t, 1H), 7.66 (d, 1H), 7.56 (dd, 1H), 7.51 (t, 1H), 7.38 (dd, 1H), 6.63 (d, 1H).
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[C:8]([C:13]([NH2:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][C:4]=1[I:25].[SH:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.O>[CH3:33][N:32]([CH3:34])[C:30]([C:29]1[CH:28]=[C:27]([S:26][C:3]2[CH:12]=[C:11]3[C:6]([C:7]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)=[C:8]([C:13]([NH2:15])=[O:14])[CH:9]=[N:10]3)=[CH:5][C:4]=2[I:25])[CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(Cl)c(I)cc23)c1
Reactant: CN(C)C(=O)c1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(Sc4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 24.6 %

Procedure:
A stirred mixture of Intermediate 63 (0.4 g), Intermediate 28 (0.16 g) and potassium carbonate (0.38 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 ml) was heated at 100° C. under nitrogen for 3 h. A further portion of Intermediate 28 (0.07 g) was added and the mixture stirred at 60° C. for 23 h. The cooled mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×70 ml) and brine (70 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with methanol followed by mass directed preparative HPLC (Method A) to give the title compound as a yellow foam (0.12 g).