Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][O:33][CH:28]([CH2:27][N:24]5[CH2:23][CH2:22][O:21][CH2:26][CH2:25]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1COC(CN2CCOCC2)CN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN4CCOCC4)C3)c(F)cc2c1=O

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(morpholinomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[2-(morpholinomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid, melting at 171°-172° C.
Reaction SMILES: C(#N)C.[ClH:4].[CH3:5][N:6]([CH3:13])[CH2:7]/[CH:8]=[CH:9]/[C:10](O)=[O:11].C(Cl)(=O)C([Cl:17])=O.C(OC)(=O)C(OC)=O>CN(C)C=O>[ClH:17].[CH3:5][N:6]([CH3:13])[CH2:7][CH:8]=[CH:9][C:10]([Cl:4])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: COC(=O)C(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)CC=CC(=O)Cl

Procedure:
A 1 L multi-neck flask equipped with agitator, thermometer, addition funnel, and nitrogen protection is charged with acetonitrile (0.67 kg, 0.85 L) followed by adding dimethylformamide (0.00086 kg, 0.91 mL, d=0.944 g/mL). At ambient temperature, is added 4-dimethylaminocrotonic acid hydrochloride (0.0709 kg) and the mixture stirred until homogeneous. Cool the reaction mixture to (0–10° C.) and add oxalyl chloride (0.0473 kg, 0.0325 L, d=1.45 g/mL) dropwise over (20 minutes) at (0–10° C.) followed by a rinse with acetonitrile (0.02 kg, 0.03 L). The temperature (0–10° C.) is maintained for about (20 minutes). The temperature of the reaction mixture is adjusted to (22–26° C.) over (20 minutes) and maintained over (2 hours). The temperature of reaction mixture is adjusted to (40–45° C.) and held for about (5 minutes). Cool the light suspension to about (20–25° C.) and check for reaction completion by high-pressure liquid chromatography (HPLC). The reaction is complete when there is ≦15% of the starting material (4-dimethylaminocrotonic acid hydrochloride) present and/or ≦2% of oxalyl chloride (detected as the dimethyl oxalate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C:30]1([C:39](O)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1)=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:39]([C:30]3([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]3)=[O:40])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CCc2ccccc21
Yield: 70.6 %

Procedure:
Preparation of example 149 from the title compound of Example 7 (hydrochloride) (52 mg, 0.17 mmol), 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2,3-dihydro-1H-indene-1-carboxylic acid (72 mg, 0.26 mmol), triethylamine (0.071 mL, 0.51 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (99 mg, 0.26 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (63 mg, 0.12 mmol) as a yellow powder in 69% yield.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][C:8]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[C:10]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:9]=1[I:40])[C:4]([OH:6])=[O:5])[CH3:2].Br[CH2:42][C:43]([OH:45])=[O:44]>CCO>[CH2:1]([CH:3]([CH2:7][C:8]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[C:10]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH2:42][C:43]([OH:45])=[O:44])[CH2:30][CH2:31][N:32]([CH2:42][C:43]([OH:45])=[O:44])[CH2:33][CH2:34][N:35]([CH2:3][C:4]([OH:6])=[O:5])[CH2:36][CH2:37]2)[C:9]=1[I:40])[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN2CCNCCNCCNCC2)c1I)C(=O)O
Reactant: O=C(O)CBr
Solvent: CCO
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)c1I)C(=O)O
Yield: 96.7 %

Procedure:
According to the procedure described in Example 2, 111 g of compound (A) α-ethyl-2,4,6-triiodo-3-[[1-oxo-6-[(1,4,7,10-tetraazacyclododec-1-yl-acetyl)amino]hexyl]amino]benzenepropanoic acid (0.12 mol) are reacted with 67.2 g of bromoacetic acid (0.48 mol) in 600 ml of 80% EtOH. 63 g of α-ethyl-2,4,6-triiodo-3-[[1-oxo-6-[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-ylacetyl]amino]hexyl]amino]benzenepropanoic acid (0.058 mol) are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[CH2:13]([Br:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[BrH:21].[NH2:1][C:2]1[N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2=[N:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2nc(N)ccc2c1C
Reactant: BrCCc1ccccc1
Solvent: CC#N
Product: Br
Product: Cc1nc2n(CCc3ccccc3)c(N)ccc-2c1C
Yield: 4.7 %

Procedure:
A solution of 6-amino-2,3 -dimethyl-pyrrolo [2,3-b]pyridine (1.0 g, 6,2 mmol ) and phenethyl bromide (1,7 g, 9,3 mmol ) in 30 ml CH3CN was refluxed for 48 h. The mixture was allowed to cool and the precipitate was filtered off. Chromatography on silica gel eluting with methylene chloride and methanol (9:1) gave the desired product (0,1 g, 6%).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:48][OH:49]>C1COCC1>[F:30][CH:29]([F:31])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:17]([N:13]2[C:14](=[O:16])[C:15]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12]2)[CH2:18][C:19](=[O:20])[NH:48][OH:49])=[CH:23][C:24]=1[O:32][CH2:33][CH3:34]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 72.1 %

Procedure:
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 8 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and hydroxylamine hydrochloride (0.23 g, 3.6 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.60 g, 80% yield): mp 116-118° C.; 1HNMR (CDCl3): δ 0.82 (m, 2H, c-CH2), 1.02 (m, 2H, c-CH2), 1.36 (t, J=6.8 Hz, 3H, OCH2CH3), 1.58 (m, 1H, c-CH), 2.86 (dd, J=5, 15 Hz, 1H, CH2), 3.15 (dd, J=10, 15 Hz, 1H, CH2), 3.30 (broad, 1H, NHOH), 4.01 (q, J=7.0 Hz, 2H, OCH2CH3), 4.02 (d, J=17.5 Hz, 1H, CH2N), 4.34 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.71 (m, 1H, CHN), 6.07 (broad, 1H, NHOH), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 6.88 (m, 3H, Ar), 7.07 (d, J=7.5 Hz, 1H, Ar), 7.30 (t, J=7.5 Hz, 1H, Ar), 8.28 (d, J=8 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13CNMR (CDCl3): 8.27, 8.39, 14.5, 16.0, 35.4, 47.3, 52.4, 64.8, 111.8, 113.3, 115.9, 116.9, 117.0, 118.9, 120.0, 122.6, 133.3, 136.6, 137.6, 140.0, 141.5, 150.8, 167.5, 169.7, 172.8; Anal. Calcd. for C24H25F2N3O6+0.34 H2O: C, 58.16; H, 5.22; N, 8.48. Found: C, 58.25; H, 5.37; N, 8.58, 1.25 H2O
Reaction SMILES: [CH2:1]([I:3])[CH3:2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([O:16][CH3:17])[CH:15]=1)[CH:12]=[N:11][CH2:10][CH2:9]2>C(#N)C>[I-:3].[CH2:10]([N+:11]1[CH2:2][CH2:1][C:8]2[C:13](=[C:14]([O:16][CH3:17])[CH:15]=[C:6]([O:5][CH3:4])[CH:7]=2)[CH:12]=1)[CH3:9]
Reactant: CCI
Reactant: COc1cc2c(c(OC)c1)C=NCC2
Solvent: CC#N
Product: CC[N+]1=Cc2c(cc(OC)cc2OC)CC1
Product: [I-]
Reaction time: 20 h
Yield: 59 %

Procedure:
Ethyl iodide (0.6 mL, 7.32 mmol) was added to a solution of 6,8-dimethoxy-3,4-dihydroisoquinoline (700 mg, 3.66 mmol) in acetonitrile (15 mL) and the mixture was left to stir in the dark for 20 h. The resultant precipitate was collected by filtration, washed with acetonitrile and left to air dry to afford the title compound as a yellow solid (750 mg, 95%). 1H NMR (CD3OD, 300 MHz): 8.96 (s, 1H), 6.63 (d, J=2.2 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H), 4.02-3.88 (m, 7H), 3.18 (t, J=7.9 Hz, 2H), 2.03 (s, 5H), 1.47 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:36][OH:37])[C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH:28]([C:32]([F:35])([F:34])[F:33])[CH2:27]4)=[O:25])=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.F[CH:40](F)OC1C=CC(C2C=NC(NC3C=CC(C(CO)C(NCCF)=O)=CC=3)=NC=2)=CC=1.C=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH2:36][OH:37])[C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:40])[CH:28]([C:32]([F:35])([F:34])[F:33])[CH2:27]4)=[O:25])=[CH:21][CH:22]=3)=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C(NCCF)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Reactant: O=C(C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1)N1CCNC(C(F)(F)F)C1
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C(=O)C(CO)c2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)piperazin-1-yl)-3-hydroxypropan-1-one C37 (prepared as described for C1, 0.05 mmol), HCHO (0.15 mmol, 30% aqueous) and anhydrous Na2SO4 (1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)3 (0.3 mmol) is added and the resulting mixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient 10-70%) affords 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-one C38. MS (m/z) (M+1)+: 552.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-nitroindole (6.0 g, 37 mmol) and 4-piperidone hydrochloride hydrate (11.4 g, 74 mmol). The product was isolated as an orange solid. Yield 8.8 g (97%). mp 247°-250° C.(dec.) FDMS m/e=243 (M+ of free base).
Reaction SMILES: ClC1C2C(=O)C3C(=CC=C(OC)C=3)NC=2C([N+]([O-])=O)=CC=1.[Cl:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32](OC)[CH:33]=3)[N:28]([CH3:40])[C:27]=2[C:26]([N+:41]([O-:43])=[O:42])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:40])[C:27]=2[C:26]([N+:41]([O-:43])=[O:42])=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)c(=O)c1c(Cl)ccc([N+](=O)[O-])c1n2C
Agent: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Product: Cn1c2ccccc2c(=O)c2c(Cl)ccc([N+](=O)[O-])c21

Procedure:
In the same manner, 7.62 g (0.025 mol) of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone was converted to 5.05 g (63%) of 1-chloro-7-methoxy 10-methyl-4-nitro-9(10H)-acridinone, mp 235°-240° C. after recrystallization from toluene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7])[CH3:2].[CH2:9](N(CC)CC)C.[Cl:16][C:17](Cl)(CCl)[C:18]#[N:19].C(OCC)C>O1CCCC1>[Cl:16][C:17](=[CH:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH3:9])[C:18]#[N:19]
Reactant: CCOC(=O)CNC
Reactant: N#CC(Cl)(Cl)CCl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CN(C)C=C(Cl)C#N
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of sarcosine ethyl ester (58.5 g, 0.499 mol), tetrahydrofuran (200 ml) and triethylamine (101.2 g, 1 mol) is added dropwise within 15 minutes to a solution of 2,2,3-trichloropropionitrile (79.0, 0.499 mol) in tetrahydrofuran (200 ml). Within 1 hour, the temperature of the mixture rises spontaneously to 30° C. To complete the reaction, the mixture is then refluxed for 3 hours. It is left to cool, stirred into diethyl ether (4 liters), filtered to remove the precipitated triethylamine hydrochloride and the etheral solution is concentrated. The residue is distilled under high vacuum to give a colorless oil (97.1 g), boiling point 0.3 mm Hg 120°-130° C. containing both isomers in a ratio of approximetely 1:1 according to 1H-NMR spectroscopy. An isomer, presumably the isomer of (E) configuration, crystallises out of this oil occasionally, mp. 57° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1Br
Yield: 72 %

Procedure:
4-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-trifluoromethylbenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 155-158° C., yield 72%.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[NH:23][CH:22]=[C:21]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:34]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23]([CH3:34])[CH:22]=[C:21]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(S(=O)(=O)c4ccccc4)c[nH]c23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(S(=O)(=O)c2ccccc2)c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Sodium hydride (0.12 g of 60% dispersion in mineral oil, 3 mmol) was added to a solution of 4-(3-benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 2.3 mmol) in 20 mL of DMF with ice cooling. After stirring 15 min at room temperature the mixture was treated with methyl iodide (0.17 mL, 3 mmol). Water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and evaporated. Silica gel chromatography (20% ethyl acetate-hexane) afforded 0.9 g of 4-(3-benzenesulfonyl-1-methyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester as a foam, mass spec. M+ 455.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[OH-].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[CH:23]1[C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][C:25]=2[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][S:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A solution of 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid methyl ester (210 mg, 0.46 mmol) in THF (2 mL) and methanol (2 mL) was cooled to 0° C. and treated with 2 N KOH (1.0 mL) After stirring at room temperature for 1 h the solution was acidified with 10% HCl to pH 2 and diluted with ethyl acetate (25 mL). After being seperated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid (180 mg, 90%) as white solid. 1H NMR (CDCl3), 8.01 (d, J=8 Hz, 2 H), 7.94 (d, J=8 Hz, 2 H), 7.78 (d, J=8 Hz, 2 H), 7.66 (m, 4 H), 7.42 (m, 5 H), 3.82 (s, 2 H), 3.82 (s, 2 H), 2.76 (m, 2 H), 2.56 (t, J=6 Hz, 2 H). LCMS 462 (M++23).
Reaction SMILES: N1(C[C:8](O)=[O:9])CCCCC1.C(O)(=O)C.N1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21]([CH2:23][C:24]([NH2:26])=[O:25])#[N:22]>O>[O:25]=[C:24]1[NH:26][C:18]2[CH2:19][CH2:20][O:9][CH2:8][C:17]=2[CH:16]=[C:23]1[C:21]#[N:22]
Reactant: O=C(O)CN1CCCCC1
Reactant: N#CCC(N)=O
Reactant: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc2c([nH]c1=O)CCOC2
Temperature: 0 °C
Yield: 20 %

Procedure:
Then, an aqueous piperidine—acetic acid solution prepared by dissolving acetic acid (1.5 mL) in water (3.5 mL) and adding piperidine (2.6 ml) thereto, and 2-cyanoacetamide (4.62 g, 54.9 mmol) were added to the above-mentioned aqueous solution A, and the mixture was stirred with heating under reflux for 4 hr. To the mixture was added acetic acid (3.6 mL) and, after cooling 0° C., the precipitated solid was collected by filtration to give 2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile (1.72 g, 20%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[CH:5][C:4]=1[CH3:14].[Se](=O)=[O:16].C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:16])=[N:10]2)=[CH:5][C:4]=1[CH3:14]
Reactant: COc1cc2nc(C)ccc2cc1C
Reactant: O=[Se]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc2nc(C=O)ccc2cc1C

Procedure:
To 7-methoxy-2,6-dimethylquinoline (580 mg, 3.10 mmol) in dioxane/water (15/0.015 mL) was added selenium dioxide (447 mg, 4.03 mmol) and the reaction was heated to reflux for 5 hours. After cooling, DCM was added followed by MgSO4. After concentration, the residue was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol) were reacted according to Example 5 (step a) to provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][C:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[C:54]([CH3:63])[O:53][N:52]=1>CN(C=O)C>[CH3:50][C:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)=[C:54]([CH3:63])[O:53][N:52]=1
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
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: COc1cccc2cc(C(=O)Nc3cccc(-c4c(C)noc4C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(3,5-dimethyl-isoxazol-4-yl)-phenylamine (0.012 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 80% yield: LCMS (ESI) m/z 391 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>>[CH3:14][N:15](/[CH:17]=[C:6]1/[CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:2]/1=[O:1])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 105 °C

Procedure:
A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (40 g, 216 mmol) was treated with DMF-DMA (267 g, 2241 mmol) and heated at 105° C. for 40 min. The solution was cooled and evaporated under reduced pressure and the resulting orange solid was treated with hexane (200 mL) and cooled in the refrigerator over the weekend. The resulting brownish-yellow solid was collected by filtration, dried and used in the next setp without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH3:14])=[C:7]([CH2:11][CH2:12][OH:13])[C:8](=[O:10])[O:9][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25].[CH2:27](O)[CH3:28]>>[CH2:27]([O:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH3:14])=[C:7]([CH2:11][CH2:12][OH:13])[C:8](=[O:10])[O:9][C:4]=2[C:3]=1[O:17][CH2:24][CH3:25])[CH3:28]
Reactant: Cc1c(CCO)c(=O)oc2c(O)c(O)ccc12
Reactant: CCI
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc2c(C)c(CCO)c(=O)oc2c1OCC

Procedure:
30.0 g (127 mmol) of 7,8-dihydroxy-3-(2-hydroxyethyl)-4-methyl-2H-1-benzopyran-2-one (Example 52), 52.7 g (381 mmol) of potassium carbonate and 43.6 g (280 mmol) of ethyl iodide are stirred under reflux for 50 hours in 800 ml of ethanol. The solution is evaporated, extracted with chloroform, and the organic phase is washed with water, dried with Na2SO4, and re-evaporated. Yield 21.0 g (57%); m.p. 130°-131° C. (from isopropanol).