Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][CH3:23].Cl>>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:17][C@@H:16]([CH3:20])[N:15]([CH2:21][CH2:22][CH3:23])[C@@H:14]([CH3:13])[CH2:19]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CCCN1[C@H](C)CNC[C@@H]1C
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: Cl
Product: CCCN1[C@H](C)CN(c2ccc(Cl)c(C(F)(F)F)c2)C[C@@H]1C

Procedure:
Beginning with 5-bromo-2-chlorobenzotrifluoride and cis-2,6-dimethyl-1-propyl-piperazine, the title compound was recovered by the procedure described in Preparation 9: m.p. 256° C. (HCl), MS m/z (rel. intensity, 70 eV)) 335 (M+, 5), 305 (55), 112 (bp), 70 (67), 56 (82).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.Cl.[F:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1>>[F:11][C:5]1[CH:4]=[N:3][C:2]2[N:25]=[C:24]([CH2:23][O:22][CH2:21][CH2:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)[NH:26][C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: O=C(O)c1cc(F)cnc1F
Reactant: N=C(N)COCCc1cccc(F)c1
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(F)c2)nc2ncc(F)cc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,5-difluoropyridine-3-carboxylic acid and 2-[2-(3-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 101). Light brown solid. MS: m/e=318.2 [M+H+].
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH4+:15].[OH-]>C1COCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[S:11](=[O:13])(=[O:12])[NH2:15]
Reactant: [NH4+]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Temperature: 0 °C

Procedure:
2-Acetamido-4-methylthiazole-5-sulfonyl chloride (0.50 g, 1.96 mmol) was dissolved in THF (7 mL), cooled to 0° C., and concentrated NH4OH (0.7 mL) was added. After 3 hours the reaction was concentrated, diluted with water, and extracted with CHCl3/methanol. The organic layer was dried over Na2SO4. Filtration and concentration gave the product that was used Example 11B.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C:24]2=[O:29])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].C(O)CCC>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:13][CH2:14][N:16]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:2][CH2:3]2)=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(N)cc2)C1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: COc1ccc(N2CCN(c3ccc(N4CCN(C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 16.5 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 12.5 parts of 1-(4-aminophenyl)-3-methyl-2-imidazolidinone, 11 parts of sodium hydrogen carbonate and 240 parts of 1-butanol was stirred and refluxed for 24 hours. After cooling, 100 parts of water were added and the whole was stirred. The precipitated product was filtered off, washed with water and with 1-butanol and dried, yielding 17.5 parts (73%) of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2-imidazolidinone; mp. 240.9°-241.0° C. (28).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](O)[CH2:3]1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CN(C)C(N=NC(N(C)C)=O)=O>C1(C)C=CC=CC=1.CCCCCCC>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:3]1
Reactant: c1c[nH]cn1
Reactant: CC1(C)CC(O)c2ccccc21
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC1(C)CC(n2ccnc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,3-dimethyl-indan-1-ol (CAS#38393-92-9, 1.62 g, 1.0 mmol)] in toluene (30 mL) is added imidazole (1.36 g, 20.0 mmol) followed by tri-t-butylphosphine (2.5 mL, 10.1 mmol). The reaction is put at 0° C. and N,N,N′,N′-tetramethylazodicarboxamide (1.72 g, 10 mol) is then added. The reaction is permitted to stir for 10 minutes at 0° C. and then is heated at 60° C. over night. The next morning the reaction is diluted with heptane (30 mL) and filtered. The filtrate is extracted twice with 1 N aqueous HCl. The aqueous extracts are combined, washed with ethyl acetate and then basified (pH>10) by the careful addition of 5 N aqueous NaOH. The aqueous solution is then extracted three times with dichloromethane. The combined organic extracts are dried with Na2SO4. filtered and concentrated. The resulting residue is purified by semi-preparative reverse phase HPLC (15 to 85% acetonitrile/water w/0.1% NH4OH) to afford 1-(3,3-dimethyl-indan-1-yl)-1H-imidazole; HRMS: (ESI) m/z 213.1397 [(M+H)+; calcd for C14H17N2: 213.1392]; 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (s, 3 H), 1.42 (s, 3 H), 2.11 (dd, J=12.9, 8.3 Hz, 1 H), 2.57 (dd, J=12.9, 7.6 Hz, 1 H), 5.72 (t, J=8.1 Hz, 1 H), 6.86 (s, 1 H), 7.01 (d, J=8.3 Hz, 1 H), 7.09 (s, 1 H), 7.19-7.29 (m, 2 H), 7.35 (t, J=7.5 Hz, 1 H), 7.62 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-(3,3-dimethyl-indan-1-yl)-1H-imidazole.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:19][CH2:20][C@H:21]([C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])[CH2:22][OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:21]([CH2:20][O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H](COCc2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
p-Toluenesulfonyl chloride (1.4 g. 7.4 mmol) was added in one portion to a cold (ice/water bath) stirred solution of 4 (2.0 g, 6.16 mmol) in anhydrous pyridine (25 ml). The reaction was allowed to warm up to room temperature and stirred for 6 hrs until no starting material was found by HPLC analysis. Ethyl acetate (100 ml) and 10% citric acid (enough to neutralize pyridine) were added. The organic phase was washed with saturated NaCl, saturated NaHCO3 and dried over MgSO4. The crude tosylate 9 (2.9 g) was used in the next step without additional purification. 1H NMR (CDCl3): δ 7.80 (d, J=8.1 Hz, 2H). 7.40-7.25 (m, 7H), 4.41 (d, J=3.6 Hz, 2H), 4.25 (m, 1H), 4.11 (m, 1H), 3.98 (m, 1H), 3.45 (m, 2H), 2.45 (s, 3H), 1.96 (m, 1H), 1.12 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.036 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1cccc(F)c1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1cccc(F)c1
Reaction time: 20 h

Procedure:
From 3-fluorobenzyl alcohol (5.1 g; 40 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 20 h at 100° C. The yield was 1.04 g (72%). Mp 115–119° C.
Reaction SMILES: Br[C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[O:7]2.[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:15][C:6]1([CH3:16])[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([CH3:14])[C:10]([CH3:13])=[C:11]([OH:12])[C:2]=2[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=2)[O:7]1
Reactant: Cc1c(C)c2c(c(Br)c1O)CCC(C)(C)O2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: Cc1c(C)c2c(c(-c3cccc([N+](=O)[O-])c3)c1O)CCC(C)(C)O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2,2,7,8-tetramethyl-chroman-6-ol (400 mg, 1.40 mmol), 3-nitrophenyl boronic acid (300 mg, and Pd(PPh3)4 (100 mg, 5% mol) in glycol dimethyl ether (DME, 20 mL) and 2M Na2CO3 solution (5 mL) was stirred at 120° C. for 3-5 h. After pouring it into water, the mixture was extracted with EtOAc. The EtOAc layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 10% EtOAc in hexane to give a yellow solid (140 mg). 1H NMR (300 MHz, CDCl3): 8.25-8.16 (μ, 2H), 6.76 (μ, 2H), 4.13 (σ, 1H, OH), 2.27 (μ, 2H), 2.21, 2.19 (2σ, 6H), 1.68 (μ, 2H), 1.32 (σ, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 167.36, 148.79, 145.85, 143.34, 138.27, 136.95, 130.10, 126.51, 125.56, 122.76, 122.29, 115.84, 73.10, 32.83, 27.07, 26.71, 12.95, 12.24, 12.14 ppm. MS: m/z: 328 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C@@H:12]2[C@@H:17]3[CH2:18][C@@H:14]([CH:15]=[CH:16]3)[C@@H:13]2[C:19]([NH2:21])=[O:20])[C:5]([Cl:22])=[CH:4][N:3]=1>O1CCCC1.C(O)(=O)C.O.[Fe]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][C@@H:12]2[C@@H:17]3[CH2:18][C@@H:14]([CH:15]=[CH:16]3)[C@@H:13]2[C:19]([NH2:21])=[O:20])[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2C=C[C@@H]1C2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Temperature: 30 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
(1S,2S,3R,4R)-3-(2-Amino-5-chloro-3-nitro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100 mg, 0.3 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and acetic acid (1.6 mL). Powdered iron (121 mg, 2.162 mmol) was added and the mixture was stirred at 30° C. for four hours. Two drops of water was added and suspended solids were removed by filtration. The solid was washed with ethyl acetate (5 mL) and the combined filtrates were portioned between ethyl acetate and saturated sodium bicarbonate solution. The organics were extracted with ethyl acetate (3×25 mL), were dried (sodium sulfate) and were concentrated. Purification was effected via ISCO chromatography (12 g silica cartridge: gradient elution—0 to 15% MeOH:DCM) to afford 77 mg (80%) of the title compound as a tan solid. 1H NMR (d-chloroform): 7.49 (s, 1H), 6.18-6.20 (m, 4H), 6.09 (m, 1H), 4.51 (d, J=11 Hz, 1H), 4.09 (br s, 2H), 3.79 (d, J=9 Hz, 1H), 2.97 (s, 1H), 2.64 (s, 1H), 2.53 (d, J=8 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 2.06 (s, 1H), 1.66 (d, J=9 Hz, 1H). MS: 294.99 (M+H). HPLC retention time: 1.62 minutes (G Method).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C[N:23](C=O)C>>[Br:1][C:2]1[N:3]([CH2:12][CH2:13][CH2:14][CH3:15])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:23])[N:7]=[CH:6][N:5]=2
Reactant: Brc1nc2ncncc2[nH]1
Reactant: CCCCBr
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCCn1c(Br)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
8-Bromopurine (2.2 g, 10 mmole) was dissolved in 50 ml of DMF before adding 1-bromo-butane (2.2 ml, 20 mmol) and cesium carbonate (6.7 g, 20 mmol) into the solution. The reaction mixture was left stirring at room temperature for 16 hours before quenching with water and extracting with EtOAc. The organic layer was w ashed with water and dried with MgSO4 before removing solvent under reduced pressure. A white powder (0.9 g, 33%) of 8-Bromo-9-butyl-9H-purin-6-ylamine was isolated using silica gel column chromatography (50% EtOAc/Hexanes). 1H NMR (CDCl3) δ 8.32, (s, 1H), 5.81 (s, 2H), 4.20 (t, 2H), 1.82 (m, 2H), 1.40 (m, 2H), 0.96 (t, 3H). Rf (75% EtOAc/Hex)=0.6.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1.[OH-].[Na+]>[CH2:32]([N:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)N(Cc3ccccc3)Cc3ccccc3)cc2S(=O)(=O)N(C)C)CC1

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were added portionwise at room temperature, while stirring, to a solution of 22 g of dibenzylamine and 20 g of triethylamine in 0.2 l of tetrahydrofurane. Subsequently the reaction mixture was heated for another hour under reflux, and then the tetrahydrofurane was eliminated in vacuo. The amorphous residue was dispersed in 0.5 l of acetic ester and 0.5 l of 1N NaOH. The acetic ester phase was separated and was dried over magnesium sulfate. The acetic ester solution was then concentrated to half its volume and was mixed with the same volume of petroleum ether under heat. Upon trituration the final product crystallized and was suction-filtered after having been cooled with ice water for 1 hour.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)=O.C([NH:26][NH2:27])(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C(O)(=O)C.C(O)C>[C:11]([C:9]1[O:10][C:6]([C:4]2[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:27][N:26]=2)=[CH:7][CH:8]=1)([OH:13])=[O:12]
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2F)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1

Procedure:
2.5 g (11 mmol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid, 3.28 g (24 mmol) of benzhydrazide and 2 drops of glacial acetic acid in 50 ml of ethanol were heated under reflux for 10 h. The mixture was subsequently concentrated using a rotary evaporator and the residue was taken up in water, made alkaline using 2 N NaHCO3 solution and extracted with ethyl acetate. The aqueous phase was made acidic using 2 N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated using a rotary evaporator. The residue was dissolved in 25 ml of THF, 2.74 g (24.2 mmol) of potassium tert-butoxide were added and the mixture was stirred at reflux temperature for 1.5 h. After cooling, the mixture was concentrated using a rotary evaporator and the residue was taken up in 1 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The precipitate that resulted when the aqueous phase was acidified was filtered off with suction, washed with water and dried in a vacuum drying cabinet at 40° C. This gave 1.88 g (75%) of the title compound. m.p.: 205° C. (decomp).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32]OC1C=C2C(=CC=1)NC(C)=C2CC(O)=O.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:27][C:4]1[CH:5]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][C:15]=2[CH3:32])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: COc1ccc2[nH]c(C)c(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid in step 10 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 10 (B), the title compound was prepared. MS (ESI) (M+H)+=476.05 1H-NMR (300 MHz, CD3OD) δ 7.42 (s, 2 H), 7.18 (d, J=8.42 Hz, 1 H), 6.96 (d, J=2.56 Hz, 1 H), 6.64-6.84 (m, J=2.56 Hz, 1 H), 4.48 (s, 2 H), 3.88 (s, 2 H), 3.80 (s, 3 H), 2.40 (s, 3 H), 2.19 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:11]3=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[C:4]([F:21])[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:11]3=[C:10]([C:18]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([S:38](=[O:40])(=[O:39])[NH2:41])=[CH:34][CH:33]=3)=[O:20])[N:9]=2)=[C:4]([F:21])[CH:3]=1
Reactant: CN1CCn2c(-c3ccc(Cl)cc3F)nc(C(=O)O)c2C1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
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
Product: CN1CCn2c(-c3ccc(Cl)cc3F)nc(C(=O)Nc3ccc(S(N)(=O)=O)cc3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The carboxylic acid intermediate 18D (400 mg) and DIEA (600 μL) were dissolved in DMF (10 mL). An aliquot of this stock solution (400 μL) was dispensed into a vial charged with 4-aminobenzene-sulfonamide (0.10 mmol). TBTU was added (0.50 mmol) to the vial and the mixture was stirred at room temperature for 2 hours. The crude mixture was purified by prep LC-MS using a gradient elution of 5% to 95% MeCN/water in 15 min. The product was taken up with DCM and diluted with hexanes. Evaporation under nitrogen flow gave the desired product, Compound 208 as a solid. LCMS (+ESI) m/z 464 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH2:24]/[C:25](/[CH3:29])=[CH:26]\[C:27]#[N:28].C(O)(=O)C>CC(O)C>[C:27]([C:26]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[NH:24][C:25]=1[CH3:29])#[N:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: C/C(N)=C/C#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c(=O)cc(C)oc12
Temperature: 25 °C

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 69.1 mg (0.53 mmol) of ethyl 3-oxobutanoate, 43.6 mg (0.53 mmol) of 3-aminocrotononitrile and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 4 h. After cooling to room temperature, the crystallized product is filtered off and washed with 2-propanol and diethyl ether. 43 mg (22% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N([CH2:20][CH3:21])CC)C.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27]>C1(C)C=CC=CC=1>[P:2]([N:27]([P:2]([C:21]1[CH:20]=[CH:14][CH:9]=[CH:10][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:26][CH2:25][CH2:24][O:23][CH3:22])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCCCN
Reactant: CCN(CC)CC
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COCCCN(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 70.8 %

Procedure:
Chlorodiphenylphosphine (4.9 mL, 26 mmol, 2.5 equiv.) was dissolved in dry toluene (150 mL). Under an atmosphere of argon, an excess of triethylamine (8.0 mL, 58 mmol) was syringed into the reaction flask, which was stirred for 5 minutes. 3-Methoxypropylamine (1.1 mL, 11 mmol) was then syringed dropwise under argon. A precipitate immediately formed. The reaction mixture was then allowed to stir for 36 hrs at 110° C. The ammonium salt was filtered off and the solvent and the excess triethylamine and diphenylphosphine were removed in vacuo to leave a yellowish residue. The residue was passed through a silica gel plug using a CH2Cl2/petroleum ether (1:1) mixture as the eluent. Removing the solvent and triturating with petroleum ether afforded 3.564 g of a fine white powder in 75% yield. 1H NMR (RT, 300 MHz, CDCl3): δ=1.39 (2H, br tt, JHH=8.1 Hz, JHH=6.3 Hz, CH2), 3.03 (2H, t, JHH=6.3 Hz, CH2O), 3.10 (3H, s, OCH3), 3.27-3.44 (2H, m, NCH2), 7.28-7.46 (20H, m, ArH). 31P NMR (RT, 121 MHz, CDCl3): δ=63.1 ppm (s). MS (FAB+): 458 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][CH2:14][C@@H:15]([CH3:18])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][C@H:15]([CH3:18])[CH2:14][Br:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: C[C@@H](CO)CBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(OC[C@H](C)CBr)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.75 g, 0.0045 mol) in anhydrous toluene (30 mL) was added (S)-(+)-3-bromo-2-methyl-1-propanol (0.90 g, 0.0059 mol). Polymer bound triphenylphosphine (2.4 g, 0.0072 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture was stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.1 g, 0.0056 mol) was added in a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered, and the solid washed with toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 0.86 g (63% yield) of the title compound as an oil: MS (ESI) 303.0 (M+2H+).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH:16]([OH:17])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 3-bromopyridine (286 μl, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution thus obtained was added dropwise 2,5-difluorobenzaldehyde (328 μl, 3 mmol) under ice cooling. The temperature of the reaction mixture was gradually raised to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The solvent was then dried. The residue remaining after concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (296 mg, 45%) as needle crystals.