Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(C(=O)OC)cc1
Yield: 53 %

Procedure:
Alkylation of 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step A) with methyl 4-(bromomethyl)benzoate was carried out according to the procedure of Example 13, Step A. Purification of the crude product by flash chromatography on silica gel (gradient elution with 0.3-1% MeOH in CH2Cl2) provided a 53% yield of the title compound as a clear, glassy solid; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 434 (M+1)+.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[CH2:5]([P:8]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:28]=[C:27](I)[N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3[CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:15][CH:14]=1)([CH2:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH3:7].CCOC(C)=O>CN(C=O)C.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:5]([P:8]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:28]=[C:27]([CH:1]([CH3:3])[CH3:2])[N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3[CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:15][CH:14]=1)([CH2:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH3:7]
Reactant: CC(C)I
Reactant: CCCP(=O)(CCC)c1ccc(Nc2nc(I)nc3c2ncn3C2CCCCO2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(C(C)C)nc3c2ncn3C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a oven-dried 10 mL round bottom flask was transferred under Ar 2.88 mL Rieke Zinc (0.14 g Zn, 2.2 mmol, 5 g/100 mL THF) using a 12 gauge needle. Then isopropyl iodide (200 □L, 2 mmol) was added via syringe. The solution turned warm and the content was stirred at rt for 3 h. In a separate flask (25 mL) was dissolved N-(4-(dipropylphosphoryl)phenyl)-2-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.28 g, 0.5 mmol) and PdCl2(PPh3)2 (0.035 g, 0.05 mmol) in 4.0 mL dry DMF. The Zinc reagent was transferred to the reaction via a syringe. The reaction mixture was stirred at rt overnight. 20 mL EtOAc/20 mL water was added to the reaction mixture and the content was filtered through Celite, washed with 1% MeOH/EtOAc (30 mL). The organic layer was separated and washed with water, brine, and dried Na2SO4. The final product was purified on silica gel (4-7.5% MeOH/DCM).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (Compound 101, 0.58 g, 2 mmol) in toluene (10 ml) was added phenylisocyanate (0.22 ml, 2 mmol). The reaction mixture was heated for 20 hours on a steam bath. After cooling the reaction mixture to room temperature the resulting precipitate was collected by filtration and washed with toluene. The crude product was dissolved in hot isopropanol and crystallized on the addition of water to afford the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][C:30]=1[O:39][CH3:40]>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([NH:11][C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([NH:2][S:35]([C:32]3[CH:33]=[CH:34][C:29]([OH:28])=[C:30]([O:39][CH3:40])[CH:31]=3)(=[O:37])=[O:36])[CH2:4][CH2:5]2)=[O:10])[CH3:13])=[CH:15][CH:16]=1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1O
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](N)CC1)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-4-Amino-N—((R)-1-(4-fluorophenyl)ethyl)cyclohexanecarboxamide hydrochloride (Intermediate 45, 200 mg, 0.66 mmol) and Et3N (371 ul, 2.66 mmol) were dissolved in DCM (10 ml). 4-Hydroxy-3-methoxy-benzenesulphonyl chloride (178 mg, 0.798 mmol) was added, and the reaction mixture was stirred for 3 hr at room temperature, after which LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo, and the crude material was purified via reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA). Fractions containing the product were lyophilized to yield the title compound as a white solid (14 mg, 0.031 mmol). MS MH+ 451.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([C@@H](C3C=CC=CC=3)C)[CH2:14]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>ClCCl>[CH2:30]([O:29][C:27]([N:15]1[CH2:16][CH2:17][CH:13]([CH2:12][C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]2)[CH2:14]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1CCC(CC2(NC(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CC2CCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
3-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (1.234 g, 3.582 mmol) was dissolved in dry dichloromethane (20 ml) to which, under ice cooling, was subsequently added dropwise benzyl chloroformate (1,278 μl, 8.955 mmol). After 8 hours of stirring at room temperature, the reaction solution was concentrated under a reduced pressure. The thus obtained residue was subjected to a flash silica gel chromatography, and 959 mg (71.5%) of the title compound was obtained from an eluate of n-hexane:ethyl acetate=2:1 as a colorless oil component.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21]>C1(C)C=CC=CC=1>[Br:21][C:16]1[CH:17]=[CH:18][C:19]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:15]=1
Reactant: Brc1ccccc1Br
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 37.5 %

Procedure:
In a two-neck round bottom flask, diphenylamine (50 g, 0.30 mol), dibromobenzene (104 g, 0.44 mol), BINAP[2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl] (7.4 g, 4% mol), Pd(OAc)2[Palladium(II)acetate] (2.0 g, 3% mol), and NaOtBu[Sodium tert-butoxide] (42.6 g, 0.44 mol) are dissolved in toluene (400 mL), and then are maintained for 24 hours by reflux. On completion of the reaction, the flask having the resultant solution is cooled, and then toluene, a solvent of the reaction, is removed from the resultant solution. After that, the resultant solution having no toluene reacts on methylene-chloride and water, and then methylene-chloride is removed therefrom, and is performed by silica gel column chromatography with a solvent of methylene-chloride and hexane at a ratio of 3 to 1. After that, the solvent is removed from the resultant solution of completing silica gel column chromatography, and is recrystallized and filtered with methylene-chloride and petroleum ether, thereby obtaining a white solid, (4-bromo-phenyl)-diphenyl-amine (36.5 g, 40%).
Reaction SMILES: Cl.[CH3:2][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:17]1[O:18][C:19]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:26][C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([N:9]3[CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH3:2])[CH2:11][CH2:10]3)[O:18][C:19]=2[CH:25]=1
Reactant: CC(=O)NC(C)CCC1CCNCC1
Reactant: Oc1ccc2nc(Cl)oc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)CCC1CCN(c2nc3ccc(O)cc3o2)CC1
Yield: 77 %

Procedure:
A solution of N-[1-methyl-3-(piperidin-4-yl)propyl]acetamide hydrochloride (500 mg), 2-chloro-1,3-benzoxazol-6-ol (361 mg) and N,N-diisopropylethylamine (826 mg) in DMF (15 mL) was stirred at 100° C. for 10 hr. The reaction mixture was allowed to cool, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate/THF mixed solvent (10/1), and the solution was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (543 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].C1(C)C=CC(S([CH2:22][N+:23]#[C-:24])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[C:6]1[O:7][CH:24]=[N:23][CH:22]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1cnco1

Procedure:
To a solution of 2-nitro-4-chlorobenzaldehyde (2.2 g, 11.8 mmol) and p-toluenesulfonyl-methylisocyanide (2.8 g, 14.2 mmol) in methanol (50 mL) was added potassium carbonate (8.2 g, 59 mmol) solid. The heterogeneous mixture was heated to reflux for 2.5 hours. Upon moving to room temperature, the reaction was filtered and concentrated in vacuo. The residue was dissolved in 0.1N sodium hydroxide and extracted with methylene chloride two times. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give crude 5-(2-nitro-4-chlorophenyl)oxazole.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O>C(Cl)Cl>[OH:1][C:2]1[C:9]([Br:15])=[C:8]([Cl:10])[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)c1cc(C=O)c(O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c(O)c(Br)c1Cl
Yield: 81.3 %

Procedure:
A solution of 1.84 g (8.65 mmol) of 2-hydroxy-4-chloro-5-(1,1-dimethylethyl)benzaldehyde and 1.85 g (10.4 mmol) of N-bromosuccinimide in 30 ml of methylene chloride was stirred overnight at ambient temperature. The solvent was evaporated and the residue was partitioned between water and hexane. The organic phase was dried and evaporated. The residue was chromatographed on 150 g of silica gel using a gradient from 1:99 to 5:95 (v/v) of ether:hexane as eluent. There was obtained 2.05 g (7.03 mmol, 81%) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde after crystallization from hexane; mp 92°-94° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[NH:5][C:6](=[O:26])[N:7]2[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.CO>[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[NH:5][C:6](=[O:26])[N:7]2[CH2:17][CH2:18][CH2:19][N:20]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCN(C)C)c2n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCN(C)C)Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
The product from step (iii) (0.1 g) and benzaldehyde (0.0362 g, 0.0347 ml) were combined in NMP (4 mL) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (0.0904 g) was added. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with methanol and purified by RP-prep-HPLC 75:05 NH3:acetonitrile over 15 mins to give title compound (0.068 g)
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=O)[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].P(Cl)(Cl)[Cl:21]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:21][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: ClP(Cl)Cl
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Reaction time: 5 h

Procedure:
Benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (26 mg, 0.1 mmol) in anhydrous DMF (0.5 ml) containing PCl3 (27 mg, 0.2 mmol) is kept at 25° C. for 5 hrs. The mixture is diluted with toluene (5 ml), washed with H2O (5×1 ml) 5% HCl (2 ml), 5% NaHCO3 (2 ml) and brine, dried with MgSO4, and filtered. Evaporation of the solvent in vacuo provides crude benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: CC1C=C[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.Br[C:17]1[C:18](C(O)=O)=[N:19]C=C[CH:22]=1.ClC1N=C(C)C=CC=1C(O)=O>>[N:15]1[N:11]([C:4]2[C:5]([C:6]([OH:8])=[O:7])=[N:19][CH:18]=[CH:17][CH:22]=2)[N:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Reactant: O=C(O)c1ncccc1Br
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1ncccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 70 substituting 3-bromo-2-pyridinecarboxylic acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C8H6N4O2, 190.10; m/z found 191.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.77 (d, J=4.3 Hz, 1H), 8.26 (dt, J=6.5, 3.3 Hz, 1H), 7.88 (s, 2H), 7.65 (dd, J=8.2, 4.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[CH3:31])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Yield: 52.7 %

Procedure:
A solution of 0.57 g (1.67 mmol) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonyl chloride and 0.61 g (3.34 mmol, 2 eq) of sarcosine t-butyl ester hydrochloride in 0.51 mL of pyridine and 15 mL of chloroform was allowed to react overnight at room temperature. The reaction was concentrated in vacuo, diluted with water/ethyl acetate, neutralized with NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford a yellow oil which was purified via flash chormatography using 6:1 hexane: ethyl acetate to afford 0.396 g (53%) of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetate as a white solid. Electrospray Mass Spec 450.4 (M+H)+
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.Br.C([N:29]1[CH2:37][CH2:36][C:35]2[CH2:34][NH:33][CH2:32][C:31]=2[CH2:30]1)C1C=CC=CC=1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:32][C:31]5[CH2:30][NH:29][CH2:37][CH2:36][C:35]=5[CH2:34]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ccc(CN2CCC3=C(CNC3)C2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNCC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 60.9 %

Procedure:
0.3 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.6 g of 3-benzyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene hydrobromide were suspended in 30 ml of acetonitrile. 0.6 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added to the suspension. The reaction mixture was refluxed for 5 hours and then kept overnight at room temperature. The produced precipitate was filtered and dissolved in 30 ml of 5% acetic acid in ethanol. After adding 0.5 g of 10% Palladium charcoal, the reaction mixture was stirred under hydrogen stream for 6 hours and then filtered. The filtrate was concentrated under reduced pressure. 0.25 g of the title compound (yield 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][CH2:15][C:16]([O-])=[O:17]>>[CH3:21][O:20][C:13](=[O:19])[CH2:14][CH2:15][C:16](=[O:17])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: COc1cccc(OC)c1OC
Product: COC(=O)CCC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 72.7 %

Procedure:
A mixture of 75 g of polyphosphoric acid (Acros), 1,2,3-trimethoxybenzene (5.0 g, 29.73 mmol), and mono-methyl succinate (5.9 g, 44.59 mmol) were mechanically stirred at 45° C. for 2.5 h. The reaction mixture was then poured into a 1000 mL beaker containing round 250 mL of ice, and stirred well until all the product was precipitated out. The tan colored product was then filtered and washed with water and dried under vacuum. 6.1 g (72%) of 55 was obtained, which was pure by NMR.
Reaction SMILES: [CH:1]1[C:14]2[C:5]3=[C:6]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:15][C:4]3=[CH:3][CH:2]=1.[H][H]>CCO.[Pd]>[CH:10]1[C:11]2[CH2:12][CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[C:4]4[CH2:15][C:7]([C:6]=2[C:5]=34)=[CH:8][CH:9]=1
Reactant: c1cc2c3c(c1)ccc1cccc(c13)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Yield: 85 %

Procedure:
10.0 g (52.6 mmol) of 4H-cyclopenta[def]phenanthrene and 8.40 g of 5% Pd/C were dissolved in 70 ml of EtOH in a Par reactor bottle, and the resultant solution was stirred at room temperature for 24 hours with hydrogen pressure being maintained at 40 psi. After the reaction was completed, the reaction solution was filtered and the solvent was evaporated therefrom to obtain 8.60 g of white target material (yield: 85.0%). The obtained compound was confirmed by liquid chromatography-mass spectrometry (LC-MS).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([Br:13])=[CH:5][C:6](Br)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].O=O.Cl>[Cu-]=O.C(OCC)(=O)C>[Br:13][C:4]1[CH:5]=[C:6]([NH2:1])[C:7](=[CH:11][C:3]=1[Cl:2])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc(Cl)c(Br)cc1Br
Reactant: N
Agent: O=[Cu-]
Agent: Cl
Agent: O=O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)c(Cl)cc1C(=O)O
Reaction time: 0.67 h
Yield: 96.2 %

Procedure:
2.8 g (0.0196 mol) of copper(I) oxide are suspended in 120 ml (corresponding to 1.6 mol of NH3) of 25% aqueous ammonia solution under nitrogen. To this is added dropwise, at 25° C. with stirring and over the course of 40 minutes, a suspension of 63.2 g (0.2 mol) of 5-chloro-2,4-dibromobenzoic acid, 160 ml (corresponding to 2.14 mol of NH3) of 25% strength aqueous ammonia solution and 180 ml of ethyl acetate, with the exclusion of oxygen. The temperature rises to about 35° C. during the addition. Stirring is continued for 21/4 hours at30° C. Finally, 11.6 g (0.04 mol) of ethylenediaminetetraacetic acidis added to the mixture and the pH is adjusted to 3.1 by acidifying with hydrochloric acid. The ethyl acetate is distilled off at 90° C., the suspension is stirred at room temperature, and the anthranilic acid isfiltered off under suction and washed. 48.2 g of 4-bromo-5-chloroanthranilic acid is obtained as a pale-brown powder, corresponding to 96.2% of theory relative to 5-chloro-2,4-dibromobenzoic acid.
Reaction SMILES: [CH:1]([CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:4](OC)=O)=[O:2].Cl.[CH:19]([NH2:21])=[NH:20].C(N(C(C)C)C(C)C)C>C(O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:3]2[C:1](=[O:2])[NH:21][CH:19]=[N:20][CH:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: N=CN
Reactant: COC(=O)C(C=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc[nH]c2=O)cc1OC
Yield: 23 %

Procedure:
Methyl 2-formyl-2-(3,4-dimethoxyphenyl)acetate (7.2 g) (30 mmol), 4.8 g (60 mmol) of formamidine hydrochloride and 7.74 g (60 mmol) of N-ethyldiisopropylamine (Hunig base) are stirred in 60 ml of ethanol for 55 hours at 50° C. and subsequently concentrated in a vacuum. The residue is washed several times with diethyl ether and then crystallized using ethanol/diethyl ether. The yellowish product is filtered off under suction, washed with ethanol/diethyl ether and dried in a high vacuum at room temperature. There are obtained 1.6 g of 5-(3,4-dimethoxyphenyl)-4(3H)-pyrimidinone of m.p. 205°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:50][CH2:49][CH:46]1[O:45][C:44]2[CH:51]=[C:40]([O:39][CH3:38])[CH:41]=[CH:42][C:43]=2[O:48][CH2:47]1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccc(F)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
5-Fluoroindole-3-butyric acid (1.2 g, 5.4 mmole), 1-hydroxybenzotriazole hydrate (0.88 g, 6.5 mmole) and 1,3-diisopropylcarbodiimide (2.0 ml, 13.0 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 5.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (56%) of the desired product, (7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3-yl)-butanamide, as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:29]=[N:28][NH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3cn[nH]c3)cc21
Product: CC1c2cc(-c3cn[nH]c3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.