Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH:32]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][C:36]=1[F:42].CC(O)=O>CCOC(C)=O.ClCCCl>[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][CH2:32][C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[N:26][CH:27]=2)=[CH:37][C:36]=1[F:42]
Reactant: COC(=O)c1ccc(-c2cc(F)ccc2C=O)cn1
Reactant: Nc1ccc(Br)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc(-c2cc(F)ccc2CNc2ccc(Br)c(F)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (491 mg, 2.3 mmol) was added to a DCE solution (4 mL) of methyl 5-(5-fluoro-2-formylphenyl)picolinate (300 mg, 1.2 mmol), 4-bromo-3-fluoroaniline (242 mg, 1.3 mmol), and AcOH (0.27 mL, 4.6 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+].[S:8](=O)(=[O:11])([OH:10])[O-:9].[NH4+].N>O>[S:1]([O:5][S:8]([O-:11])(=[O:10])=[O:9])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+:6]
Reactant: O=S(=O)([O-])O
Reactant: O=S(=O)([O-])[O-]
Agent: N
Agent: [NH4+]
Solvent: O
Product: O=S(=O)([O-])OS(=O)(=O)[O-]

Procedure:
Halstead (J. Appl. Chem., 1970, 20:129-132) describes the decomposition of ammonium sulfate at 400° C. The first reaction converts ammonium sulfate to ammonium bisulfate and ammonia. In a second reaction, the ammonium bisulfate dehydrates to form a water molecule and ammonium pyrosulfate, (NH4)2S2O7. Further heating of the ammonium pyrosulfate to form sulfur dioxide and nitrogen, which are not desired products from ammonium sulfate, is also carried out.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:12][N:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC(F)(F)c1ccc(-n2nnnc2CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (613 mg, 1.486 mmol, Intermediate 15) in methanol was added 4M hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 1 hour.
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1.Br[CH:15]([C:20]1[CH:28]=[C:27]([O:29][CH3:30])[C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)C>[Br:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]([C:20]3[CH:28]=[C:27]([O:29][CH3:30])[C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: COC(=O)C(Br)c1cc(OC)c2c(c1)OCO2
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C(c1cc(OC)c2c(c1)OCO2)c1c[nH]c2cc(Br)ccc12
Yield: 88.9 %

Procedure:
Methyl magnesium bromide (3.6 ml of 3M solution in diethyl ether) was added dropwise to a stirred solution of 6-bromo-indole (2.13 g, 10.9 mmol) in toluene (20 ml) under a nitrogen atmosphere. After 20 minutes the reaction mixture was transferred via a cannula, over ˜10 minutes, to a stirred solution of methyl 2-bromo-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (from step (b), 2.2 g, 7.26 mmol) in toluene (20 ml) at ambient temperature. After a further 2 hours the mixture was poured into a mixture of diethyl ether and aqueous ammonium chloride. The organic layer was separated and dried (magnesium sulphate), and the solvent was removed in vacuo. The residue was flash chromatographed using dichloromethane as eluant to give the subtitle compound (2.7 g).
Reaction SMILES: Br[CH:2]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[O:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]1[CH2:30][C:31](=[S:33])[NH2:32].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:32]=[C:31]([CH2:30][N:21]2[C:20](=[O:19])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:29])[S:33][C:2]=1[S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=S)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(c1ccccc1F)C(Br)Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2F)c(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of 2-bromo-1-(2-fluorophenyl)-2-(phenylthio)ethanone (496 mg) in N,N-dimethylformamide (5 mL) was added 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanethioamide (357 mg), and the mixture was stirred at room temperature for 12 hr. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 351 mg, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:28][C:29]([O:31]CC)=[O:30])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:28][C:29]([OH:31])=[O:30])=[CH:18][CH:17]=3)=[CH:34][CH:35]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 16.9 %

Procedure:
Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetate (10 mg, 0.0195 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.0389 ml, 0.195 mmol) and 200 μL of water. After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetic acid (1.6 mg, 16.9% yield) as a white solid. MS ESI negative M−H=485.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8](CC=C)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1.C(O)=O.C(N(CC)CC)C>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>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[NH:8][C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OC)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 200 mg (0.65 mmol) of the compound from Example 214A, 49 μl of formic acid (1.3 mmol), 226 μl of triethylamine (1.63 mmol) and 38 mg of tetrakis(triphenylphosphine)palladium(0) (32 μmol) are dissolved in 2 ml degassed dioxan and stirred overnight at reflux temperature. To dissolve the precipitated solid, the reaction mixture is diluted with 20 ml of methanol after cooling to RT. The palladium catalyst is filtered off and the filtrate freed of the volatile components on the rotary evaporator. The residue is stirred with 5 ml acetonitrile and then suction-filtered. The solid is washed with acetonitrile and dried under high vacuum. It corresponds to the title compound with a purity of ca. 76% (130 mg, 57% of theory) and is used in the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cc(O)c1

Procedure:
To a solution of 3,5-dihydroxybenzoic acid (30.0 g) in methanol (300 mL) was added dropwise thionyl chloride (20 mL) at 0° C., and the mixture was heated under reflux for 2 hr. The reaction mixture was concentrated, and the obtained crystals were washed with diethyl ether to give the title compound (30.0 g) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:27]C(=O)C)([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[OH:8])[CH3:2]
Reactant: CCN(CCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CCCCC(C)(C)O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 24 h
Yield: 35 %

Procedure:
A stirred mixture of the product from Example 25 (0.92 g, 2.08 mmol) and 17.2 mL of a solution of potassium carbonate (5 g) in MeOH (80 mL) and water (20 mL) was refluxed, under nitrogen for 24 h. An additional 17.2 mL of the potassium carbonate solution was added and reflux was continued for 24 h. The mixture was then concentrated to remove MeOH and the aqueous residue was adjusted to pH 8 and washed with EtOAc. The aqueous solution was then concentrated to dryness, and the solid residue was extracted with CH2Cl2. This extract was concentrated and the residue was chromatographed on silica gel with 10% MeOH--1% NH4OH-CHCl3 to give 0.292 g (35.1%) of the titled product, a compound of Formula I': NMR (CDCl3) δ1.09 (t, 3H), 1.21 (s, 6H), 1.53 (m, 9H), 1.97 (m, 1H), 2.55 (m, 6H), 2.94 (s, 3H), 4.61 (m, 1H), 7.15 (d, 2H), 7.35 (d, 2H); MS m/z (relative intensity) 400 (M+, 17.4), 385 (14.5), 367 (11.1), 321 (36.6), 299 (92.8), 172 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CCN(CC)CC.ClC(Cl)(Cl)[C:24](Cl)=[O:25].[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]>C(Cl)Cl>[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:24]([C:8]2[N:7]([CH2:6][C:5]3[CH:12]=[CH:13][CH:14]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:11]=[CH:10][N:9]=2)=[O:25])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc(Cn2ccnc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Cn2ccnc2C(=O)NC2CCN(C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-methoxy-benzyl)-1H-imidazole (100 mg) and NEt3 (147 μL) in DCM (5 mL) was added trichloroacetyl chloride (106 μL) dropwise. The mixture was stirred for 2 h at RT. More NEt3 (147 μL) and 1-isopropyl-piperidin-4-ylamine (76 mg) were added and stirring was continued for 1 h at RT. The mixture was quenched by the addition of MeOH, concentrated and the residue was purified by preparative HPLC. The fractions containing the product were evaporated to provide 30 mg of the title compound as its trifluoroacetate salt. MS (ESI+): m/e=357.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Br.[Br:13][CH2:14][CH2:15][NH2:16].O1CCOCC1.Br.BrCCN.[OH-].[Na+]>O.O1CCOCC1>[Br:13][CH2:14][CH2:15][NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution prepared by adding 1,4-dioxane (50 mL) to benzyl chloroformate (17.5729 g; manufactured by Wako Pure Chemical Industries, Ltd.), an aqueous solution of 2-bromoethanamine hydrobromide-1,4-dioxane [104 mL; solution prepared by dissolving 2-bromoethanamine hydrobromide (21.3617 g; manufactured by Tokyo Chemical Industry Co., Ltd.) in water (54 mL) and 1,4-dioxane (54 mL)]and a 2 mol/L aqueous solution of sodium hydroxide (104 mL; manufactured by Kanto Chemical Co., Inc.) were simultaneously added dropwise. The mixture was stirred for 2 hours at 0° C. Water was added to the reaction solution, and the mixture was extracted two times with ethyl acetate. The organic layer was washed with a saturated solution of sodium hydrogen carbonate, and was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=94:6→73:27), and thus the title compound (19.2014 g) was obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C:12]2=[O:17])=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27]([N:14]3[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:5]4[CH:6]=[CH:7][N:2]=[N:3][CH:4]=4)[C:12](=[O:17])[CH2:13]3)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1
Reactant: O=C1CNCCN1CCNc1ccnnc1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CCNc1ccnnc1
Yield: 50 %

Procedure:
1-[2-(Pyridazin-4-ylamino)-ethyl]-piperazin-2-one hydrochloride (0.5 g, 1.7 mmol), EXAMPLE 95, is reacted with 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (0.40 g, 1.5 mmol), EXAMPLE 1, using essentially the same procedure as described in EXAMPLE 719. Reverse phase HPLC purification gives the title compound (0.34 g, 0.75 mmol) as a white solid. MS m/z (M+H=452); 1H NMR (CD3OD, 300 MHz) δ8.6 (d, 1H), 8.4 (d, 1H), 8.05 (s, 1H), 8.05 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 3.8 (s, 2H), 3.4-3.7 (m, 8H).
Reaction SMILES: CC([CH:5]1[CH:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[N:23][C:22]([NH2:25])=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[N:20]=3)[CH:14]=2)=[O:12])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:22]1[C:21]([C:26]([NH:28][CH3:29])=[O:27])=[N:20][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C@@H:9]3[CH2:8][CH2:7][NH:6][CH2:5]3)=[O:12])[CH:14]=2)=[CH:24][N:23]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)NC3CCN(C(=O)[O-])C3C(C)(C)C)c2)cnc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1nc(-c2cccc(C(=O)N[C@@H]3CCNC3)c2)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
1,1-dimethylethyl-3-{[(3-{5-amino-6[(methylamino)carbonyl )pyrazin-2-yl}phenyl}carbonyl}amino}pyrrolidine-1-carboxylate (0.7 g, mmol) was suspended in dichloromethane (4 mL) and TFA (3 mL) was added. The mixture was stirred at ambient temperature for 2 hr. After removal of volatiles under reduced pressure, the residue was partitioned between saturated solution K2CO3 (300 mg) and dichloromethane (10 mL). The organic layer was separated, dried (Na2SO4) and evaporated to dryness to afford 0.4 g (74% yield) of 3-amino-N-methyl-6-(3-{[(3R)-pyrrolidin-3-ylamino]carbonyl}phenyl) pyrazine-2-carboxamide. 1H NMR (400 MHz; DMSO-D6): 8.9 (s, 1H); 8.85 (m, 1H); 8.71 (d, 1H); 8.48 (m, 1H); 7.4 (d, 1H); 7.84 (d, 1H); 7.6 (t, 1H); 4.54 (m, 2H); 3.6-3.18 (m, 4H); 2.85 (d, 3H); 2.25 (m, 1H); 2.1 (m, 1H); MS (EI) for C17H20N6O2: 341 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[CH:3]=1.[N:11]([O-])=[O:12].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N:11]=[O:12]
Reactant: O=N[O-]
Reactant: Cc1cc(N)n(CCO)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(CCO)c(N)c1N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
5-Amino-1-(2-hydroxyethyl)-3-methylpyrazole (Bull. soc. chim. France, 255 (1975)) (1.41 g, 10 mmoles) was dissolved in a mixture of water (7 ml) and glacial acetic acid (1.4 ml). Sodium nitrite (0.8 g, 11.6 mmoles) in water (7 ml) was added dropwise over 0.5 hour at 0° C. The red solution was stirred at 0° C., and after 1 hour, the solid which had precipitated was filtered off and dried in vacuo giving the title compound as a red solid (1.2 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24](Br)[C:23](O)=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37].C([O-])([O-])=[O:42].[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19]([C:20]1[CH:21]=[C:22]([C:33]2[CH:34]=[CH:35][C:36]([F:37])=[C:31]([Cl:30])[CH:32]=2)[CH:23]=[CH:24][C:25]=1[OH:42])=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(O)c(Br)c1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound 3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic acid methyl ester in 2.0 mL of DME were added 52.0 mg (0.3 mmol) of 3-chloro-4-fluorophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (DCM) to give 35 mg (70%) of title compound LC/MS (m/z): 490 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([O-:3])=[O:2].C([O-])(C)(C)C.[K+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:39]([O:38][C:36]([CH2:35][N:17]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:37])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)Nc2c([N+](=O)[O-])cc([N+](=O)[O-])c3ccccc23)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
60 g (155 mmol) of N-(2,4-dinitro-1-naphthyl)-4-methylphenylsulfonamide (J. Soc. Chem. 1935, 1855) were dissolved in 500 ml of anhydrous dimethylformamide under protective gas and 19.1 g (170 mmol) of potassium tert-butanolate were added a little at a time. The mixture was stirred at room temperature for about 30 minutes, and then 25.9 g (155 mmol) of ethyl bromoacetate dissolved in 50 ml of anhydrous dimethylformamide were added dropwise. The mixture was then heated at 100° C. for 90 minutes and, after cooling, poured into ice-water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was heated with a mixture of 50 ml of toluene and 100 ml of ethanol and the resulting crystals were filtered off with suction to yield 55.7 g (76%) of the product. Melting point 106°-107° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:21]C(OC(C)(C)C)=O)[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([C@:6]1([NH2:21])[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
Dissolve (1S,2S,4S,5R,6R)-4-acetyloxy-2-(tert-butoxycarbonyl)aminobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.25 g, 3.13 mmol, Preparation 19) in a solution of 95% TFA in dichloromethane (60 mL) and stir under nitrogen at room temperature for 5 minutes. After this time remove the TFA/dichloromethane in vacuo. Dissolve the crude product in a suspension of NaHCO3 (1.00 g) in dichloromethane (50 mL) and stir for 30 minutes. Filter the suspension, wash with dichloromethane (3×25 mL), and concentrate in vacuo to afford 916 mg (98%) of the product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.O.[H-].[Na+].[CH3:22]OS(OC)(=O)=O>OS(O)(=O)=O.CN(C=O)C>[Br:1][C:2]1[C:3]2[C:11](=[O:13])[C:10]3[C:9](=[CH:17][C:16]([Cl:18])=[CH:15][CH:14]=3)[N:8]([CH3:22])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cc1Nc1cccc(Br)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2cc(Cl)ccc2c(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
(Method E-3) 2-(3-Bromo-phenylamino)-4-chlorobenzoic acid, 14 (4 g, 12.2 mmol) was heated in conc. H2SO4 (50 ml) for 30 min then allowed to cool to room temperature. Water was added slowly and the precipitate filtered off, washed with water and dried over phosphorous pentoxide. The crude material was suspended in DMF (50 mL) and added under nitrogen to NaH (1.2 g, 50 mmol) in DMF (50 mL). After 30 min dimethylsulphate (3 ml, 18 mmol) was added and stirring continued for 1 hr. Addition of water gave a precipitate the title compound (625 mg, 2.02 mmol, 17%) as the more polar product after separation by column chromatography (ethyl acetate:hexane 1:4)
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[Br:33][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: c1ccc(-c2nc(-c3ccccn3)cc(-c3c4ccccc4cc4ccccc34)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2cc(-c3ccccn3)nc(-c3ccccc3)n2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Dissolving 12 g (30 mmol) of 4-anthracen-9-yl-2-phenyl-6-pyridine-2-yl-pyrimidine obtained in the foregoing step (2) into 100 milliliter of N,N-dimethylformamide, and adding 5.9 g (33 mmol) of N-bromosuccinimide, stirred at room temperature for 8 hours. After completion of the reaction, precipitated solids were separated by filtration and washed with water and methanol, thereby obtaining 10.8 g of 4-(10-bromo-anthracen-9-yl)-2-phenyl-6-pyridine-2-yl-pyrimidine (yield: 73%).