Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[NH:17][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]C(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[N:17]([CH3:22])[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(N2CCN(Cc3ccccc3)CC2)c2sccc21
Temperature: -30 °C

Procedure:
To a stirred solution of 3-(4-benzyl-piperazin-1-yl)-1H-thieno[3,2-c]pyrazole (318.0 g, 1.07 mol) in THF (2.5 L) was added a mixture of potassium t-butoxide (134.4 g, 1.2 mol) in THF (1.5 L) dropwise over a period of 1 hour while keeping the reaction temperature below 25° C. After complete addition, the mixture was cooled to −30° C. and Mel (65.4 mL, 1.05 mol) was added dropwise over a period of 30 minutes. The mixture is then slowly warmed to room temperature overnight. To the reaction mixture is slowly added saturated NaHCO3 (1 L). The solution is then evaporated to remove the THF and the resulting aqueous mixture is taken up in EtOAc and washed with water and brine. The EtOAc extract is dried (Na2SO4), filtered and evaporated. The viscous concentrate is filtered through a silica gel plug with 1:1 EtOAc/heptane and evaporated yielding a viscous oil that is then dried under vacuum where it solidifies and yields 326.03 g (98%) as a 12:1 ratio of regioisomers in favor of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.FC1C=CC(C=O)=CC=1.[CH3:16][O:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35](N4C=CN=C4C)=[CH:34][CH:33]=3)[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:16][O:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:34][CH:33]=3)[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Cc1c[nH]cn1
Reactant: COC1(c2cccc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Agent: O=Cc1ccc(F)cc1
Product: COC1(c2cccc(OCc3ccc(-n4cnc(C)c4)cc3)c2)CCOCC1

Procedure:
The title compound was prepared using 4-methylimidazole and 4-fluorobenzaldehyde according to the procedure as described for 4-methoxy-4-[3-[4-(2-methylimidazol- 1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran (Example 2).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][C:13]([OH:15])=O)=[CH:3]1.C1(=O)O[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C([O-])(=O)C.[Na+]>O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:12]=[C:13]2\[O:15][C:19](=[O:20])[C:18]3[C:22]\2=[CH:23][CH:24]=[CH:25][CH:17]=3)=[CH:3]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cccc2c1c(CC(=O)O)cn2C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c1c(/C=C1\OC(=O)c3ccccc31)cn2C
Temperature: 200 °C

Procedure:
A reaction flask equipped with a nitrogen line and a stir bar is charged with (1,4-Dimethyl-1H-indol-3-yl)-acetic acid (0.5 g, 2.4 mmol), 0.3 g (2.4 mmol) of phthalic anhydride followed by 1.2 g (15.2 mmol) of anhydrous sodium acetate. The flask is heated to 200° C. under a stream of nitrogen for 2 h. Water formed is azeotropically evaporated using toluene. The resulting brown melt (98%) is taken immediately to the next step LC/MS (M++1): 290.3.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH3:38][NH2:39]>O1CCCC1>[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([NH:39][CH3:38])=[O:18])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CN
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccnc2cc1OC
Temperature: 30 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Similar to the synthesis of Example 1, compound 1e (20 mg), 40% aqueous solution of methylamine (5 μL), and DMTMM•n-hydrate (22 mg) were dissolved in tetrahydrofuran (1 mL), followed by stirring at 30° C. for 1 hour, to thereby yield the titled compound 6 (18.4 mg, yield: 96%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:9])=[C:5]([CH2:7]O)[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[N:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([CH3:9])=[C:5]([CH2:7][N:29]2[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[N:30]2)[N:6]=1
Reactant: Cc1sc(Br)nc1CO
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(Br)sc2C)c1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (10 mL) of the compound (590 mg, 2.8 mmol) obtained in Example 80d, triphenylphosphine (970 mg, 3.7 mmol) and ethyl 1H-pyrazole-4-carboxylate (480 mg, 3.4 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (1.9 M toluene solution, 1.9 mL, 3.7 mmol), and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (940 mg, 100%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12](O)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:46][N:47]([CH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([NH2:61])[CH2:57][CH2:56]1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[C:11]([C:12]([NH:61][C@H:58]2[CH2:57][CH2:56][C@H:55]([CH2:54][N:47]([CH3:46])[CH:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[CH2:60][CH2:59]2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: Cc1ccc(-c2ccc3nc(C)c(C(=O)O)cc3c2)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2ccc3nc(C)c(C(=O)N[C@H]4CC[C@H](CN(C)C5CCOCC5)CC4)cc3c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 2-methyl-6-(4-methylphenyl)-quinoline-3-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (109 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (242 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (246 mg) and triethylamine (0.15 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 4 days. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:2→1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-2-methyl-6-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]quinoline-3-carboxamide (compound 70) (142 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17]1([C:23]2[CH:24]=[C:25]3[C:33](=[CH:34][CH:35]=2)[N:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]3=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.COCCOC>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:35][CH:34]=4)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc2c(c1)c1cc(-c3ccccc3)ccc1n2-c1ccccc1
Reactant: Brc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2ccc3c(c2)c2cc(-c4ccc(-c5nc6ccccc6o5)cc4)ccc2n3-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a 100 mL three-neck flask were put 0.75 g (2.8 mmol) of 2-(4-bromophenyl)benzoxazole, 1.0 g (2.8 mmol) of 6,9-diphenyl-9H-carbazole-3-boronic acid, and 0.060 g (0.20 mmol) of tri(ortho-tolyl)phosphine. To this mixture were added 15 mL of 1,2-dimethoxyethane (abbreviation: DME) and 5 mL of a 2M potassium carbonate aqueous solution. This mixture was degassed under reduced pressure, and then the atmosphere in the flask was replaced with nitrogen. To this mixture was added 6.2 mg (0.028 mmol) of palladium(II)acetate, and the resulting mixture was stirred at 90° C. for 3 hours while being heated. After that, chloroform was added to this mixture, and this suspension was washed with a saturated aqueous sodium carbonate solution and saturated brine in that order. Then, magnesium sulfate was added to the organic layer to dry it. After that, this mixture was suction filtered. The resulting filtration was suction filtered through Celite 545 (produced by Kishida Chemical Co., Ltd., Catalog No. 020-14815), whereby a filtrate was obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1.C(N(CC)CC)C>[N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:37][C:38]5[CH:47]=[CH:46][C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[N:39]=5)=[O:26])=[CH:28][CH:29]=4)[CH:15]=3)[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Reactant: Nc1ccc2ccccc2n1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccccc2n1)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
Triethylamine (0.22 ml) was added to THF suspension (6 ml) of 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate (300 mg). Further, trimethylacetyl chloride (0.095 ml) was added dropwise to under ice-cooling, which was stirred for 30 minutes. The temperature of the reaction mixture was raised to room temperature, which was stirred for 1 hour. THF solution (1.0 ml) of 2-aminoquinoline (170 mg) was added dropwise to the reaction mixture under ice-cooling, which was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: THF), and recrystallized (ethyl acetate-diisopropyl ether) to give the titled compound (45 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[OH:11][CH:8]([C:6]1[N:7]=[C:2]([NH:12][C:13]2[S:14][C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[CH:16][C:17]=2[C:18]([NH2:20])=[O:19])[CH:3]=[CH:4][CH:5]=1)[CH2:9][OH:10]
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Reactant: OCC(O)c1cccc(Br)n1
Product: NC(=O)c1cc(-c2ccccc2F)sc1Nc1cccc(C(O)CO)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 1-(6-bromopyridin-2-yl)ethane-1,2-diol (71 mg, 0.33 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (78 mg, 0.33 mmol) as the starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][NH:6][CH2:5][C:4]2[CH:8]=[N:9][NH:10][C:3]1=2.[CH3:12][O:13][C:14](=[O:32])[C:15]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH2:16]>CO>[CH3:12][O:13][C:14](=[O:32])[CH:15]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][N:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[C:3]2[NH:10][N:9]=[CH:8][C:4]=2[CH2:5]1
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)C(CN1Cc2cn[nH]c2C(C)(C)C1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (160 mg) in methanol (3 mL) was added 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (331 mg). A gentle stream of nitrogen was applied and the reaction stirred overnight. In the morning, the volume was greatly reduced. The last traces of solvent were removed under high vacuum to give 490 mg (quant.) which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.24 (s, 3H), 1.26 (s, 3H), 1.38 (s, 18H), 2.33 (d, J=11.3, 1H), 2.57 (d, J=11.3, 1H), 3.09 (dd, J=13.1, 5.5, 1H), 3.15 (dd, J=13.4, 9.5, 1H), 3.35 (d, J=12.8, 1H), 3.57 (d, J=12.8, 1H), 3.68 (s, 3H), 5.13 (dd, J=9.5, 3.7, 1H), 7.16 (s, 1H). Mass spec.: 453.30 (MH)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([OH:14])[CH3:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:15]([SiH2:19][O:20][C:21]([CH3:38])([CH3:37])[C@@:22]([CH3:36])([CH:34]=[CH2:35])[C:23]([N:25]1[C@H:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][O:27][C:26]1=[O:33])=[O:24])([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([SiH2:19][O:20][C:21]([CH3:37])([CH3:38])[C@@:22]([CH3:36])(/[CH:34]=[CH:35]/[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][C:8]([C@H:12]([OH:14])[CH3:13])=[CH:7][CH:6]=2)[CH:11]=1)[C:23]([N:25]1[C@H:29]([CH:30]([CH3:31])[CH3:32])[CH2:28][O:27][C:26]1=[O:33])=[O:24])([CH3:18])([CH3:17])[CH3:16]
Reactant: C=C[C@@](C)(C(=O)N1C(=O)OC[C@H]1C(C)C)C(C)(C)O[SiH2]C(C)(C)C
Reactant: C[C@@H](O)c1ccc2ccc(Br)cc2c1
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)[C@@H]1COC(=O)N1C(=O)[C@](C)(/C=C/c1ccc2ccc([C@@H](C)O)cc2c1)C(C)(C)O[SiH2]C(C)(C)C
Yield: 45.9 %

Procedure:
A solution of (R)-1-(7-bromo-naphthalen-2-yl)-ethanol (121.5 mg, 0.484 mmol), (R)-3-[(R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-but-3-enoyl]-4-isopropyl-oxazolidin-2-one (172.0 mg, 0.484 mmol), palladium(II)acetate (22 mg, 0.097 mmol), tri(o-tolyl)phosphine (29.5 mg, 0.097 mmol) and N,N-dicylohexylmethylamine (0.26 mL, 1.210 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at reflux for 1.5 h. The mixture was treated with palladium(II) acetate (22 mg, 0.097 mmol) and tri(o-tolyl)phosphine (29.5 mg, 0.097 mmol). After stirring at reflux for 24 h and cooling to warm temperature the reaction was quenched with hydrochloric acid (1 M, 20 mL). The aqueous layer was extracted with ethyl acetate. The combined organics were washed with a saturated solution of sodium bicarbonate dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (116.7 mg, 46%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.07 (s, 6H), 0.91 (s, 9H), 1.15-1.30 (m, 6H), 1.55-1.65 (m, 6H), 2.29-2.46 (m, 1H), 3.83 (d, J=9.6 Hz, 1H), 4.10-4.33 (m, 2H), 4.50-4.60 (m, 2H), 5.00-5.15 (m, 1H), 6.47 (d, J=16.5 Hz, 1H), 6.70 (d, J=16.5 Hz, 1H), 7.11-7.22 (m, 2H), 7.40-7.50 (m, 2H), 7.72-7.82 (m, 2H). LCMS (m/z) 526.3 [M+H], Tr=4.03 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17](Cl)[N:16]=2)[CH:9]=1)=[O:6].Cl>COCCO.O1CCOCC1>[ClH:21].[Cl:21][C:20]1[CH:19]=[N:18][C:17]2[NH:1][C:2]3[CH:25]=[CH:24][CH:23]=[C:4]([CH:3]=3)[C:5](=[O:6])[NH:7][C:8]3[CH:9]=[C:10]([NH:14][C:15]=1[N:16]=2)[CH:11]=[CH:12][CH:13]=3
Reactant: Nc1cccc(C(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: O=C1Nc2cccc(c2)Nc2nc(ncc2Cl)Nc2cccc1c2
Temperature: 150 °C
Yield: 121 %

Procedure:
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}benzamide (20.0 mg, 0.053 mmol) in 2-methoxyethanol (0.295 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (67 μL). The resulting mixture was heated at 150° C. in a microwave for 15 min. After filtration of the reaction mixture, the crude was triturated with MeOH/EtOAc to give the desired product as an off-white powder (12 mg, 66%). LCMS for C17H12ClN5O (M+H)+: m/z=337.9. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 10.16 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 9.66 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 9.38 (s, 1H), 6.30 (br, 1H), 8.24 (m, 1H), 7.38 (ddd, J=8.0, 2.0, 1.2, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.25 (m, 2H), 7.16 (m, 1H), 6.95 (t, J=2.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][CH3:16].[OH-].[Na+]>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:15][CH3:16])[N:7]=1
Reactant: CN
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(-c2ccccc2)n1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a cooled (0° C.) solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (16.0 g, 70.8 mmol, 1.00 equiv) dissolved in 1:1 CH3CN:H2O (80 mL) was added NH2Me (8.00 g, 27.5% solution in H2O, 70.8 mmol, 1.00 equiv). The solution was treated with 1 N NaOH to maintain a pH of 9-10 and stirred for 15 min. The resulting suspension was diluted with water and filtered to provide 12 g of crude product. A portion of this material (8 g) was purified by reverse-phase HPLC to afford 3.6 g of the title compound. MS (ES+): m/e 221.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([OH:31])=[O:30])[CH2:28][O:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]([Cl:57])([Cl:56])[CH2:34][O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44](=[O:55])[C@@H:45]([NH:47][C:48](=[O:54])[C@@H:49](O)[CH:50]([CH3:52])[CH3:51])[CH3:46])[NH:39]1)=[O:37].C(N(CC)C(C)C)(C)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:56][C:33]([Cl:32])([Cl:57])[CH2:34][O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44](=[O:55])[C@@H:45]([NH:47][C:48](=[O:54])[C@@H:49]([O:30][C:29]([C:23]2(/[CH:22]=[CH:21]/[C:15]3[CH:14]=[C:13]4[C:18]([CH:19]=[CH:20][C:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])=[N:12]4)=[CH:17][CH:16]=3)[CH2:28][O:27][CH2:26][CH2:25][O:24]2)=[O:31])[CH:50]([CH3:51])[CH3:52])[CH3:46])[NH:39]1)=[O:37]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)COCCO3)cc2n1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Yield: 55.7 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carboxylic acid (50 mg, 0.1 mmol), [(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (44 mg, 0.1 mmol), N,N-diisopropylethylamine (32 mg, 0.043 mL, 0.25 mmol), 4-dimethylaminopyridine (6 mg, 0.05 mmol) and 2-methyl-6-nitrobenzoic anhydride (58 mg, 0.17 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated ammonium chloride solution, ice-cold saturated sodium hydrogen carbonate solution and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 1:3 to afford the title compound (47 mg, 55%) as a white solid and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 842.2/844.0 [M+H], Tr=3.25 and 3.31 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].II.[C:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:21]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1ccc(Br)cc1F
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Yield: 42.6 %

Procedure:
Preparation according to Preparation 1. 1-Bromo-3,4-difluorobenzene (5 g, 25.9 mmol) in dry tetrahydrofuran (100 ml), magnesium turnings (0.62 g, 25.9 mmol) and one crystal of iodine. 1-N-boc-3-pyrrolidone (4.79 g, 25.9 mmol) in dry tetrahydrofuran (50 ml). The crude product was purified by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (3.3 g, 43%). MS m/z (rel. intensity, 70 eV) 243 (33), 198 (45), 141 (39), 127 (44), 57 (bp).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].N.Cl[P:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:13]1([P:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:3][CH2:1][CH3:2])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: N
Product: CCOP(c1ccccc1)c1ccccc1
Yield: 82.4 %

Procedure:
330 g (7.17 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 18 g (1.06 mol) of ammonia gas are then introduced at this temperature. 200 g (0.907 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature in one hour. The mixture is then allowed to come to room temperature with stirring and is stirred for a further 3.5 hours. The mixture is then cooled, filtered by suction and washed with ethanol. The filtrate is freed from ethanol and any ammonia present in vacuo. The remaining residue is freed from a slight precipitate by filtration through a glass frit. 172 g of ethyl diphenylphosphinite are then obtained by thin film distillation at a bath temperature of 140° C. and 0.3 mbar. This corresponds to a yield of 83% of theory.