Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl-:4].[Cl-].[CH3:6][C:7]1([Zr+2:13][C:14]2([CH3:20])[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15]2)[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8]1>C1(C)C=CC=CC=1>[CH3:6][C:7]1([Zr+2:13][C:14]2([CH3:20])[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15]2)[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8]1.[Cl-:4].[CH3:1][N-:2][CH3:3]
Reactant: CNC
Agent: CC1=CC(C)([Zr+2]C2(C)C=CC(C)=C2)C=C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[N-]C
Temperature: -10 °C

Procedure:
Into a 500 ml glass reactor thoroughly purged with nitrogen were charged 100 ml of dry hexane and n-butyl lithium (hexane solution of 1.62 M, 15.6 ml), and they were stirred at -10° C. To the reaction liquid was added 1.25 g of dimethylamine at -10° C. and stirred for 30 min. The temperature of the reaction system was raised to 0° C. After the reaction of 1 hour, nitrogen was blown into the reaction system to remove the residual dimethylamine. To the reaction liquid was dropwise added 200 ml of a toluene solution containing 3.66 g of bis(1,3-dimethylcyclopentadienyl) zirconium (IV)-dichloride over a period of 30 min, and the reaction liquid was stirred at 0° C. The temperature of the reaction system was raised to room temperature. After the reaction of 1 hour, the reaction liquid was heated at 95° C. for 6 hours, and the produced salt was removed by means of filtration. The filtrate was concentrated (about 20 ml). The precipitated solid was filtered, and the obtained brown solid was purified by means of sablimation (200° C. 0.5 mmHg), to obtain 0.60 g of a crystal of bis(1,3-dimethylcyclopentadienyl)-zirconium (IV)-(dimethylamide)chloride (yield: 18%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:56][CH2:55][CH2:54][N:53]([CH3:57])[CH3:52])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN(C)CCN
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NCCN(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and N,N-dimethylethylenediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:24]1([C:35](O)=[O:36])[CH:25]=[CH:26][CH:27]=[C:28]2[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=23)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (169 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (351 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=4[C:4]=3[CH:3]=2)[CH:21]=1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCc2[nH]c3ccc(-c4cccnc4)cc3c2C1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 7. A mixture of ethyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (See Example 7) (100 mg, 0.3 mmol), pyridine-3-boronic acid (76 mg, 0.62 mmol) and K3PO4 (120 mg, 0.57 mmol) in DMF:H2O (2:1, 3 ml) was purged with nitrogen for 30 minutes. PdCl2(PPh3)2 (25 mg, 0.04 mmol) was added and the reaction was heated at 100° C. for 4 h. The contents were concentrated in vacuo and the crude product was purified by silica gel chromatography (230-400 mesh) using ethyl acetate-hexane gradient to obtain 62 mg of ethyl 3,4-dihydro-8-(pyridin-3-yl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate. This intermediate (25 mg, 0.078 mmol), 2-methyl-5-vinylpyridine (0.120 ml, 1 mmol) and NaH (10 mg, 60% dispersion in oil, 0.02 mmol) were heated in DMSO (0.3 ml) at 100° C. for 48 h, after which methanol was added and the contents were concentrated to dryness. The resulting crude product was purified by silica gel chromatography (100-200 mesh or 230-400 mesh) using methanol-dichloromethane gradient to obtain 7 mg of 3,4-dihydro-5-(2-(6-methylpyridin-3-yl)ethyl)-8-(pyridin-3-yl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N2CCN(c3ccccc3)CC2)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 1-phenylpiperazine (810 mg) and 2-butanone (15 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed with a 10% aqueous solution of citric acid (100 ml), dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(4-phenyl-1-piperazinyl)oxazole was obtained as an oil (168 mg, 33%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([Si:15]2(CCCC=C)[CH2:20][CH2:19][CH:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)C=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:9]([Si@H:15]1[CH2:16][CH2:17][C@H:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:26])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1)[CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Oc1ccc(Cl)cc1
Product: C=CCCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 4-chlorophenol and 4-(4-phenyl-4-(4-pentenyl)-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])=[C:11]2[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CC(O)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH:21]1([C:19]([C:12]2[C:13]([CH3:18])=[N:14][C:15]3[C:10]([C:11]=2[C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[CH:9][C:8]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:17][CH:16]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Temperature: 110 °C
Yield: 52.5 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg) and cesium carbonate (110 mg, 0.33 mmol). [6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-cyclopropyl-methanone [example 50] (100 mg, 0.22 mmol) in t-BuOH (5 ml) was added, followed by morpholine (24 mg, 0.27 mmol). The tube was sealed and heated at 110° C. for 6 hrs. The reaction mixture was cooled to 20° C., diluted with heptane, and filtered through Celite and purified directly by flash chromatography on silica gel in heptane/AcOEt 80:20 to give a yellow solid (52 mg, 51%). MS: m/z=451 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=[C:7]2[CH:6]=1)=[O:4].[NH3:38]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:13]=[C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH2:38])[CH:10]=[CH:9][N:8]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N
Reactant: COC(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C(N)=O)ccn4c3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (150 mg) and a solution of ammonia in methanol (7M, 2.15 mL) was heated at 130° C. for 90 minutes under microwave irradiation. On cooling, the reaction mixture was concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12]P(=O)(OC)OC)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].O=[C:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH:12]=[C:34]3[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COP(=O)(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of dimethyl (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylphosphonate (0.32 g) in anhydrous THF (3 mL) at 0° C. was added 2.0 M of lithium diisopropylamide in tetrahydrofuran (1.4 eq). The resulting solution was allowed to warm to RT (room temperature) before adding a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.4 eq) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 1 h, then partitioned between brine and DCM. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo to give 0.34 g of crude tert-butyl 3-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylene)azetidine-1-carboxylate.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])(=[O:4])=[O:3].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[CH:14]1([NH:20][C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([F:1])(=[O:4])=[O:3])=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: O=C=Nc1ccccc1S(=O)(=O)F
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1S(=O)(=O)F)NC1CCCCC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-fluorosulphonyl phenyl isocyanate (804 g, 4 moles) in benzene (4 l), cyclohexylamine (457 ml, 4 moles) was added dropwise, whilst the temperature was kept at 60°. The mixture was left standing overnight at room temperature, whereupon the product was collected, washed with benzene (4 l) and dried. Yield : 1070-1090 g (89-90 %), melting point: 177° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]1[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:4]=21.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:5]2[N:6]=[C:7]3[C:3]([C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=4)=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:14]=1
Reactant: Clc1nc2c3c(Br)cccc3nn2cc1-c1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(Cl)nc4c23)cc1
Temperature: 105 °C
Yield: 26.7 %

Procedure:
400 mg (1.12 mmol) 10-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole, intermediate example Int-1-3, 172.1 mg (1.17 mmol) 4-cyanophenylboronic acid, 91 mg (0.112 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 354.6 mg (3.35 mmol) sodium carbonate in 12 mL degassed dioxane and 1.68 mL water were heated in the microwave for 45 min. at 105° C. The reaction mixture was poured on a mixture of water/saturated ammonium chloride/dichloromethane and stirred vigorously for 30′. The organic phase was separated, washed twice with brine and dried (sodium sulfate). After filtration and evaporation of the solvent the residue was purified by HPLC yielding 114 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@@H:14]1[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@@H:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Yield: 88.1 %

Procedure:
N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.07 g, 10.0 mmol) was stirred in refluxing absolute ethanol (40 mL) under nitrogen to achieve partial dissolution. To this stirred mixture was added a solution of freshly prepared (1S,4R)-4-amino-2-cyclopentene-1-methanol (PCT Application 9204015.3, 1.57 g, 12.5 mmol as 90%) in ethanol (15 mL) followed by triethylamine (3.5 mL, 25 mmol, freshly distilled from calcium hydride). After 14 hours of reflux, the resulting dark solution was cooled and 1 N sodium hydroxide (10 mL) was added. The volatiles were evaporated in vacuo. The residual tan solid foam was dissolved in 5% methanol-ethyl acetate, and the solution was washed through a silica gel pad to give the title compound as an off-white solid (2.50 g, 88%), after evaporation of solvents. Recrystallization of the solid from ethyl acetate-methanol (20:1) gave the title compound (VIa) as fine white crystals (2.29 g, 81%), m.p. 177-178° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6)δ: 8.99 and 8.58 (s and d, J=11.1 Hz, total 1, amide NH), 8.11 and 7.80 (s and d, J=11.1 Hz, total 1, amide CH), 6.77 and 6.61 (two d, J=8.0 Hz) overlapping 6.60 and 6.48 (two br s, total 3, NH and NH2), 5.85 and 5.70 (two m, 1 each, CH=CH), 5.15-5.00 (m, 1, NCH), 4.71 (t, J=5.1, 1, OH), 3.45-3.30 (m overlapping H2O, OCH2), 2.80-2.65 (m, 1, CH), 2.45-2.25 and 1.45-1.30 (both m, 1 each, CH2); [α]20 589+21.2°, [α]20 578+22.2°, [α]20546+25.2°, [α]20436+41.4°, [α]20365+48.3° (c 0.50, methanol).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2].[F:16][C:17]([F:22])([F:21])[CH:18]([OH:20])[CH3:19]>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:20][CH:18]([CH3:19])[C:17]([F:22])([F:21])[F:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B4(c) from 5-Ethanesulfonyl-2-fluoro-benzoic acid and rac-1,1,1-Trifluoro-propan-2-ol (commercial). White solid. MS (m/e): 325.1([M−H], 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirring solution of 4-aminobiphenyl (9.53 g, 56.3 mmol) and triethylamine (5.70 g, 56.3 mmol, 7.85 mL) in methylene chloride (60 mL), cooled to 0° C., was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0° C. for 1 h, the mixture was diluted with methylene chloride (120 mL) and washed with 1N NaOH and saturated brine, then dried (MgSO4), filtered and concentrated. The residue was washed with ether and dried to provide the title compound as a pale yellow crystalline solid (9.83 g, 73%). 1HNMR (400 MHz, CDCl3/CD3OD) δ7.58 (d, 2H), 7.50 (m, 4H), 7.40-7.25 (m, 3H), 2.55-2.49 (m, 1H), 1.18 (d. 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[F:17][CH:18]([F:24])[C:19](OCC)=[O:20].[Cl-].[NH4+]>O1CCCC1.CO>[Br:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([CH:19]([OH:20])[CH:18]([F:24])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of tert-butyl 3,5-dibromobenzoate (18.43 g, 54.9 mmol) in tetrahydrofuran (137 mL) at 0° C. was added isopropylmagnessium chloride (2.0 M in THF; 46.6 mL, 93 mmol). The reaction mixture was warmed to ambient temperature. The reaction was monitor by LC-MS for disappearance of tert-butyl 3,5-dibromobenzoate. The mixture was cooled back to 0° C. and ethyl difluoroacetate (13.7 mL, 137 mmol) was added. The mixture was stirred at 0° C. for 1 h, then warmed to ambient temperature. After 18 h, methanol and saturated ammonium chloride were added and the mixture was concentrated to remove organic solvents. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (4.04 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C@H:10]([CH3:22])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from Example 1, Step A (2.2 g, 7.33 mmol) in THF (30 mL) was added lithium hexamethyldisilazide (16.0 mL, 1M in THF, 16.0 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 min. Iodomethane (2.8 mL, 45.0 mmol) was then added. After stirring at −78° C. for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (30:70 hexanes/ethyl acetate) afforded the desired product (major diastereoisomer from the reaction).
Reaction SMILES: C(O[N:19]1[C:24](=O)[CH2:23][CH2:22][C:20]1=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl.N[C@@H:28](CC=CC)[C:29]([OH:31])=[O:30].C([O-])(O)=O.[Na+].Cl>CC(C)=O.O>[CH2:24]([NH:19][CH2:28][C:29]([OH:31])=[O:30])[CH:23]=[CH:22][CH3:20]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC=CC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC=CCNCC(=O)O
Yield: 211.3 %

Procedure:
2-N-Fluorenylmethoxycarbonylaminohex-4-enoic acid 100 was prepared according to the procedure described by Paquet.230 Fmoc-OSu (2.36 g, 7.00 mmol) was added to a stirred suspension of L-crotylglycine.HCl 101 (1.16 g, 7.03 mmol) and NaHCO3 (2.95 g, 35.0 mmol) in a mixture of acetone:water (1:1, 30 mL). The resultant suspension was stirred at room temperature for 15 h. The reaction mixture was then acidified with concentrated HCl (pH 2) and the acetone was removed under reduced pressure. The resultant suspension was extracted into DCM (3×25 mL) and the combined organic extract was washed with dilute HCl solution (1 M, 2×25 mL), water (2×25 mL), dried (MgSO4) and evaporated under reduced pressure to afford the titled Fmoc-amino acid 100 as colourless solid (1.91 g, 78%), m.p. 119-121° C. νmax (KBr): 3390bm, 3033m, 2961s, 2357w, 1730s, 1651w, 1505w, 1450w, 1395w, 850w cm−1. 1H n.m.r. (300 MHz, CDCl3): δ 1.67 (d, J=6.2 Hz, 3H, H6), 2.37-2.69 (m, 2H, H3), 4.23 (t, J=6.8 Hz, 1H, H9′), 4.42-4.48 (m, 3H, CH2O, H2), 5.30-5.37 (m, 2H, H5, NH), 5.61 (m, 1H, H4), 7.31 (td, J=7.2, 1.3 Hz, 2H, H2′, 7′), 7.34 (td, J=7.4, 1.5 Hz, 2H, H3′, 6′), 7.60 (d, J=7.3 Hz, 2H, H1″, 8′), 7.74 (d, J=7.0 Hz, 2H, H4′, 5′), one exchangeable proton (OH) not observed. 13C n.m.r. (75 MHz, CDCl3): δ 16.7 (C6), 34.1 (C3), 46.2 (C9′), 52.3 (C2), 66.2 (CH2O), 118.9 (C5), 123.0 (C2′, 7′), 124.6 (C3′, 6′), 125.2 (C1′, 8′), 127.5 (C4′, 5′), 129.7 (C4), 140.3 (C8′a, 9′a), 142.7 (C4′a, 4′b), 154.9 (OCONH), 175.0 (C1). Mass Spectrum (ESI+, MeOH): m/z 352.1 (M+H)+, C21H22NO4 requires 352.2. Spectroscopic data were in agreement with those reported in the literature.146