Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[CH:6]=[C:7]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)=O.ClC1N=C(OC)N=C(NCC[C:42]2[CH:47]=[CH:46][C:45](OC)=[C:44](OC)[CH:43]=2)C=1.ClC1N=[C:57]([O:59]C)N=C(NCCC2C=CC(OC)=CC=2)C=1.C(C1C=C(B(O)O)C=CC=1)(O)=O>>[C:10]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:9]=[CH:8][C:7]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:59][CH3:57])[CH:23]=3)[CH:12]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(C)(=O)=O)c3)nc(OC)n2)cc1
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC)c(OC)c2)n1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Agent: O=C(O)c1cccc(B(O)O)c1
Product: COc1nc(NCCc2ccc(OC)c(OC)c2)cc(-c2ccc(-c3ccccc3)cc2)n1

Procedure:
By proceeding in a similar manner as above in Example 35(a) but (i) substituting (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine [100 mg, Intermediate (42)] for (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine, and (ii) substituting 4-Biphenylboronic acid (122 mg) for 3-carboxyphenyl boronic acid, and (iii) subjecting the crude reaction product to flash column chromatography on silica (10 g) eluting with 20 to 60% EtOAc in heptane gradient, there is prepared (6-biphenyl-4-yl-2-methoxy-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine [79.7 mg, 58.6%, Example 35(e)]. LCMS: RT=3.05 minutes, MS: 442 (M+H). 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, d, J=0.027 Hz), 8.09 (2H, d, J=0.027 Hz), 7.84 (1H, d, J=0.027 Hz), 7.78 (1H, d, J=0.027 Hz), 7.68 (9H, m), 7.45 (4H, m), 6.84 (1H, t, J=0.027 Hz), 6.79 (2H, m), 6.44 (1H, s), 4.93 (1H, s), 4.77 (1H, s), 4.07 (3H, s), 3.9 (6H, s), 3.72 (2H, m), 2.94 (2H, t, J=0.022 Hz). IC50=369 nM
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:5][C:6]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[CH:31](=O)[CH2:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:5][C:6]([CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: COc1cc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)cc1N1CCCCC1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CCN(c2cc(OC)c(N3CCCCC3)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (5 mg, 0.0121 mmol) produced in Example (72b), propionaldehyde (1.4 mg, 0.0242 mmol) and tetrahydrofuran (0.3 mL) was added sodium triacetoxyborohydride (5 mg, 0.0242 mmol), followed by stirring for 1 hour and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled off nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled of by nitrogen stream. Heptane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant heptane solution was removed and the resulting solid was dried to give 6.1 mg of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:49]([O:48][C:47]([NH:46][C@H:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:53])([CH3:50])([CH3:51])[CH3:52]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Reactant: O=C(Nc1cc2ccc(N3CCCCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(2-oxopiperidin-1-yl)quinoline-2-carboxylic acid (0.015 g, 0.036 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.3 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.005 g, 20%). LCMS calc. for C39H46N7O6 [M+H]: m/z=708.3. found: 708.4.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)([O:13]CC)[CH2:11][Br:12])[N:9]=1)[C:2]([NH2:4])=[NH:3]>Br>[BrH:12].[Br:12][CH2:11][C:10]([C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)=[O:13]
Reactant: CCOC(CBr)(OCC)c1csc(NC(=N)N)n1
Agent: Br
Product: N=C(N)Nc1nc(C(=O)CBr)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 209.7 %

Procedure:
A mixture of 9.5 g (28 mmol) of 2-guanidino-4-(2-bromo-1,1-diethoxyethyl)thiazole in 50 ml of 48% hydrobromic acid was stirred at room temperature for 15 hours The mixture was evaporated to complete dryness to afford 10.1 g (100%) of 2-bromo-1-(2 -guanidino-4-thiazolyl)ethanone hydrobromide mp 247° (dec). This material could be converted to the free base by triturating with saturated sodium bicarbonate, stirring for 15 minutes, filtering the solid, and drying it under vacuum. In this way, 3.0 g of the hydrobromide salt was converted to 1.7 g (88%) of the free base, mp 210° (dec); nmr (DMSO-d6 (δ): 7.84 (s, 1H); 6.92 (s, 4H); 4.78 (s, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[CH3:14][C:15]1([CH3:33])[C:19]([CH3:21])([CH3:20])[O:18][B:17](C2C=CC(N3N=NC=N3)=CC=2)[O:16]1>>[CH3:14][C:15]1([CH3:33])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[O:5][C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[O:16]1
Reactant: CC1(C)OB(c2ccc(-n3ncnn3)cc2)OC1(C)C
Reactant: Ic1cccc(Oc2nccs2)c1
Product: CC1(C)OB(c2cccc(Oc3nccs3)c2)OC1(C)C

Procedure:
The title compound (1.33 g) was prepared as a crude brown solid from 2-(3-iodophenoxy)-1,3-thiazole (500 mg, 1.65 mmol) using a procedure analogous to that described for 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole, Example 1, Step A. MS (LCMS) m/z 304.0 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[C:31]([NH:32][C:33]2[NH:59][C:36]3=[N:37][C:38]([O:54][CH2:55][CH:56]([F:58])[F:57])=[C:39]([C:41](=[O:53])[NH:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([C:49]([F:52])([F:51])[F:50])[CH2:45][CH2:44]4)[CH:40]=[C:35]3[N:34]=2)=[C:30]([Cl:60])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27].CCN(C(C)C)C(C)C.[F:70][C:71]([CH3:76])([CH3:75])[C:72](O)=[O:73]>CN(C=O)C>[Cl:23][C:24]1[C:31]([NH:32][C:33]2[NH:59][C:36]3=[N:37][C:38]([O:54][CH2:55][CH:56]([F:57])[F:58])=[C:39]([C:41](=[O:53])[NH:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([C:49]([F:52])([F:50])[F:51])[CH2:45][CH2:44]4)[CH:40]=[C:35]3[N:34]=2)=[C:30]([Cl:60])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:72](=[O:73])[C:71]([CH3:76])([F:70])[CH3:75]
Reactant: NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Reaction time: 72 h

Procedure:
TBTU (1.0 ml of a 0.11 M solution in DMF) is added to a mixture of 2,4-dichloro-3-[6-(trans-4-trifluoromethyl-cyclohexylcarbamoyl)-5-(2,2-difluoro-ethoxy)-3H-imidazo[4,5-b]pyridin-2-ylamino]benzylamine (1.0 ml of a 0.10 M solution in DMF), DIPEA (52 μl, 0.3 mmol) and 2-fluoro-2-methylpropionic acid (1.0 ml of a 0.13 M solution in DMF) and it is stirred for 3 d and the mixture is purified by prep. HPLC.
Reaction SMILES: [B:1](Br)(Br)Br.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8]>>[F:5][C:6]([F:11])([F:10])[C:7]([O-:9])=[O:8].[F:5][C:6]([F:11])([F:10])[C:7]([O-:9])=[O:8].[F:5][C:6]([F:11])([F:10])[C:7]([O-:9])=[O:8].[B+3:1]
Reactant: BrB(Br)Br
Reactant: O=C(O)C(F)(F)F
Product: O=C([O-])C(F)(F)F
Product: [B+3]

Procedure:
Place boron tribromide (215 mg, 0.86 mmol) in a flask and cool to 0° C. Cautiously add trifluoroacetic acid (5 mL) with stirring. Evaporate the solvent to give boron tris(trifluoroacetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[CH2:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C.CCOC(C)=O.CCCCCC>Br>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[CH2:22][CH3:23])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(OC)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCc1cc(O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Ethyl-4-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester is refluxed in 48% HBr for 2 hours. After concentration, the residue is dissolved in DCM and (Boc)2O (1.5 eq) and triethylamine (4 eq) are added. The resulting mixture is stirred at room temperature for 30 minutes. After aqueous workup, flash column chromatography (30% EtOAc/hexane) gave 4-(2-Ethyl-4-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: (ES+): 307.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: BrCC=Cc1ccccc1
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(c1ccccc1)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.30 g; 1.04 mmol), cinnamyl bromide (1.6 mL; 10.5 mmol) and indium (1.22 g; 10.7 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude oil. The crude oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:33](C(OC(C)(C)C)=O)[C:14]2=[N:15][C:16]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:18]=[C:13]2[CH2:12][CH2:11]1)C.[OH-].[Na+].CO.Cl>CCO.O>[C:22]1([CH3:25])[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]3[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])[NH:33][C:14]3=[N:15][C:16]=2[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCCCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(CCCCCC(=O)O)CC3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl 6-(6-ethoxy-6-oxohexyl)-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 4) (83 mg, 0.149 mmol) in EtOH (2 ml) was treated with 2M NaOH (0.223 ml, 0.446 mmol) and stirred at RT for 16 hours. MeOH (1 ml) and 2M HCl (0.372 ml, 0.744 mmol) were added and stirring continued at RT for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (30 ml). The mixture was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. The crude product was dissolved in EtOH (1 ml) and treated with 2M NaOH (0.223 ml, 0.446 mmol). After stirring at RT overnight, the mixture was diluted with water (30 ml) and the pH was adjusted to pH1 using 1 M HCl. The aqueous portion was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure to afford an enantiomeric mixture.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[C:22]([CH3:23])=[C:21]([CH2:24][CH3:25])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>C(OCC)(=O)C>[CH2:24]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[CH3:23])[CH3:25]
Reactant: CCc1ncnc(Cl)c1C
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCc1ncnc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)c1C
Temperature: 120 °C
Yield: 29.8 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 129 mg, 0.6 mmol), 4-chloro-6-ethyl-5-methylpyrimidine (Intermediate 41, 141 mg, 0.900 mmol) and DIPEA (0.210 mL, 1.200 mmol) were added together with N-methyl-2-pyrrolidone (1 mL) and the resulting mixture was stirred and heated to 120° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen carbonate solution, water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was triturated with ether/isohexane (1:1) and the resulting solid was collected and dried affording the title compound (60 mg);
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[CH:18]=[C:19]([C:48]2[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:20]=[CH:21][C:22]=1[CH2:23][N:24]1[C:29]2[S:30][C:31]([CH2:33][CH3:34])=[CH:32][C:28]=2[C:27](=[O:35])[N:26]([CH2:36][C:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[O:38])[C:25]1=[O:47])[CH2:14][CH2:15][CH3:16]>C(Cl)(Cl)Cl>[CH2:13]([C:17]1[CH:18]=[C:19]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[NH:3][C:4](=[O:7])[O:5][N:55]=2)[CH:20]=[CH:21][C:22]=1[CH2:23][N:24]1[C:29]2[S:30][C:31]([CH2:33][CH3:34])=[CH:32][C:28]=2[C:27](=[O:35])[N:26]([CH2:36][C:37]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)=[O:38])[C:25]1=[O:47])[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1cc(-c2ccccc2C#N)ccc1Cn1c(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)c2cc(CC)sc21
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(-c2ccccc2-c2noc(=O)[nH]2)ccc1Cn1c(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)c2cc(CC)sc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1.07 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-butyl-4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (40 mL). N,N′-Carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.26 g, 32%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50]([O:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62]I)=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:62][C:61]2[CH:64]=[CH:65][C:58]([O:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:59][CH:60]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Reactant: ICc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one (Example 46 c)) dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -70° C. with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (60 min) with 1.946 g (6.0 mmol) of p-benzyloxybenzyl iodide (Example 44a)) in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 4:1) and crystallisation from ethyl acetate/hexane yields the pure title compound: TLC Rf (D)=0.45; tRet (I)=19.9 min; FAB-MS (M+H)+ =608.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([C:24](=O)[CH3:25])[C:20](OC)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29]>Cl.C(O)C.CC(O)C.O>[CH:28]([N:31]1[C:20](=[O:21])[C:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[C:24]([CH3:25])[NH:32]1)([CH3:30])[CH3:29]
Reactant: COC(=O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)=O
Reactant: CC(C)NN
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCO
Product: Cc1[nH]n(C(C)C)c(=O)c1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-oxobutanoate (2.766 g, 7.83 mmol) in 1.25M HCl in ethanol (25 mL) was added isopropylhydrazine hydrochloride (1.298 g, 11.74 mmol). The reaction mixture was stirred at reflux. Upon completion the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography using a gradient of 0-100% EtOAc in iso-hexane and 10% MeOH in EtOAc afforded crude material. The crude material was dissolved in IPA to which water was added to give a cloudy mixture that was sonicated and left to stand at room temperature. The resulting suspension was filtered and the solid dried under reduced pressure to afford the title compound;
Reaction SMILES: C1([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:11](=[O:23])[CH:10]([NH:24][C:25]([O:27]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:9]=2)CCCCCC1.C(N([CH2:42][CH3:43])CC)C.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)[CH:46]=1>CN(C)C=O>[CH2:43]1[CH2:42][CH2:17][CH:18]([C:10]2([NH:24][C:25]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([N:51]4[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]4)[CH:46]=3)=[O:27])[N:9]=[CH:8][C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:11]2=[O:23])[CH2:13][CH2:14][CH2:8]1
Reactant: CC(C)CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Reactant: CN1CCN(c2cccc(N)c2)CC1
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)Nc2cccc(N3CCN(C)CC3)c2)(C2CCCCCC2)N=Cc2ccccc21
Temperature: 50 °C

Procedure:
To a stirred solution of 5-cycloheptyl-1,3-dihydro-1-(2-methylpropyl)-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (150 mg) in anhydrous dimethylformamide (3 ml), under an atmosphere of nitrogen, was added triethylamine (42 μl). After 5 min a solution of 1-amino-3-(N-methyl-N'-piperazinyl)benzene (64 mg) in anhydrous dimethylformamide (2 ml) was added and the solution heated at 50° C. for 1 h. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The undissolved solid was filtered off, washed with ethyl acetate and water, then triturated with anhydrous diethyl ether to yield the desired urea (87 mg) as a white solid. 1H NMR (360 MHz, D6 -DMSO) δ 0.66 (3H, d, J=6.6 Hz), 0.77 (3H, d, J=6.6 Hz), 1.20-1.80 (12H, m), 1.96-2.10 (1H, m), 2.20 (3H, s), 2.18-2.20 (4H, m), 3.03-3.05 (4H, m), 3.14-3.18 (1H, m), 3.62 (1H, dd, J=13.9 and 4.4 Hz), 4.13 (1H, dd, J=13.9 and 9.6 Hz), 5.00 (1H, d, J=8.5 Hz), 6.49 (1H, d, J=8.3 Hz), 6.61 (1H, d, J=7.7 Hz), 7.03 (1H, t, J=8.1 Hz), 7.11 (1H, m), 7.23 (1H, d, J=7.7 Hz), 7.37 (1H, dd, J=7 and 7 Hz), 7.59-7.68 (2H, m), 7.78 (1H, d, J=6.8 Hz), 8.84 (1H, s). MS (FAB) 545 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CC(C)=O>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCCBr
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCBr
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a stirred solution of 1,6-dibromohexane (9) (16.5 g, 67.5 mmol) in acetone (100 mL) was added potassium phthalimide (5.00 g, 27.0 mmol). The resulting mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. MPLC purification of the residue (Hexanes:EtOAc/70:30) gave 10 as a colorless oily liquid (6.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.85-7.83 (m, 2H), 7.72-7.70 (m, 2H), 3.68 (t, J=7.2 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 1.89-1.82 (m, 2H), 1.73-1.66 (m, 2H), 1.52-1.45 (m, 2H), and 1.41-1.33 (m, 2H).