Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][C:13]([CH3:16])([CH3:15])[C:12](=O)[NH:11][C:10]3[N:18]([CH3:24])[N:19]=[C:20]([CH:21]4[CH2:23][CH2:22]4)[C:9]2=3)=[C:4]([CH3:25])[CH:3]=1.O1CCCC1.B.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][C:13]([CH3:15])([CH3:16])[CH2:12][NH:11][C:10]3[N:18]([CH3:24])[N:19]=[C:20]([CH:21]4[CH2:23][CH2:22]4)[C:9]2=3)=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C1SC(C)(C)C(=O)Nc2c1c(C1CC1)nn2C
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C1SC(C)(C)CNc2c1c(C1CC1)nn2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 4-(4-chloro-2-methyl-phenyl)-3-cyclopropyl-1,6,6-trimethyl-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (1.2 g, 3.19 mmol) in THF (20 mL) was added a solution of borane tetrahydro-furan complex (14 mL, 1M in THF, 4 mmol, Acros) at about 4° C. Subsequently, the mixture was stirred for about 18 h at rt. After cooling to about 4° C., HCl (5 M aqueous, 12 mL) was added dropwise and the mixture was stirred for about 2 h at about 4° C., then NaOH (1 M aq, 60 mL) and ethyl acetate (200 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (2×25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1 to 100:0) to give 4-(4-chloro-2-methyl-phenyl)-3-cyclopropyl-1,6,6-trimethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine as white solid (0.75 g, 2.1 mmol, 65%). LC-MS (Table 1, Method e) Rt=7.48 min, m/z: 362 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 0.38-0.65 (4H, m) 0.91-0.99 (1H, m) 1.01 (3H, s) 1.35 (3H, s) 2.52 (3H, s) 3.09 (1H, dd, J=14.5, 5.5 Hz) 3.40 (1H, dd, J=14.5, 5.0 Hz) 3.62 (3H, s) 3.65 (1H br.t.) 5.17 (1H, s) 7.07 (1H, dd, J=8.5, 2.0 Hz) 7.16 (1H, d, J=2.0 Hz) 7.21 (1H, d, J=8.5 Hz).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]=[N:11][N:12]([CH:13]([CH3:15])[CH3:14])[C:8]=2[CH:7]=1)=[O:5].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH:13]([N:12]1[C:8]2[CH:7]=[C:6]([CH:4]=[O:5])[CH:17]=[CH:16][C:9]=2[N:10]=[N:11]1)([CH3:15])[CH3:14]
Reactant: CON(C)C(=O)c1ccc2nnn(C(C)C)c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)n1nnc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred, cold (−78° C.) solution of 3-isopropyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (4.26 g) in 20 mL of toluene was added drop-wise 17.2 mL of DIBAL in toluene (1 M). The mixture was stirred for 1 hour at −78° C. before warming to 0° C. The reaction was quenched with aqueous 1 N hydrochloric acid, diluted with water and extracted with ethyl acetate (3 times). The combined extracts were washed with water, brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to give a yellow oil. This oil was purified by flash chromatography (eluting with 2:1 hexanes/ethyl acetate) to give 2.24 g of 3-isopropyl-3H-benzotriazole-5-carbaldehyde as a yellow oil which crystallized upon standing; MS 190 M+1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[O:27][C@@H:26]1Br)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:26]1[O:27][C@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:25]1[O:24][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[N:5][NH:6]2
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: Oc1n[nH]c2cccc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C

Procedure:
A mixture of 4-bromo-1H-indazol-3-ol (1.27 g), potassium carbonate (1.65 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-gluco-pyranosyl bromide (which can be prepared in a manner described in literature, for example, Liebigs Ann. Chem. 1982, pp. 41-48; J. Org. Chem. 1996, vol.61, pp. 9541-9545) (4.15 g) in acetonitrile (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over an hydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-2/1) to give the title compound (2.04 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:16].[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:16])=[CH:21][CH:20]=1)#[N:18]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCN(CC)S(=O)(=O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)c(F)c1
Reaction time: 16 h
Yield: 23.2 %

Procedure:
According to general procedure B, 4-bromo-N,N-diethyl-3-fluorobenzenesulfonamide (183 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3-fluorobenzenesulfonamide (46 mg, 23%) was provided after purification. HRMS: calcd for C16H18FN3O2S+H+, 336.11765; found (ESI, [M+H]+), 336.117. HPLC purity 99.7% at 210-370 nm, 9.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Cl:16])=[CH:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10](Cl)[N:11]=1)=[O:5])[CH3:2].[CH2:25]([Sn](CC)(CC)CC)[CH3:26]>CN(C=O)C.CCOC(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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Cl:16])=[CH:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([CH2:25][CH3:26])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CCOC(=O)c1nc(Cl)c2c(c(Cl)cn2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CC)c2c(c(Cl)cn2Cc2ccccc2)c1O
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-benzyl-3,7-dichloro-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (126.1 mg, 0.19 mmol), tetraethyltin (50 mg, 0.21 mmol), and Pd(PPh3)2Cl2 (6.7 mg, 0.0095 mmol) in DMF (1 mL) was stirred at 120° C. for 2.5 h. The mixture was then diluted with EtOAc, washed with water and saturated NaCl aqueous solution, respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column to give a white solid, the desired title compound. The title compound, ESI MS (m/z): 359 (M+H+).
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH3:15])[C:12](=[O:14])[N:13]=1.[Li+].CC([N-]C(C)C)C.[CH3:24][C:25]([CH3:27])=[O:26]>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([C:25]([OH:26])([CH3:27])[CH3:24])([CH3:15])[C:12](=[O:14])[N:13]=1
Reactant: CC1SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)C1(C)SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one (1.10 g, 5.0 mmol) in THF (5 ml) at −78° C. was added LDA (2.0 M, 10 ml). After 5 min, acetone was added, and the reaction mixture was stirred for 1 h at −78° C. The resulting reaction mixture was poured into a sat'd NaH2PO4, and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as a white solid. MS (ES+): 283 (M+H)+. The diastereomers were separated using standard HPLC methods described within this text.
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH3:17])[C:5]2[N:6]=[C:7](S(C)(=O)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:18][NH2:19].C(O)C>CC(O)C>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH3:17])[C:5]2[N:6]=[C:7]([NH:19][CH3:18])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Cn1c(=O)c(Br)cc2cnc(S(C)(=O)=O)nc21
Reactant: CN
Solvent: CC(C)O
Solvent: CCO
Product: CNc1ncc2cc(Br)c(=O)n(C)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Charged a flask with 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.910 g, 2.86 mmol, prepared by reference in Scheme 6E) and 10.0 mL IPA. Chilled suspension to 0° C. and treated with methylamine 33% wt. solution in ethanol (1.78 ml, 14.3 mmol). After addition was complete, the bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The crude reaction mixture was filtered and washed with ethanol (2×30 mL) and air-diced to afford a white microcrystalline solid: 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (0.637 g, 82.8% yield). MS (M+H)+ 269, 271.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=O)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>C(O)(=O)C>[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 120 °C
Yield: 99.5 %

Procedure:
To a mixture of piperidine-4-carboxamide (1.05 g, 8.2 mmol), 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 1.94 g, 8.2 mmol), methanol (30 mL) and acetic acid (3 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 1.9 g). The reaction mixture was heated for 5 min at 120° C. using microwave single node heating. The resin was filtered off and the solvent was removed by evaporation. There was obtained 2.85 g (99%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxamide. 1H NMR (500 MHz, CDCl3): 1.6-1.9 (m, 6H), 2.1-2.2 (m, 1H), 2.7-2.8 (d, 2H), 2.9-3.0 (m, 3H), 3.4 (t, 2H), 4.4 (s, 1H), 5.7-5.8 (b, 1H), 6.2 (b, 1H), 7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 350 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][C:20]=2[C:19]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)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:15])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:32]2[CH:33]=[CH:34][C:29]([C:19]3[C:20]4[O:21][C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[C:24]=4[CH:16]=[CH:17][CH:18]=3)=[CH:30][CH:31]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCSCc1ccc(Br)cc1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 3-(4-bromophenylmethylsulfanyl)-propanoic acid methyl ester (289 mg, 1 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (302 mg, 1.05 mmol) and Pd(PPh3)4 (52 mg, 5 mol %) in toluene (10 mL) and ethanol (3.0 mL) was treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid methyl ester (330 mg, 72%) as white solid. 1H NMR (CDCl3), 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 3.81 (s, 2H), 3.71 (s, 3H), 2.76 (t, J=6 Hz, 2H), 2.56 (t, J=6 Hz, 2H). LCMS 475 (M++23).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])[CH3:2].[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)(=[O:19])[CH3:18]>>[CH2:1]([O:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[C:14]([O:15][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])[CH3:2]
Reactant: CCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CC(=O)OCCCCBr
Product: CCOc1c(O)c2cccc(OCCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-ethoxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 4-bromobutyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-ethoxy-4-hydroxy-8-(4-acetoxybutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([O:19][CH:20]([CH:22]3[CH2:24][CH2:23]3)[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH:22]1([CH:20]([O:19][C:17]2[CH:16]=[CH:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH3:21])[CH2:24][CH2:23]1
Reactant: CC(Oc1ccc2c(n1)OCCN(Cc1ccccc1)C2)C1CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc2c(n1)OCCNC2)C1CC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A mixture of the compound obtained in step 1 (0.15 g), 20% Pd(OH)2/C (0.020 g) and methanol (3 mL) was stirred at 50° C. for 15 hr under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give the title compound (0.11 g, quantitatively) as a colorless oil.
Reaction SMILES: C(C1C=CC(C2C=CC(C[C@H](NC(C3CC4C=C5C(O[C@@H](C6C=CC(OCC7C=CC(Cl)=C(Cl)C=7)=CC=6)C(=O)N5C)=CC=4CN3C(O)=O)=O)C(OC)=O)=CC=2)=CC=1)#N.[CH3:59][O:60][C:61](=[O:126])[C@@H:62]([NH:78][C:79]([CH:81]1[CH2:94][C:93]2[CH:92]=[C:91]3[C:86]([O:87][C@@H:88]([C:97]4[CH:102]=[CH:101][C:100]([O:103][CH2:104][C:105]5[CH:110]=[CH:109][C:108]([Cl:111])=[C:107]([Cl:112])[CH:106]=5)=[CH:99][CH:98]=4)[C:89](=[O:96])[N:90]3[CH3:95])=[CH:85][C:84]=2[CH2:83][N:82]1[S:113]([C:116]1[S:120][C:119]([NH:121]C(=O)C)=[N:118][C:117]=1[CH3:125])(=[O:115])=[O:114])=[O:80])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][C:73]([C:76]#[N:77])=[CH:72][CH:71]=2)=[CH:66][CH:65]=1>>[CH3:59][O:60][C:61](=[O:126])[C@@H:62]([NH:78][C:79]([CH:81]1[CH2:94][C:93]2[CH:92]=[C:91]3[C:86]([O:87][C@@H:88]([C:97]4[CH:98]=[CH:99][C:100]([O:103][CH2:104][C:105]5[CH:110]=[CH:109][C:108]([Cl:111])=[C:107]([Cl:112])[CH:106]=5)=[CH:101][CH:102]=4)[C:89](=[O:96])[N:90]3[CH3:95])=[CH:85][C:84]=2[CH2:83][N:82]1[S:113]([C:116]1[S:120][C:119]([NH2:121])=[N:118][C:117]=1[CH3:125])(=[O:115])=[O:114])=[O:80])[CH2:63][C:64]1[CH:65]=[CH:66][C:67]([C:70]2[CH:71]=[CH:72][C:73]([C:76]#[N:77])=[CH:74][CH:75]=2)=[CH:68][CH:69]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Agent: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)O)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C

Procedure:
(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tent-butyl ester 7-methyl ester was hydrolyzed as described in general procedure B to furnish (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tent-butyl ester as a mixture of diastereomers (1:1) at the morpholino center. This mixture of acids was converted to (S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tent-butyl ester using the general procedure O. This intermediate was further converted to (S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester as a mixture of diastereomeres following the general procedure C and E. This sulfonamide was deacylated using the general procedure P to furnish (S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester as a mixture of diastereomeres. The diasteromers were separated by flash column chromatography (DCM: EtOAc, 9:1-7:3)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]1[C:20](=[O:37])[CH2:21][NH:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1.COC1C=CC=CC=1C1CCC(C2C=CC=CC=2)N1.COC(CC1C=C(NC(=O)NCC(O)=O)C=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]1[C:20](=[O:37])[CH2:21][NH:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3OC)CC[C@H]2c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COC(=O)Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: COc1ccccc1C1CCC(c2ccccc2)N1
Solvent: CC#N
Product: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2OC)c1

Procedure:
Methyl cis-3-{3-{2-[2-(2-methoxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetate may be prepared in a fashion similar to that described in Example 41 §A, but starting from 0.57 g of (2RS,5SR)-2-(2-methoxyphenyl)-5-phenyl-pyrrolidine, 0.6 g of 2-[3-(3-methoxycarbonylmethylphenyl)ureido]acetic acid and 0.46 g of N,N'-dicyclohexylcarbodiimide in 4.5 cm3 of acetonitrile. After treatment, 1.2 g of methyl (2RS,5SR)-3-{3-{2-[2-(2-methoxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetate are obtained in the form of an oil used as it is in subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Br:11]N1C(=O)CCC1=O>CC#N>[Br:11][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[CH:6][N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cncc(OC)c1
Solvent: CC#N
Product: COc1cnc(Br)c(OC)c1
Yield: 70.4 %

Procedure:
To a stirred solution of 3,5-dimethoxypyridine (780 mg, 5.6 mmol) in dry MeCN (24 ml) was added N-bromosuccinimide (1.0 g, 5.6 mmol) and the reaction was heated to reflux for 1 hour. After cooling, the solvent was removed under vacuum and the residue was triturated with diethyl ether to precipitate the succinimide by-product and filtered. The filtrate was concentrated onto silica-gel and the residue purified by flash chromatography (silica-gel, eluted with hexanes:EtOAc, 3:1) to afford the product as a white solid (860 mg, 70%). 1H-NMR (300 MHz, CDCl3) δ 7.67 (d, J=2.5 Hz, 1H), 6.71 (d, J=2.5 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: Br[C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:19][CH2:18][C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:6]=1)=O.[NH2:27][C:28]1[C:29]([OH:35])=[N:30][CH:31]=[N:32][C:33]=1[NH2:34].Cl>CCO>[NH2:34][C:33]1[C:28]2[N:27]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:19][CH2:18][C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH2:16][CH2:17]4)[CH2:14][CH2:13][CH2:12]5)=[CH:7][CH:6]=3)[C:2]([CH3:26])([CH3:25])[O:35][C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: COC(=O)CC12CCCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Reactant: Nc1ncnc(O)c1N
Agent: Cl
Solvent: CCO
Product: COC(=O)CC12CCCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of methyl {5-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[3.2.2]non-1-yl}acetate (Intermediate 24; 80 mg, 0.19 mmol) in absolute EtOH (20 mL) was added 5,6-diaminopyrimidin-4-ol (30 mg, 0.21 mmol) followed by 1M HCl (0.21 mL). The suspension was heated under gentle reflux (80° C.) overnight then allowed to cool, the solvent removed and the residue treated with 2M NaOH (2 mL). The aqueous phase was extracted into EtOAc (3×50 mL), the organic extracts were combined, dried (MgSO4) and concentrated to leave a pale yellow gum. This was purified on a 12 g Crawford silicycle cartridge, loading in DCM and eluting with 0-5-10% MeOH-DCM, giving the title compound as a pale yellow gum (55 mg, 0.123 mmol, 65%); 1H NMR (CDCl3) 1.41-1.61 (14H, m), 1.71 (6H, s), 2.07 (2H, s), 3.61 (3H, s), 7.11 (2H, d), 7.51 (2H, d), 8.14 (1H, s); MS m/e MH+ 449.