Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CCN[C:7](=[O:34])/[CH:8]=[CH:9]/[C@@H:10]([NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.[CH:37]([NH:40][CH2:41][CH2:42][NH2:43])([CH3:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH:37]([NH:40][CH2:41][CH2:42][NH:43][C:7](=[O:34])/[CH:8]=[CH:9]/[C@@H:10]([NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:39])[CH3:38]
Reactant: CC(C)NCCN
Reactant: CCN(CC)CCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
To a solution of (E)-(S)-4-(3-biphenyl-4-yl-ureido)-5-phenyl-pent-2-enoic acid (Example 19, step A) (0.30 g, 0.78 mmol), N-isopropyl-ethane-1,2-diamine (0.087 g, 0.85 mmol) and HOBt (0.16 g, 1.16 mmol) in DMF (7.8 mL), was added EDCl (0.22 g, 1.16 mmol). The resulting solution was stirred under N2 at rt for 20 h. The solution was diluted with H2O (50 mL) and extracted with 3:1 EtOAc/iPrOH (3×60 mL). The combined organic extracts were washed with 1 N NaOH (1×50 mL) and brine (75 mL), dried (Na2SO4) and filtered, and the solvent was removed. The residue was purified by column chromatography on silica gel using a gradient of 2–10% (MeOH (1% NH4OH)/CH2Cl2 to afford 0.18 g (51%) of the desired product as a white solid. Rf=0.26 (10% MeOH (1% NH4OH)/CH2Cl2). MS (electrospray): mass calculated for C29H34N4O2, 470.27; m/z found, 471.3 [M+H]+, 493.2 [M+Na]+, 941.5 [2M+H]+. 1H NMR (400 MHz, CDCl3): 8.10 (s, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.39–7.33 (m, 5H), 7.31–7.25 (m, 3H), 7.21 (d, J=7.24 Hz, 2H), 6.76 (dd, J=15.3, 5.7 Hz, 1H), 6.25 (d, J=8.3 Hz, 1H), 6.00 (d, J=15.3 Hz, 1H), 4.86–4.79 (m, 1H), 3.46–3.41 (m, 1H), 3.31–3.27 (m, 1H), 2.95–2.85 (m, 2H), 2.77–2.67 (m, 3H), 1.01 (d, J=6.0 Hz, 6H).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16](/[CH:18]=[N:19]/[OH:20])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:22]=[C:23]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.C(OCC)(=O)C.Cl>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([C:18]2[CH2:22][C:23]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[O:20][N:19]=2)[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O/N=C/c1cc(OCc2ccccc2)ccc1Br
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 16.42 g) was added dropwise to a solution of (E)-1-(5-(benzyloxy)-2-bromophenyl)-N-hydroxymethanimine (3.07 g) and di-tert-butyl 2-methylenesuccinate (2.43 g) in THF (30 mL) at 0 C, and the obtained mixture was stirred at 0 C for 2 hours. The reaction mixture was diluted with ethyl acetate, and 1 M hydrochloric acid was added thereto. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (4.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:50][C:51]1[CH2:55][O:54][C:53](=[O:56])[CH:52]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:38])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]([CH3:35])[CH2:50][C:51]4[CH2:55][O:54][C:53](=[O:56])[CH:52]=4)[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: O=C1C=C(CBr)CO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1=CC(=O)OC1)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) in DMF (4 mL) was added DIEA (46 mg, 0.36 mmol), 4-(bromomethyl)-2,5-dihydrofuran-2-one (63 mg, 0.36 mmol). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (40.0% up to 48.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector, UV 254/220 nm. This resulted in 15.5 mg (13%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxo-2,5-dihydrofuran-3-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=655.2, RT=1.91 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.09 (t, 1H, J=73.2 Hz), 6.04 (s, 1H), 5.24-5.22 (m, 2H), 4.86 (d, 2H, J=1.2 Hz), 4.39-3.37 (m, 1H), 4.01-3.93 (m, 1H), 3.47 (s, 2H), 3.10-3.01 (m, 1H), 2.67-2.62 (m, 2H), 2.20 (s, 3H), 1.76-1.73 (m, 2H), 1.56-1.42 (m, 1H), 1.40-1.29 (m, 1H).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH:9]([CH2:18][OH:19])[N:8]3[CH:7]=1)=O.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:22]1>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:20])[C:4]=2[C:6]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=[CH:15]3)[CH2:11][CH2:10][CH:9]([CH2:18][OH:19])[N:8]4[CH:7]=2)=[CH:22]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2CO
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3CO)=C1c1c[nH]c2ccccc12

Procedure:
Beginning with (4-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester and (1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[N:10]([C:16]([O:18]CC)=O)[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14]>C(O)C.Cl>[Br:8][C:7]1[C:2]2[NH:1][C:16](=[O:18])[N:10]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:3]=2[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: CCOC(=O)N(CCN(C)C)c1cc(Br)cc(Br)c1N
Agent: Cl
Solvent: CCO
Product: CN(C)CCn1c(=O)[nH]c2c(Br)cc(Br)cc21
Yield: 78.2 %

Procedure:
In ethanol (21 ml) and concentrated hydrochloric acid (7 ml) was dissolved N-(2-amino-3,5-dibromophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine (0.85 g) and the solution was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The solution was alkalized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=10:1) to give 0.59 g of 4,6-dibromo-1,3-dihydro-1-(2-dimethylaminoethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CCN(CC)CC.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:21]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
Into a round bottom flask containing 3-hydroxybenzaldehyde (0.658 g, 5.23 mmol) and DMAP (0.0646 g, 0.52 mmol), first 10 mL of anhydrous CH2Cl2 and then 0.89 mL of NEt3 (0.634 g, 6.27 mmol) were added. After the reaction mixture was stirred under nitrogen at 0° C. for 10 minutes, 5 mL of a CH2Cl2 solution of TBSCl (0.976 g, 6.28 mmol) were added. The reaction mixture was stirred for 2.5 h at room temperature and, then it was filtered through silica gel-florisil, rinsed with CH2Cl2 and the organic phase dried under Na2SO4. After evaporating the solvent, 1.1308 g (4.79 mmol) of pure product was obtained in a 92% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:9]([CH3:15])([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:27][CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:3][CH:4]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:22][CH:21]=1)([CH3:24])[CH3:25]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(C(C)C)cc1
Yield: 77.1 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)-2-methylpropionate (1.00 g), which is the product of Reference example 9(b), 2-(2-bromoethoxy)tetrahydropyran (1.84 g) and potassium carbonate (1.62 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (1.06 g) as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13].Cl.CCOCC>CO>[CH3:21][O:20][C:11]([CH:12]1[CH2:14][C:15](=[O:16])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13]1)=[O:19]
Reactant: COc1ccc(CN)cc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Reaction time: 96 h

Procedure:
To 4-methoxybenzylamine (42 g, 0.306 mol) in methanol (40 mL) at 0° C. was added the dimethyl itaconate (48 g, 0.306 mol) in methanol (13 mL). The solution was at room temperature for 4 days. 1N HCl was added to the solution followed by ether. The two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4). Upon filtration of the drying agent the desired material 79 precipitated from solution that was collected and dried under vacuum. 23.26 g, 29%. MS, m/z (relative intensity): 264 [M+H, 100%]. Anal. Calcd for C14H17N1O4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.96; H, 6.55; N, 5.29.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2]C(C)=O.[N+:10]([O-])([OH:12])=[O:11]>C(OC(=O)C)(=O)C>[N+:10]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])([O-:12])=[O:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C[N+](=O)[O-]

Procedure:
Another route was disclosed by early researchers Bouveault and Wahl, Bull. Soc. Chim. France, 31, 847-54 (1904), whereby ethyl acetoacetate was reacted with absolute nitric acid in acetic anhydride at 30°-35° C., but low yields of ethyl nitroacetate were reported. This work was later confirmed by Arndt and Rose in J. Chem. Soc. 1935, 1-10. The major product produced using the conditions of Bouveault and Wahl was found to be diethyl2-oxofurazan dicarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O-:18])(=O)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([Cl:22])(=[O:18])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a flask containing 4-Benzyloxy-benzenesulfonate, sodium salt (42.07 g) is added thionyl chloride (170 mL). This solution is treated with dimethyl formamide (0.5 mL) and is heated to 70° C. for 4 hours. The reaction is allowed to cool and is concentrated under reduced pressure then is diluted with ethyl acetate and washed with water (3 times) followed by three washes with saturated sodium bicarbonate and brine. The organic layer is dried over sodium sulfate and concentrated to give 4-Benzyloxy-benzenesulfonyl chloride as white solid (39.18 g).
Reaction SMILES: C(O[CH:5]([O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1)[C:6](Cl)([Cl:8])[Cl:7])(=O)C>C(O)(=O)C.[Zn]>[Cl:7][C:6]([Cl:8])=[CH:5][O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cccc(OC=C(Cl)Cl)c1
Temperature: 25 °C

Procedure:
By a metallic reductive dehydrohydrogenation method. 1(3-tolyloxy)-2,2,2-trichloroethyl acetate (14.2 g) was dissolved in glacial acetic acid (40 ml) and zinc dust (3.6 g) was slowly added to the solution was stirring at the ambient temperature. The temperature rose to 60° C in response to the exothermic reaction which occurred, after which the mixture was heated at 50°-60° C for 4 hours. The mixture was filtered and the filtrate poured in an excess of water and extracted with chloroform. The extracts were washed twice with water, with saturated sodium bicarbonate solution, and finally with water. After drying the chloroform extracts over anhydrous magnesium-sulphate, the solvent was removed by evaporation under reduced pressure and the residual oil distilled to yield crude 3-tolyl 2,2-dichlorovinyl ether, collected as a fraction boiling at 92°-95° C/0.3 mm, which was redistilled and the fraction boiling at 84° C/0.2 mm Hg collected.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7])[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41]
Reactant: COc1cccc(CN)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: COc1cccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-methoxylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9](O)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([Cl:24])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21]
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Solvent: c1ccccc1
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)Cl)C2

Procedure:
A benzene solution (25 ml.) containing 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid (3.4 g., 0.01 mole) and thionyl chloride (2 ml.) is refluxed for two hours. Evaporation of the benzene and excess thionyl chloride leaves the 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carbonyl chloride which is used in Step B without further purification.
Reaction SMILES: [ClH:1].[C:2]([NH:6][CH2:7][CH:8]([C:10]1[CH:18]=[C:14]([C:15]([NH2:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)[OH:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[ClH:1].[C:2]([NH:6][CH2:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH:18]=1)[C:15]([NH2:17])=[O:16])[OH:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CCCCCBr
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(C(N)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(O)CNC(C)(C)C)cc1C(N)=O

Procedure:
A mixture of 5-(2-tert-butylamino-1-hydroxyethyl) salicylamide, hydrochloride (8.7 g) and anhydrous potassium carbonate (8.25 g) in dimethylformamide (100 ml) were heated at 100° for 1 hour. 1-Bromopentane (4.5 g) in dimethylformamide (25 ml) was added and the mixture was heated at 100° for a further 2 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The dried (MgSO4) ethyl acetate solution was evaporated to yield a red oil which was chromatographed on alumina. Eluation with ethyl acetate gave the required benzamide which was obtained as a colourless oil which was converted into its hydrochloride (1.55 g) m.p. 162°-167°. Recrystallisation from ethyl acetate-methanol raised the m.p. to 169°-172°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:42])[CH:12]([CH:15]([OH:41])[C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:43]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:42])[CH:12]([CH:15]([OH:41])[C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:43]
Reactant: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1C(O)C1CCc2c(C)c3cc(Cl)ccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
A solution of the mixture of two diastereoisomers of 2-chloro-8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (0.50 g) in acetic acid-water (5:2, 7 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was partitioned between water and chloroform and neutralized with an aqueous sodium hydroxide, to give precipitates. The organic layer and the precipitates were combined and chromatographed on silica gel eluted by chloroform-methanol (0-10% V/V), to give two isomers of 2-chloro-8,9-dihydro-10-methyl-7-[(hydroxy)(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.037 g), respectively.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[C:9]([O:15][C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[C:1]([O:5][C:6](=[O:27])[C:7]1[C:12]([CH2:13][Br:48])=[CH:11][CH:10]=[C:9]([O:15][C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(CO)c(C(=O)OC(C)(C)C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(CBr)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of 650 mg of 3-(tert-butoxycarbonylaminoacetoxy)-6-hydroxymethylbenzoic acid tert-butyl ester and 580 mg of triphenylphosphine was added 848 mg of carbon tetrabromide, and the mixture was stirred for 2 h at room temperature. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Column chromatography on silica gel gave 322 mg of 3-(tert-butoxycarbonylaminoacetoxy)-6-(bromomethyl)benzoic acid tert-butyl ester as a colourless oil; 1H-NMR(CDCl3) δ 1.34(9H,s), 1.51(9H,s), 4.08(2H,br.d,J=5.6 Hz), 4.80(2H,s), 4.95(1H,br.s), 7.12(1H,dd,J=8.6,2.6 Hz), 7.34(1H,d,J=8.6 Hz), 7.51(1H,d,J=2.6 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:21]=1.[CH3:22][C:23]([OH:40])([CH3:39])[CH2:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[OH:40][C:23]([CH3:39])([CH3:22])[CH2:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:21]=2)[CH:27]=[N:26]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(NC(C)(C)CO)nc2-3)cn1
Yield: 18 %

Procedure:
2-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-ol from Example 356, was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 428. Yield 18%. MS(ESI+): 429.2. 1H NMR (400 MHz, DMSO) δ 8.14-8.04 (m, 2H), 7.87 (s, 1H), 7.29 (dd, J=8.2, 1.8, 1H), 7.17 (d, J=1.8, 1H), 7.07 (s, 1H), 4.97 (t, J=5.6, 1H), 4.70 (s, 1H), 4.26 (t, J=5.0, 2H), 4.02 (s, 2H), 3.58 (d, J=5.6, 2H), 3.05 (t, J=5.0, 2H), 1.34 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].CC([O-])=O.[Na+]>C(OC(=O)C)(=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]2=[O:16])=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2]
Reactant: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 38.6 %

Procedure:
A solution of 4-(4-nitro-3-(trifluoromethyl)phenylamino)-4-oxobutanoic acid (1.1 g, 3.6 mmol) and NaOAc (1.62 g, 19.75 mmol) in acetic anhydride (15 mL) was stirred overnight at 80° C. The reaction mixture was diluted with water and extracted twice with dichloromethane. The organic layers were combined and washed with NaOH (1 N) until pH was 9. The organic layer was separated, dried with MgSO4, filtered and concentrated in vacuo to provide 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2,5-dione (0.4 g, 39%). LC/MS: m/z 288.9 (M+H)+.