Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5][C@:4]([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([O:13][CH3:14])[CH2:3]1.[C:30](=O)([O:41]CCCC=C)[O:31][C:32]1C=[CH:36][C:35]([N+]([O-])=O)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:14][O:13][C@:4]1([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:3][C@H:2]([NH:1][C:30](=[O:41])[O:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5]1
Reactant: C=CCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C=CCCC[C@@H]1C[C@@H](N)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCOC(=O)N[C@@H]1C[C@@H](CCCC=C)O[C@@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)C1
Reaction time: 24 h
Yield: 83 %

Procedure:
A solution of the title compound from Example 67 (113 mg, 0.269 mmol) in dichloromethane (2 mL) was treated with a solution of 4-nitrophenyl pent-4-enyl carbonate (88 mg, 0.35 mmol) in dichloromethane (0.8 mL), diisopropylethylamine (0.061 mL, 0.35 mmol), and a catalytic amount of DMAP (0.2 mg). The mixture was stirred for 24 h, after which it was chromatographed directly on silica gel, eluting with ethyl acetate/dichloromethane, to give the title compound (119 mg, 83%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:24]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccco4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.8 %

Procedure:
Route 2: 2-(4-aminophenyl)-6-methyl benzothiazole (2.0 g, 8.3 mmole) and 2-Furoyl chloride (1.086 g, 8.32 mmole) were suspended in methylene chloride (30 ml, anhydrous). triethylamine (1.24 g, 12.25 mmole) was added to the reaction mixture with stirring at room temperature for 2 days. (pH 7.0-7.2). Methylene chloride (50 ml) was added to the reaction mixture, and the reaction mixture extracted with 1 N HCl (50 ml) to separate a solid. The solid was filtered and washed with water to yield 1.3 g (46%) of the desired compound. The product was crystallized from MeOH to obtain 0.99 g, mp 238-240° C. 1H and 13C NMR were consistent with the expected product. TLC showed one spot (5% MeOH-CH2Cl2 as developing solvent on silica gel plate).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)[CH:25]=[C:24]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])C.[OH-].[Na+]>>[C:40]([CH2:39][CH2:38][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)[CH:25]=[C:24]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])([OH:42])=[O:41]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncn3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccncn2)c1

Procedure:
Title compound was prepared according to a similar procedure described in Example 21, step 2 by reaction of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-methanesulfonyl-5-pyrimidin-4-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (164 mg) with 3 N NaOH (1 mL). Preparative HPLC provided the title compound. LC/MS indicated a purity of 84% as measured by UV 214 nM. HR-ES(+): calculated for C30H37N2O8S (M+H)1+ 582.2265, found 585.2267.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:7]2[CH:8]=[CH:9][N+:10]([O-])=[CH:11][C:6]2=[N:5][N:4]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[C:6]2[N:7]([C:3]([C:2]([F:14])([F:13])[F:1])=[N:4][N:5]=2)[CH:8]=[CH:9][N:10]=1
Reactant: [O-][n+]1ccn2c(C(F)(F)F)nnc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nnc2c(Cl)nccn12

Procedure:
A suspension of 40 mg (0.196 mmol) of 3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyrazine 7-oxide in 0.9 mL of phosphorus oxychloride was stirred at reflux for 2.5 h. The cooled solution was concentrated to dryness. Purification of the residue by preparative HPLC (C18 reverse phase column, 10-70% acetonitrile in water containing 0.05% trifluoroacetic acid) and then by flash chromatography on silica gel (10-30% ethyl acetate in hexanes) yielded the title compound as a white solid. LC-MS 223 (M+1).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:30]([O:34][C:35]([N:37]1[CH2:44][C@@H:43]([OH:45])[CH2:42][C@H:38]1[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[C:30]([O:34][C:35]([N:37]1[CH2:44][C@H:43]([OH:45])[CH2:42][C@H:38]1[C:39]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:40])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CC(C)(C)N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
17.16 g (62.40 mmol) of diphenylphosphoryl azide, 5.70 g (78.08 mmol) of t-butylamine and 10.4 g (104.00 mmol) of triethylamine were added, in that order, to a solution of 12.0 g (51.95 mmol) of (4S)-1-t- butoxycarbonyl-4-hydroxy-L-proline in 100 ml of dimethylformamide, whilst ice-cooling, and the mixture was stirred for 5 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which the mixture was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 10.0 g of the title compound as colorless crystals, melting at 192°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:14](O)[CH3:15].OS(O)(=O)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH:5][CH2:6][C:7]([O:9][CH2:14][CH3:15])=[O:8]
Reactant: CCO
Reactant: O=C(O)CNc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CNc1ccc(Cl)c(Cl)c1
Yield: 78 %

Procedure:
A solution of 27.5 g (0.125 mol) of 3,4-dichloroanilinoacetic acid, 190 ml of dichloroethane, 15 ml (0.2 mol) of ethanol and 1.5 ml of concentrated H2SO4 is heated for 4 hours under reflux. It is washed with water and with dilute sodium bicarbonate, dried and evaporated to dryness in vacuo. The ester is recrystallised from ethanol and is obtained in a yield of 78%. It melts at 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[K+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:7])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)C(O)c1ccc(Cl)cc1
Yield: 76.7 %

Procedure:
To a solution of 4-chlorobenzaldehyde (240 g, 1.707 mol) in 144 mL of methanol was added 2.40 g of potassium cyanide in 4.8 mL water over 6 min. The mixture was refluxed for another 50 min (mixture became deep red), cooled, then concentrated under reduced pressure. The red residue was taken up in 1500 mL of hexane-ethyl acetate (1:1), and washed successively with water (1×150 mL), 20% sodium bisulfite (6×150 mL), brine (1×150 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the product was boiled in 400 mL of hexane to remove small amounts of 4-chlorobenzaldehyde. The mixture was cooled and the white solid was collected by suction filtration to give 183.94 g of 4,4′-dichlorobenzoin (76%). This procedure was adapted from Lutz et al. J. Am. Chem. Soc. 1949, 71, 478.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:26][C:14]([F:13])([F:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2C(F)(F)F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-trifluoromethylbenzenesulfonyl chloride according to METHOD A, giving 0.13 g (31%) of a red solid after recrystallization from acetone/ether/petroleum ether: mp 171° C.; MS (Ionspray, [M+H]+) m/z 395; Anal. Calcd (found) for C14H13F3N2O4S2: C, 42.6 (43.0)%, H, 3.3 (2.9)%, N, 7.1 (6.9)%.
Reaction SMILES: [NH:1]([CH:3]([CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH2:4][OH:5])N>CO.[Ni]>[NH2:1][CH:3]([CH2:6][CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[CH2:4][OH:5]
Reactant: NNC(CO)CC1CCOCC1
Agent: [Ni]
Solvent: CO
Product: NC(CO)CC1CCOCC1
Yield: 91.5 %

Procedure:
To a solution of 2-hydrazino-3-(tetrahydro-pyran-4-yl)-propan-1-ol (6.15 g, 0.035 mol) in MeOH (120 mL) was added Raney Ni. The flask was evacuated and equipped with a hydrogen inflated balloon. The flask was dipped into an ultrasound bath filled with water and sonicated for 4 h at rt until the starting material was completely consumed. The mixture was filtered through celite, and the filter cake was washed with MeOH (2×30 mL). Concentration of the filtrate under reduced pressure gave 2-amino-3-(tetrahydro-pyran-4-yl)-propan-1-ol (5.1 g, 91%). 1H NMR (CD3OD) δ 1.2-1.5 (m, 4H), 1.5-1.7 (m, 3H), 1.9-2.2 (s, 3H), 2.9-3.0 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.4 (m, 2H), 3.5-3.6 (m, 1H), 3.9-4.0 (m, 2H).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[S:20][CH2:21][C@@H:22]([C:31]([OH:33])=O)[NH:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].CN(C=O)C>CCOC(C)=O>[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]([O:24][NH:23][C@@H:22]1[C:31](=[O:33])[NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[S:20][CH2:21]1)=[O:30]
Reactant: COc1cccc(SC[C@H](NOC(=O)C(C)(C)C)C(=O)O)c1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1NC(=O)[C@@H](NOC(=O)C(C)(C)C)CS2
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
0.948 mL of diethyl cyanophosphonate (1.019 g, 6.245 mmol) is placed in a 100 mL three-necked flask containing 1.80 g of 54 (5.26 mmol) and 25 mL of DMF, at 0° C., followed by addition, after 10 minutes, of 0.708 mL of TEA (5.04 mmol). The reaction medium is stirred at 0° C. for 2 hours. 50 mL of EtOAc are added and the mixture is then washed with twice 50 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (150 g) eluting with heptane/EtOAc (as an EtOAc gradient: 10% to 50%). 450 mg of expected product 55 are obtained (white solid).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].ClC[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>[O-]CC>[C:1]([NH:4][C:5]([C:29]1[CH:30]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:28]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1cccc(CCl)c1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Product: CCOC(=O)COc1cccc(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)c1
Temperature: 0 °C

Procedure:
Diethyl acetamidomalonate (2.60 g) and ethyl 3-(chloromethyl)phenoxyacetate (Robertson, J. Chem. Soc. (1933), 492; U.S. Pat. No. 3,933,895) (2.39 g) were dissolved in ethanolic ethoxide (prepared from sodium (230 mg) and absolute ethanol (10 ml)) and the mixture refluxed for 19 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract evaporated. The residual gum was crystallised from ether/hexane to give diethyl acetamido-(3-ethoxycarbonylmethoxyphenyl)malonate as white prisms, m.p. 98.5°-101.5°. This derivative (1.90 g) was refluxed with 10% aqueous hydrochloric acid (25 ml) for 31/2 hours and the cooled solution was evaporated to dryness in vacuo. The residual white solid was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (15 ml) and thionyl chloride (1.64 g). The resulting solution was set aside at room temperature for 18 hours, refluxed for 1 hour, cooled, and poured into ice-water, adjusting the pH to 9-10 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated, giving ethyl 2-amino-3-(3-ethoxycarbonylmethoxyphenyl)propionate as a colourless oil, which was used without further purification in Examples 20 and 21.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]4=[O:37])=[CH:23][C:22]=3[F:38])=[C:17]([F:39])[CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>ClCCl>[F:38][C:22]1[CH:23]=[C:24]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH2:11][CH:10]([CH2:9][OH:8])[O:14][N:13]=2)=[CH:16][C:17]=1[F:39]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO[Si](C)(C)C(C)(C)C)C4)cc3F)c(F)c2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)cc3F)c(F)c2)C(=O)O1
Reaction time: 5 h
Yield: 37.9 %

Procedure:
N-[((5S)-3-{4′-[5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-2,2′-difluoro-1,1′-biphenyl-4-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (416 mg, 0.74 mmol) was dissolved in dichloromethane (25 ml) at room temperature. A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.82 ml, 0.82 mmol) was added and the reaction mixture stirred for 300 minutes. Water (50 ml) was added and the dichloromethane layer separated, dried over magnesium sulfate, filtered then concentrated in vacuo onto silica (2 ml). This was purified by chromatography (20 g silica gel bond elut; 0 to 6% methanol/dichloromethane) to yield 125 mg (38%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@@:21]([NH:23][CH:14]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (0.79 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.66 g, 2.81 mmol, Step-3 of Amine-2) and (S)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].CCO[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1OC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.6 %

Procedure:
To a solution of 3,4-dimethoxyaniline (100 g, 0.65 mol) in 130 ml of N,N-dimethylformamide was added diethyl ethoxymethylene malonate (141.2 g, 0.65 mol). The mixture was stirred at room temperature for 21 hours. The solvent was evaporated in vacuo and the residual dark brown oil was recrystallized from 1.6 l cyclohexane and 50 g of activated carbon to give 150.5 g of desired product. Extraction of the carbon with hot cyclohexane gave another 27.1 g of product. Total yield 177.6 g, melting point 57°-59° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:22]C1C=CC(C=O)=CC=1>>[Br:22][C:7]1[CH:6]=[CH:5][C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(Br)cc2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 52 but using 4-bromobenzaldehyde in place of 3-iodobenzaldehyde. Solid (31 g, 80%);
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][CH:38]1[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1.484 g, 5.37 mmol) in dry dichloromethane (60 ml) was added triethylamine (1.88 ml, 13.49 mmol), 2-chloro-1-methylpridinium iodide (1.60 g, 6.26 mmol), and 4-amino-1-BOC-piperidine (1.30 g, 6.49 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography on an Isco Combiflash (40 g silica gel, 40 mL/min, 254 nM, 15% to 100% EtOAc/hexane over 14 column volumes then 100% EtOAc for 4 column volumes; title compound eluted at 65% ethyl acetate/hexane) to afford the title compound as a pale orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.C([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=2)[CH:18]=[C:17]1B(O)O)(OC(C)(C)C)=O>>[Cl:25][C:22]1[CH:23]=[C:24]2[C:19]([CH:18]=[C:17]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)[NH:16]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: Cc1cncc(Br)c1
Product: Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1

Procedure:
3-Methyl-5-bromopyridine and N-Boc-6-chloro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 6-chloro-2-(5-methyl-pyridin-3-yl)-1H-indole. (ESI) m/z 243.0 (M+H)+.
Reaction SMILES: [CH:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:10]=1[C:9]1[NH:11][C:12]3[C:17]([C:8]=1[CH2:7][CH2:6]2)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(O)C.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>ClCCl>[CH2:26]([O:25][C:21]([CH2:22][CH2:23][CH:1]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:9]=32)[CH2:4][CH2:3][CH2:2]1)=[O:24])[CH3:27]
Reactant: C=CC(=O)OCC
Reactant: C1=C2c3[nH]c4ccccc4c3CCN2CCC1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCC1CCCN2CCc3c([nH]c4ccccc34)C12
Reaction time: 48 h

Procedure:
2.2 g (10 mmoles) of 2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine are dissolved in 100 ml of dichloromethane, 0.5 ml of ethanol and 2.3 g (25 mmoles) of ethyl acrylate are added to the solution, and the mixture is allowed to stand at room temperature for 2 days under argon atmosphere. The solvent is evaporated in vacuo, the residue is triturated with 3×3 ml of petroleum ether, the liquid is decanted, and the solid is dried.
Reaction SMILES: C[C:2]([CH:5]([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:10]1)[C:6]([O-])=O)(C)C.Cl.[C:33](NN)(C)(C)C>>[CH3:33][C:5]([N:9]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[N:10]1)([CH3:2])[CH3:6]
Reactant: CC(C)(C)C(C(=O)[O-])n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)NN
Agent: Cl
Product: CC(C)(C)n1ccc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the minor isomer. ESMS (M−C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO)8.20 (d, 2H), 7.86 (d, 2H), 7.7(d, 1H), 6.55(d, 1H), 1.25 (s, 9H)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[O:28]>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:27](=[O:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18])[C:9]#[N:10]
Reactant: N#CCC(=O)c1ccc[nH]1
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: N#CC(C(=O)Nc1ccc(Cl)cc1Cl)C(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 2.1 g of 2-pyrroloylacetonitrile in 15 ml of glyme and 1.8 g of Et3N is treated with a solution of 3 g of 2,4-dichlorophenyl isocyanate in 15 ml of glyme similarly to the preceding examples. Mildly exothermic reaction results in formation of a thick suspension of crystals. After standing overnight, dilution with dry ether and filtration gives the triethylamine salt of β-oxo-α-(2,4-dichlorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 180°-2° dec., in form of the enol structure as represented by formula Ia, wherein Py is 2-pyrrolyl, R is hydrogen and Ph is 2,4-dichlorophenyl.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.[C:45]([O:49][C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54]([C:57]#[CH:58])=[CH:53][CH:52]=1)([CH3:48])([CH3:47])[CH3:46]>C(#N)C.[Cu]I>[C:50]([C:51]1[CH:56]=[CH:55][C:54]([C:57]#[C:58][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:53][CH:52]=1)([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:59]
Reactant: CCOC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2ccc(C#Cc3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Reaction time: 8 h

Procedure:
100 ml of triethylamine, 6.3 g of triphenylphosphine, 2.81 g of (Pφ3)2PdCl2 and 0.77 g of copper(I)iodide are added under nitrogen to 61 g of 4-bromo-4'-carbethoxybiphenyl in 300 ml of absolute acetonitrile. 44.3 g of 4-ethinyl-benzoic acid tert.-butyl ester dissolved in 300 ml of absolute acetonitrile are slowly added dropwise at the reflux temperature and the reaction mixture is boiled overnight. It is then suction filtered while hot and stirred up in water and again suction filtered and the residue is dissolved in CH2Cl2 and filtered after the addition of Tonsil.