Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([F:14])([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7])[CH:2]=[CH2:3].F[C:16](F)(F)C(C(F)(F)F)=O.[F-].[K+].C(Cl)C(=C)C>CN(C)C=O>[CH2:1]([O:4][C:5]([F:14])([C:10]([F:11])([F:12])[F:13])[C:6]([F:7])([F:8])[F:9])[C:2](=[CH2:16])[CH3:3]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=CCOC(F)(C(F)(F)F)C(F)(F)F
Agent: C=C(C)CCl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COC(F)(C(F)(F)F)C(F)(F)F
Yield: 85 %

Procedure:
this compound was prepared in a manner analogous to that used for the allyl ether (Example 1), using hexafluoroacetone, anhydrous KF, dimethylformamide, and methallyl chloride. Heptafluoroisopropyl methallyl ether was obtained in 85% yield, b.p. 82° C./760 mm., nD25 1.3129.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:7][C:6]2[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 35.5 %

Procedure:
A mixture of (R)-2-[4-(4-chloro-benzyl)-phenoxymethyl]-pyrrolidine hydrochloride (1.37 g, 4 mmol), methyl 4-bromobutyrate (916 mg, 5 mmol), and potassium carbonate (1.12 g, 8 mmol) in DMF (15 mL) was stirred for 60 h at rt. The solvent was removed in vacuo to obtain the crude mixture. The mixture was diluted with 30 mL of water and extracted with ethylacetate (130 mL). The aqueous layer was re-extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (570 mg, 35%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=[C:10](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:3]1(=[O:5])[O:4][C:10](=[O:9])[N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]12
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(=O)N2CCC[C@@H]12
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 165.3 %

Procedure:
L-Proline (11.5 g, 0.10 mol) was added to a 500 ml three neck flask fitted with a 125 ml addition funnel, thermometer and a nitrogen inlet tube. To the flask was added dry tetrahydrofuran (115 ml) and the mixture cooled to 15° C. using an ice/water bath. The addition funnel was charged with diphosgene (7.2 ml, 0.06 mol) and dry THF(50 ml). The diphosgene solution was added dropwise to the proline mixture over 45 minutes while maintaining a reaction mixture temperature in the range of 15° to 20° C. Once the addition was complete the mixture was warmed to 35° C. for 1 hour. At the end of this time a clear and colorless solution was obtained. The reaction mixture was then cooled to room temperature and concentrated under vacuum to a volume of approximately 50 ml. The residue was redissolved in 115 ml of THF and cooled to 0°-5° C. using an ice bath. Triethylamine (12 ml, 0.086 mol) was added dropwise to the cooled solution over 30 minutes. The solution was stirred a further 30 minutes after which time the solids were filtered and washed with THF(100 ml). The organics were concentrated under reduced pressure to give the desired compound (4) (14 g, 99%) as a light beige solid. The material was stored under nitrogen at -78° C. in order to avoid decomposition, and used without further purification in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:41]([O:43][C:44](=[O:57])[C@H:45]([OH:56])[C@H:46]([NH2:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54])[CH3:42].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:41]([O:43][C:44](=[O:57])[C@H:45]([OH:56])[C@H:46]([NH:55][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:4]2[C:5](=[O:7])[CH2:6][C:2]([CH3:1])=[N:3]2)=[CH:16][CH:15]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54])[CH3:42]
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)c1ccc(N2N=C(C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
4-(3-Methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid (100 mg, 0.6 mmol, 1.0 eq.) was combined with DMF (1000 μL) and HATU (250 mg, 0.7 mmol, 1.2 eq.) and stirred at room temperature for 15 minutes. (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (TFA salt, 200 mg, 0.6 mmol, 1.0 eq.) in DIPEA (200 μL, 2.0 eq.) and DMF (1000 μL) was then added and the resulting mixture was stirred overnight at room temperature. Excess solvent was removed and the product was dissolved in AcOH/H2O (50%) and purified by preparative LC (1″ column; gradient 2-50% MeCN/H2O, 0.05% TFA, over 80 minutes; 15 mL/min flow; UV 280 nm). The fractions were collected, frozen, and lyophilized to yield the title compound (100 mg, 98% purity). MS m/z [M+H]+ calc'd for C23H24ClN3O5, 458.14. found 458.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:23])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.51 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot methanol, filtered while hot, and cooled to room temperature. The resulting solid was collected by filtration and dried under high vacuum at room temperature to give 3.00 g (54%) of title compound, mp>250° C.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:14]2[CH2:19][CH2:18][N:17]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Compound 2 (150 mg, 0.41 mmol) was dissolved in DCM and cooled to 0° C. Ethanesulfonyl chloride (62.2 mg, 0.49 mmol) was added, followed by DIEA (0.21 mL, 1.22 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was diluted with DCM and washed with saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by normal phase chromatography eluting with 10-50% methanol/DCM gradient to provide Compound 91 as a white solid (0.13 g, 69%). MS: m/z 462.34 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), methyl 2-aminoacetate hydrochloride (19.35 mg, 0.154 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl and purified by HPLC to give the title compound. LCMS m/z=409.1 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.8 Hz, 0.3H), 1.46 (d, J=6.5 Hz, 2.7H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.56 (t, J=7.7 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.07-3.21 (m, 4H), 3.36-3.47 (m, 1H), 3.49-3.61 (m, 1H), 3.69 (s, 3H), 3.73-3.83 (m, 1H), 3.90 (d, 6.0 Hz, 2H), 6.80 (s, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH:26]=[CH:25][N:24]=1>CN(C=O)C.[Cu]I.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>[Cl:22][C:23]1[N:28]=[C:27]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:9]=3)[N:4]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CN(C)C(=O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc2c(c1)c(-c1ccnc(Cl)n1)nn2C1CCCCO1
Temperature: 100 °C
Yield: 103.3 %

Procedure:
To a solution of 3-iodo-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxamide (3 g, 7.53 mmol) and 2-chloro-4-(tributylstannyl)pyrimidine (3.6 g, 8.04 mmol) in DMF (35 mL) under argon atmosphere was added CuI (1.7 g, 9.02 mmol) and Pd(PPh3)4 (868.5 mg, 0.75 mmol) and argon gas was bubbled for 15 min. The reaction was heated at 100° C. for 1 h. The reaction was quenched with water to give off white precipitate. The suspension filtered, washed with water and dried. The crude was purified by neutral alumina column chromatography (eluting with 100% EtOAc) to give 3-(2-chloropyrimidin-4-yl)-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxamide (3.0 g, 58%) as an off white solid. MS (ESI, pos. ion) m/z: 386.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[S:12]>>[NH2:13][C:11]1[S:12][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1csc(N)n1
Temperature: 100 °C
Yield: 152.6 %

Procedure:
According to literature reference (Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623–4633), ethyl bromopyruvate (10.0 mL, 79.7 mmol) and thiourea (5.5 g, 72.3 mmol) are combined neat in a 100 mL flask and slowly heated to 100° C. over a 1 hour period. At approximately 70° C. a vigorous reaction occurs and the mixture becomes homogeneous. After reaching 100° C. the reaction is heated for an additional 20 minutes and then cooled to room temperature. Upon cooling the reaction product solidifies affording 19.0 grams of a crude ethyl 2-amino-4-thiazolecarboxylate which is used without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[CH3:18][NH2:19]>CO>[CH3:18][NH:19][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5]1)=[O:16]
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: CN
Solvent: CO
Product: CNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A mixture of 100 g (0.43 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 500 ml methanol and 100 g (3.2 mole) of methylamine was heated at 100° C. in a pressure reactor for 16 hours. The reaction mixture was cooled and the ammonia and methanol were removed under reduced pressure. The residue was taken up in dichloromethane and washed 3×100 ml 1N sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 88.3 g of N-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 82.5°-83.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2)[CH3:22]
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 50.5 h
Yield: 25.5 %

Procedure:
A mixture of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol), acetaldehyde (10.0 mg, 0.227 mmol), and sodium triacetoxyborohydride (52.1 mg, 0.246 mmol) was stirred at room temperature for 50.5 h. The reaction was then partitioned between EtOAc and H2O. The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the solid chromatographed (CHCl3/MeOH, 97.5:2.5) to afford the title compound (14.1 mg, 25%) as a yellow solid.
Reaction SMILES: C(O[CH:5](OC(=O)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)(=O)C.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:5]=[CH:18][C:17]([OH:20])=[O:19]
Reactant: CC(=O)OC(OC(C)=O)c1cccc(Cl)c1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1cccc(Cl)c1
Temperature: 200 °C

Procedure:
A three-neck flask was charged with 24.26 g of m-chlorobenzylidene diacetate and 6.15 g of sodium acetate, and the mixture was refluxed in a 200° C. oil bath for 9 hours. The mixture was cooled, and 100 g of ethyl acetate was added. Furthermore, saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was sufficiently stirred, to produce m-chlorocinnamic acid which was extracted into a water phase. The water phase was separated, and hydrochloric acid was added till the pH became 2, to precipitate m-chlorocinnamic acid which was secured by filtration. It was washed by water sufficiently and dried in vacuum at 60° C. for 8 hours, being weighed. The purity of the obtained product was analyzed by high performance liquid chromatography. The m-chlorocinnamic acid yield and m-chlorobenzylidene diacetate conversion were obtained from the following formulae:
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].O.C([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:18][N:17]=[N:16]1)C=C>CN(C)C=O>[CH2:1]([N:16]1[N:17]=[N:18][C:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[N:15]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCn1nnnc1-c1ccc(-c2ccc(OCOC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1nnc(-c2ccc(-c3ccc(OCOC)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Allyl bromide (0.27 ml, 3.13 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to a solution of the obtained compound in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to give a mixture of 1-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-1H-tetrazole and 2-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-2H-tetrazole (504 mg, two-step total yield: 71%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:4][C:3]=2[O:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:15])[CH:12]([N:25]3[CH2:26][CH2:27][N:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[CH2:23][CH2:24]3)[CH3:13])=[CH:4][C:3]=2[O:2]1
Reactant: CC(Cl)C(=O)Nc1ccc2c(c1)OCO2
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C(=O)Nc1ccc2c(c1)OCO2)N1CCN(c2ccccn2)CC1

Procedure:
The amide prepared in part (a) is condensed with 1-(2-pyridyl)-piperazine according to the method used in Example 1, using triethylamine as the base. The desired product is obtained with a melting point of 189°-191° C. (from toluene); Rf=0.44 (AcOEt); IR (nujol) νmax: 3280, 3250, 1680, 1660, 1595, 1540, 1520, 1490, 1450, 1440, 1250, 1165, 1035, 925, 775 cm-1.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C1(C)C(C)=CC=CC=1.C(O)C>[CH2:13]([O:12][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1)[CH3:14]
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Reactant: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CCOc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
5.1 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute ethanol. Then 6.8 gram for sodium ethoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 5.3 gram (98% yield). Mp: 133.8˜134.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])O[C:8]2=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].O.[CH2:23]1COCC1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7](=[CH2:8])[C:12]([O:11][C:10]([CH3:23])([CH3:15])[CH3:14])=[O:13])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: C1CCOC1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)c([N+](=O)[O-])c2)C(=O)O1
Solvent: O
Solvent: CC(C)(C)O
Product: C=C(Cc1ccc(Cl)c([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
11.1 g of 5-(4-chloro-3-nitrobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (contaminated by residual 1,3-diisopropylurea) were dissolved in 40 ml of THF and 40 ml (31 g) of tert-butanol, and 16.4 g (88.5 mmol) of N,N-dimethylmethyleneiminium iodide were added. The resulting suspension was stirred at 70° C. overnight and then, after cooling, added to water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10→50:1). This gave 8.22 g of the target product (about 78% of theory).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12].[CH3:13][O:14]CCl>[N+](C)([O-])=O.ClCCl.ClCCl>[C:11]([C:7]1[N:6]([CH3:5])[CH:10]=[C:9]([CH:13]=[O:14])[CH:8]=1)#[N:12]
Reactant: Cn1cccc1C#N
Reactant: COCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: Cn1cc(C=O)cc1C#N
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Aluminum trichloride (24.24 g, 180.86 mmol) was dissolved in nitromethane/dichloromethane (1/1, 320 ml), the solution was cooled to −20° C., and 1-methylpyrrole-2-carbonitrile (8 g, 75.36 mmol) was added. α,α-Dichlorodimethyl ether (10.4 g, 90.43 mmol), dissolved in dichloromethane (42 ml), was subsequently added dropwise. After stirring for 4 h at 0° C., the batch was poured onto ice (200 g). The aqueous phase was extracted with diethyl ether. The combined organic phases were washed until neutral with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent was removed in a rotary evaporator. The crude product was employed in the reactions below without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][C@H:42]1[CH2:43][CH2:44][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:8]3[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=3)[CH:22]=[CH:21][CH:20]=4)=[O:25])[CH2:35][CH2:34]2)[CH2:40][C@@H:41]1[CH3:46]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc12
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc12

Procedure:
This compound is synthesized analogously to example 1 from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 119 (see example 80) and amine 56.