Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[C:10]([C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1oc2cccc(OC)c2c1C
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3cccs3)ccc(OC)c2c1C

Procedure:
To a solution of ethyl 3-methyl-4-methoxy-benzofuran-2-carboxylate (3.48 g, 14.86 mmol) in dry 1,2-dichloroethane (15 mL) was added a solution of thiophene-2-carbonyl chloride (6.54 g, 44.61 mmol) in 1,2-dichloroethane (10 mL) followed by the portionwise addition of aluminum chloride (7.92 g, 59.40 mmol). An exothermic reaction ensued and the mixture was allowed to stir until gas evolution had slowed, then warmed to reflux for 2 hours. Upon cooling the reaction mixture was poured into 2N HCl (100 mL) and extracted with methylene chloride (4×25 mL). The combined organic extracts were washed with 5% NaHCO3, dried (Na2SO4), and concentrated to a brown solid (5.40 g). Recrystallization from ethanol/benzene afforded pure ethyl 3-methyl-4-methoxy-7-(2-thienoyl)benzofuran-2-carboxylate, compound 1. mp 179°-182° C.; 1H NMR d 1.40 (3H, t, J=6 Hz), 2.77 (3H, s), 4.04 (3H, s), 4.42 (2H, q, J=6 Hz), 6.75 (1H, d, J=8 Hz), 7.17 (1H, dd, J=4 Hz), 7.72 (2H, m), 7.86 (1H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 31.2 %

Procedure:
Beginning with 3.0 gm (20.0 mMol) 5-chloro-1H-indole and 6.0 gm (40.0 mMol) 4-piperidone hydrochloride monohydrate, 1.45 gm (31%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)=[CH:9]2)(=O)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][N:33]=[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)=[CH:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (0.823 g, 2.22 mmol) in DCM (5 mL) was added 2,4-dimethoxybenzylamine (0.38 mL, 2.53 mmol) and NEt3 (0.90 mL, 6.45 mmol). Mixture was cooled to 0° C. before TiCl4 solution (1M DCM, 1.45 mL, 1.45 mmol) was added dropwise via syringe pump over 30 min. Reaction was allowed to warm to room temperature and stirred overnight. Mixture was diluted with DCM (10 mL) and then quenched with NaHCO3 (aqueous saturated, 10 mL). Upon vigorous shaking organic phase was separated using a PTFE phase separator, dried over Na2SO4. Removal of the solvent afforded product (1.15 g, quant) as yellow oil, which was taken directly into next steps without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[N:26]=[C:25]2[NH2:50].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[N:26]=[C:25]2[NH:50][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(C(=O)O)c1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=Cc1ccc(F)c(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Temperature: 4 °C
Yield: 79 %

Procedure:
2-Fluoro-5-formyl-benzoic acid (368 mg, 2.187 mmol) in toluene (22 mL) was treated with thionyl chloride (1.59 mL, 21.87 mmol) and stirred under reflux temperature for 4 hours. The volatiles were evaporated, the residue was taken up with toluene (4 mL) and evaporated to dryness leaving an off white solid which was dissolved in dry THF (5 mL) and added drop-wise to a solution of 5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-ylamine (843 mg, 1.68 mmol) and DIPEA (0.88 mL, 5.04 mmol) in THF (10 mL), cooled to 4° C. The reaction was gradually brought to room temperature. After one night, the volatiles were evaporated. The crude was dissolved in DCM (150 mL) and washed with aqueous NaHCO3 (100 mL) then with water and finally with brine. After drying over sodium sulphate, evaporation and purification over silica gel (eluent: DCM) 868 mg of title compound as a white solid in 79% yield were obtained.
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:18]([OH:22])[CH:19]([OH:21])[CH3:20]>CCCCC>[OH:21][CH:19]([CH3:20])[CH2:18][O:22][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(O)CO
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Solvent: CCCCC
Product: CC(O)COc1c2ccccc2c(C=O)c2ccccc12
Yield: 29.5 %

Procedure:
Using the procedure outlined in Example 2A, 10-chloroanthracene-9-carbaldehyde (Aldrich) and 1,2-propyleneglycol (Aldrich) gave a 29.5% yield of 10-[2-(hydroxy)propoxy]anthracene-9-carbaldehyde, mp 84°-86°, (C,H), (pentane).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)[N:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:8][C:7]2[C:2]([F:1])=[N:3][C:4]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=3)=[CH:5][CH:6]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)c(F)n2)cc1

Procedure:
0.29 g (0.91 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine (prepared as described in Example 3), 0.19 g (0.91 mmol) of dicyclohexylcarbodiimide, 0.16 g (0.91 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.01 g of 4-(N,N-dimethylamino)pyridine are stirred in 10 ml of methylene chloride at room temperature for 18 hours. Filtration, evaporation to dryness, purification by chromatography (silica gel, 8:2 hexane/ethyl acetate) and recrystallization from acetonitrile give 0.19 g of 2-fluoro-6-(4-octyloxyphenyl)pyridin-3-yl trans-4-pentylcyclohexanecarboxylate. ##STR40##
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].S(Cl)([Cl:17])(=O)=O>C(#N)C>[Cl:17][C:12]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:13])[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc2c(cc1O)CCCC2
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: N#Cc1c(O)cc2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 mL round-bottom flask was placed 5,6,7,8-tetrahydro-3-cyano-2-naphthol (1.0 g, 5.77 mmol, 1 eq, from Method II-2) in 20 mL of dry acetonitrile under argon. Sulfuryl chloride (6.09 mL, 28.85 mmol, 5.0 eq) was added dropwise. The reaction was stirred at rt for 18 h. The reaction mixture was concentrated and purified on silica gel (flash column chromatography) eluting with 20% ethyl acetate-hexane. A 1:1 diastereomeric mixture of 4-Chloro-3-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile and 1-Chloro-3-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile was obtained as a yellow liquid (887 mg, 66.6%, isomer ratio:1:1). 1H-NMR (CD3CN) δ 7.81 (s, 1H), 3.24 (m, 1H), 2.66 (m, 1H), 2.33 (m, 1H), 2.07(m, 2H), 1.88 (m, 2H), 1.43 (m, 1H). GC-MS (M+=207)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.IC.[CH3:12]C(O[K])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(=O)O[K]
Solvent: CI
Solvent: CC#N
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-methoxypyridine (1) (500 mg, 2.66 mmol), iodomethane (755 mg, 5.32 mmol) and CH3COOK (782 mg, 7.98 mmol) in acetonitrile (5 mL) was heated at reflux for 18 h. After cooled to rt, the mixture was filtered. The filtrate was concentrated and purified by reverse phase silica gel (MeOH in 0.05% NH3.H2O/H2O 10-95% v/v as mobile phase) to afford 2 as a white solid. ESI-MS: 189.0 (M+1)+.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]([O:16]CC)=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.O.[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][CH2:16][C:14]([C:11]1[C:12]([F:13])=[C:6]2[O:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]2=[C:9]([C:20]#[N:21])[C:10]=1[CH3:19])=[O:15]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-78) (9.34 g, 30.1 mmol) was dissolved in tetrahydrofuran (450 ml), then water (27 ml) and N-bromosuccinimide (5.73 g, 31.58 mmol) were added all at a time, followed by stirring at room temperature for 45 minutes. After the reaction, the solvent was evaporated away under reduced pressure, followed by dilution with ethyl acetate and by washing with aqueous sodium thiosulfate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane/ethyl acetate (4:1, v/v) to obtain the intended product (9.63 g, 95%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8]2)[CH2:3][CH2:2]1.[N:36]1([CH2:40][C:41]2[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:44]=[C:43]([C:51](O)=[O:52])[CH:42]=2)[CH2:39][CH2:38][CH2:37]1.Cl.N1(CC2N=C(C(F)(F)F)N=C(C(O)=O)C=2)CCC1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C>[N:36]1([CH2:40][C:41]2[N:46]=[C:45]([C:47]([F:49])([F:48])[F:50])[N:44]=[C:43]([C:51]([N:1]3[CH2:6][CH2:5][CH:4]([N:7]4[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]5[CH:15]=[C:14]([C:16]6[C:17]7[CH:24]=[CH:23][NH:22][C:18]=7[N:19]=[CH:20][N:21]=6)[CH:13]=[N:12]5)[CH2:8]4)[CH2:3][CH2:2]3)=[O:52])[CH:42]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1cc(CN2CCC2)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(CN4CCC4)nc(C(F)(F)F)n3)CC2)C1
Reaction time: 2 h

Procedure:
{1-Piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.150 g, 0.30 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added to a mixture of 6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (0.20 g, 0.46 mmol, as the hydrochloride salt from Step B), triethylamine (0.255 mL, 1.83 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.150 g, 0.396 mmol) in tetrahydrofuran (3.0 mL) and DCM (3.0 mL) that was pre-stirred for 30 minutes. After stirring for 2 hours, the reaction mixture was diluted with ethyl acetate and washed successively with water, 0.1 N NaOH, and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in a 1:1 mixture of DCM:TFA, stirred for 1 hour, concentrated again, then stirred with methanol (3 mL) containing ethylenediamine (0.2 mL). After complete deprotection, the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.1% TFA) then again eluting with MeCN/H2O containing 0.15% NH4OH to afford desired product. Yield: 0.043 g (23%); LC-MS: 606.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.15 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.81 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 4.10-4.01 (m, 1H), 3.81 (s, 2H), 3.75 (dd, 2H), 3.62-3.44 (m, 5H), 3.31-3.21 (m, 5H), 3.14-3.05 (m, 1H), 2.60-2.52 (m, 1H), 2.04 (quin, 2H), 1.83-1.73 (m, 1H), 1.69-1.60 (m, 1H), 1.37-1.18 (m, 2H). 19F NMR (400 MHz, CD3OD): δ −72.38 (s, 3F).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:46]2[C@H:47]([CH3:70])[C@H:48]3[C@@H:65]([C@H:66]([OH:68])[CH3:67])[C:64](=[O:69])[N:49]3[C:50]=2[C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=2)=[O:52])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:19]1([S:16]([NH:15][CH2:14][C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:46]4[C@H:47]([CH3:70])[C@@H:48]5[C@@H:65]([C@H:66]([OH:68])[CH3:67])[C:64](=[O:69])[N:49]5[C:50]=4[C:51]([O:53][CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=4)=[O:52])[CH2:6]3)[S:10][CH:11]=2)(=[O:17])=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CNS(=O)(=O)c5ccccc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of 3-acetylthio-1-[4-(benzenesulfonylaminomethyl)-1,3-thiazol-2-yl]azetidine (1.00 g, 2.68 mmol) (obtained as described in Reference Example 65) in dimethylformamide (30 ml) was added hydrazine acetate (296 mg, 3.21 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.75 g, 2.94 mmol) in acetonitrile (60 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.87 ml, 10.7 mmol). The mixture was stirred for 3 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: hexane:ethyl acetate (1:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(benzenesulfonylaminomethyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.13 g, yield 61%) as a pale yellow solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([CH:31]2[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH2:24]3)=[O:18])[CH:12]=[CH:13][C:14]=1[CH3:15])(C(C)(C)C)(C)C.[F-].[Cs+]>CN(C=O)C.O>[O:38]=[C:32]1[CH:31]([N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([CH2:20][NH:19][C:17]([NH:16][C:11]4[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([OH:8])[CH:10]=4)=[O:18])[CH:22]=3)[C:26]2=[O:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1O[Si](C)(C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1O
Temperature: 70 °C

Procedure:
A mixture of 1-(3-(tert-butyldimethylsilyloxy)-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol) and cesium fluoride (0.15 g, 1.0 mmol) in DMF (10 mL) is heated to 70° C. for 8 hrs. The mixture is cooled and diluted with water (10 mL). The solid precipitate is filtered, rinsed with water (10 mL), and dried under vacuum to provide the product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][N:17](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[C:16]#[N:17]
Reactant: CC(=O)N(C)C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc2nccc(C#N)c2cc1OC
Temperature: 150 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.0 g, 9.0 mmol) was dissolved in N,N-dimethylacetamide (12 ml). The mixture was degassed under nitrogen. Zinc(II) cyanide (0.66 g, 5.8 mml), zinc (0.084 g, 1.3 mmol), tris(dibenzylidene-acetone)dipalladium(0) (0.17 g, 0.19 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.23 g, 0.41 mmol) were then added. The reaction mixture was heated in a microwave at 150° C. for 10 minutes. The solvent was removed and the residue was purified by silica gel chromatography (hexane to ethyl acetate) to give 6,7-dimethoxyquinoline-4-carbonitrile that was dissolved in 5% hydrochloric acid (conc) in ethanol and stirred under a hydrogen balloon with Pd/C (cat.). After filtration through celite, the filtrate was collected and concentrated to give (6,7-dimethoxyquinolin-4-yl)methanaminium chloride. MS (ESI, pos. ion) m/z: 219 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C:26]2=[N:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C@:26]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[F:8])[NH:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Fc1ccccc1Br
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccccc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Toluene (100 ml) and THF (10 ml) were added to 2-bromofluorobenzene (3.11 g). The reaction solution was cooled to −78° C., and n-butyllithium (2.63 M, 6.15 ml) was added dropwise. After stirring at the same temperature for one hour, a mixed solution of (3aR,5R)-5-benzyloxymethyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole (2.00 g) in toluene (20 ml) and THF (2 ml) and a boron trifluoride-diethyl ether complex (2.03 ml) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to the reaction solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (2.29 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH:18]1([CH2:21][C:22](N(OC)C)=[O:23])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][C:22]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:23])[CH2:20][CH2:19]1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)CC1CC1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC2CC2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2-cyclopropyl-N-methoxy-N-methylacetamide. It is used in crude form in the following reaction.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=O)CCC.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[C:22]1([S:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10]([C:28]#[N:29])=[N:9][C:8]([C:6]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])=[C:17]3[OH:18])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(S(=O)(=O)c3ccccc3)ccc12

Procedure:
Prepared from 6-benzenesulfonyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 28e (56% yield). MS-(+)-ion: M+1=412.26.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([OH:12])=[CH:14][CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(O)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-hydroxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.98 (m, 5H), 2.14 (s, 1H), 2.27-2.34 (m, 2H), 2.36-2.43 (m, 1H), 3.50 (s, 2H), 3.60 (s, 3H), 4.36 (s, 1H), 6.70-6.98 (m, 2H), 7.56-7.82 (m, 2H); MS (APCI/NH3) m/z 273 (M+H)+.