Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:14]([C@H:15]2[CH2:20][C@H:19]3[CH2:21][C@@H:16]2[CH2:17][CH2:18]3)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:23]([O:27][C:28]([N:30]1[CH:35]2[CH2:36][CH2:37][CH:31]1[CH2:32][N:33]([C:38]([C:40]1[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=1)=[O:39])[CH2:34]2)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH:31]2[CH2:37][CH2:36][CH:35]1[CH2:34][N:33]([C:38]([C:40]1[CH:41]=[N:42][C:43]([NH:46][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:22])[CH3:1])[N:14]([C@H:15]5[CH2:20][C@H:19]6[CH2:21][C@@H:16]5[CH2:17][CH2:18]6)[C:8]=4[N:9]=3)=[CH:44][CH:45]=1)=[O:39])[CH2:32]2)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1[C@H]1C[C@@H]2CC[C@H]1C2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1[C@H]1C[C@@H]2CC[C@H]1C2

Procedure:
Following general N—C coupling procedure 1 as in example 76, 7-(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (90 mg, 0.28 mmol) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester which gave 3-[6-((1S,2S,4R)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and was used as is without further characterization.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.S(O[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: CS(=O)(=O)OCCOCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCCc3ccccc3)cc2)C(O)C1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] with 2-phenethyloxy-ethanol mesylate [J.Med.Chem. (1983),26 (11),1570-1576], prepared according to a procedure known from the literature, in the presence of potassium carbonate there was obtained tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate, alkylation of which analogously to Example 1(g) yielded tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 582 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]([F:15])([F:14])[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.OS(O)(=O)=O.O=S(=O)=O>>[C:1]([O:13][CH:8]([C:9]([F:12])([F:11])[F:10])[C:7]([F:15])([F:14])[F:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C=CC(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: C=CC(=O)OC(C(F)(F)F)C(F)(F)F
Yield: 95.7 %

Procedure:
With reference to scheme (13) above, a 1000 mL three-neck flask can be equipped with a thermometer, agitator, and dropping funnel with a dip tube. Into the flask can be added about 130.6 grams of acryloyl chloride, 168.8 grams 1,1,1,3,3,3-hexafluoropropan-2-ol, and 1 grain of 2,6-di-tert-butyl-4-methylphenol to form a mixture. About 30% (wt/wt) oleum can then be added to the mixture through the dip tube while maintaining the mixture at 60° C.-75° C. After addition, the mixture can be maintained at 60° C.-70° C. for about 4 hours. Single stage vacuum distillation of the mixture can yield about 183 grains of crude product 1,1,1,3,3,3-hexafluoropropan-2-yl acrylate being about 95.7% (area percent by as chromatography). The crude 1,1,1,3,3,3-hexafluoropropan-2-yl can be distilled further to increase purity to 99.7% (area percent by gas chromatography).
Reaction SMILES: [F:1][C:2]1[C:11](F)=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(OC(=O)[NH:20][C@H:21]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23][CH2:22]1)(C)(C)C.C(OC(=O)N[C@H]1CC[C@H](OC2C(Cl)=C3C(=CC=2)C=NC=C3)CC1)(C)(C)C>>[F:1][C:2]1[C:11]([O:27][C@@H:24]2[CH2:25][CH2:26][C@H:21]([NH2:20])[CH2:22][CH2:23]2)=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Fc1cc2cnccc2c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2Cl)CC1
Product: N[C@H]1CC[C@@H](Oc2c(F)cc3cnccc3c2F)CC1

Procedure:
Starting from 5,6,7-trifluoro-isoquinoline (101) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, the Boc-protected intermediate was prepared by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10). Deprotection using standard procedures (see 11 or 13) gave the title compound, which was isolated as trifluoro acetate after prep. HPLC. Subsequent treatment of the obtained trifluoro acetate with 2N HCl, followed by lyophilisation gave the corresponding HCl-salt. Rt=0.86 min (Method #1). Detected mass: 279.1 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C(Cl)(=O)[C:11]([Cl:13])=O>ClCCl.CN(C=O)C>[Cl:13][CH2:11][C:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)=[O:9]
Reactant: O=C(O)C1CCCCO1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCl)C1CCCCO1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Tetrahydropyran-2-carboxylic acid (3.3 g) in dry dichloromethane (60 ml) was treated with oxalyl chloride (4.8 g, 3.3 ml) and DMF (2-3 drops). After the initial effervescence had ceased the mixture was left for a further 1 h at ambient temperature. The solvent and excess oxalyl chloride were removed in vacuo and the resultant oil (νmax (CH2Cl2)1830 cm-1 ] was dissolved in dichloromethane (20 ml). This acid chloride solution was then added dropwise to a freshly prepared ethereal solution of diazomethane (ca 2 fold excess) cooled to 0-5° C, t.l.c. analysis (60% ethyl acetate in hexane) showed a single mobile spot, i.r. spectrum of a sample showed clean conversion to the diazoketone [νmax (CH2Cl2) 2100 cm-1 ]. Hydrogen chloride gas was bubbled through the solution until no further starting material was observed by t.l.c. The mixture was washed with brine, dried and the solvent removed in vacuo and the residue purified by flash chromatography on silica gel. The title compound was obtained as a pale yellow oil, (2.8 g, 68%); νmax (CH2Cl2) 1740 cm-1 ; δH (CDCl3) 1.4-1.7 (4 H, m), 1.91-1.98 (2 H, m), 3.42-3.53 (1 H, m), 3.95-4.07 (2 H, m) and 4.48 (2 H, s) [Mass spectrum: +ve ion (NH3), MH+ (163), MNH4+ (180)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](O)([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 7 h
Yield: 91.7 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline (109 mg, 0.41 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (10 mg) and a trace of cone. H2 SO4 at rt for 7 h. Filtration over Celite™ afforded 93 mg (92%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.62 (d, J=8.1, 1H), 7.16 (d, J=7.8, 1H), 7.11 (ddd, J=7.8, 7.8, 1.6, 1H), 7.01 (ddd, J=7.7, 7.5, 1.0, 1H), 3.71 (m, 2H), 2.87 (ddq, J=6.8, 6.8, 6.8, 1H), 2.04 (dddd, J=7.4, 7.4, 7.4, 6.1, 1H), 1.61 (m, 1H), 1.51 (s, 9H), 1.3 (d, J=6.8, 3H).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]2[CH2:27][CH2:28][CH2:29][CH:25]2[CH3:24])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC1CCCN1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCC2C)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 89.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 85 mg of 2-methylpyrrolidine was added therein, and the mixture was stirred for 7 hours at 60° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 207 mg of 4-(2-butynyloxy)-6-(2-methyl-pyrrolidin-1-yl) pyrimidine (hereinafter, referred to as Compound (21)).
Reaction SMILES: [C:1]([C:14]1[CH:22]=[C:18]([C:19]([OH:21])=[O:20])[C:17]([OH:23])=[CH:16][CH:15]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:24][C:25]([CH2:28][C:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N+:44]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([CH3:46])[CH3:45])=[CH:36][CH:37]=1)([CH3:31])[CH3:30])([CH3:27])[CH3:26].C(=O)([O-])[O-]>C(O)C.CO>[CH3:27][C:25]([CH2:28][C:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N+:44]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([CH3:45])[CH3:46])=[CH:36][CH:37]=1)([CH3:30])[CH3:31])([CH3:24])[CH3:26].[C:1]([C:14]1[CH:22]=[C:18]([C:19]([O-:21])=[O:20])[C:17]([OH:23])=[CH:16][CH:15]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: CC(C)(C)CC(C)(C)c1ccc(OCCOCC[N+](C)(C)Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g (6.4 mmol) of 5-dodecanoylsalicylic acid, dissolved beforehand in 100 ml of ethanol, are added to a solution of 2.82 g (3.2 mmol) of benzethonium carbonate dissolved in 100 ml of methanol; the mixture is stirred for 1 hour at room temperature, the solution is then filtered and the filtrate is evaporated to dryness to give 4.5 g (97% yield) of benzethonium 5-dodecanoylsalicylate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]1([C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[CH:37][CH2:38]Br)[O:29]1)=[O:28].O.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:38][CH:37]=[C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:27](=[O:28])[O:29]4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: O=C1OC(=CCBr)c2ccccc21
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC=C3OC(=O)c4ccccc43)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (1.4 g) in N,N-dimethylformamide (40 ml) was added 3-phthalidylideneethyl bromide (1.0 g), and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was poured into a mixture of water and ethyl acetate (each 200 ml) with stirring. The separated organic solution was washed with 5% aqueous sodium bicarbonate and then water, followed by drying over magnesium sulfate. The resultant solution was evaporated to dryness to give 2-(3-phthalidylidene)ethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (1.5 g), mp 150° to 156° C. (dec.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([NH2:19])[C:16]([C:20]([Si](C)(C)C)=[CH:21][C:22]#[C:23][Si](C)(C)C)=[C:15]([O:32][CH2:33][CH3:34])[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[NH2:19][C:17]1[C:16](/[CH:20]=[CH:21]/[C:22]#[CH:23])=[C:15]([O:32][CH2:33][CH3:34])[N:14]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:35]=[CH:36][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:12])[CH:18]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C(=CC#C[Si](C)(C)C)[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C#C/C=C/c1c(N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of compound from Example 274A (28 mg, 0.05 mmol) in tetrahydrofuran (5 ml) was added tetrabutyl ammonium fluoride (52 mg, 0.2 mmol). The mixture was stirred at room temperature for overnight, and then water and ethyl acetate (20 ml, 1:1) were added. The organic layer was washed with brine and dried over MgSO4. The crude product was purified by reverse phase HPLC (10 mM ammonium acetate, 5% acetonitrile in H2O/CH3CN) to give the titled compound (18.5 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.02 (t, 1H), 7.87 (d, J=8.14 Hz, 2H), 7.54 (d, J=8.48 Hz, 2H), 7.08 (d, J=16.28 Hz, 1H), 7.04 (s, 1H), 6.57 (s, 2H), 6.48 (dd, J1=16.28, 2.37 Hz, 1H), 4.56 (d, J=6.44 Hz, 2H), 4.46 (q, J=7.01 Hz, 2H), 4.09 (d, J=2.37 Hz, 1H), 3.17 (s, 3H), 1.34 (t, J=7.12 Hz, 3H); MS (APCI) m/z 400 [M+H]+, 398 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:15][C:7]1[C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1CBr
Yield: 75.6 %

Procedure:
A mixture of ethyl 5-chloro-3-methyl-2 -benzofurancarboxylate (52.5 g, 0.22 mol), N-bromosuccinimide (39.15 g, 0.22 mol) and benzoyl peroxide (0.4 g) in carbon tetrachloride (750 ml) was stirred and refluxed for 10 hours. The mixture was cooled, filtered and the filtrate was concentrated. The crude product was recrystallized from hexane to give 52.8 g (76%) of ethyl 3-bromomethyl-5-chloro-2-benzofurancarboxylate: mp 112-114° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])=[CH:17]1.C([O-])(=O)C.[Na+]>CNC=O>[CH:14]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]=1[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: COC(=O)c1cccc(-c2coc3ccccc23)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CNC=O
Product: COC(=O)c1cccc(-c2c(C=O)oc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a mixture of phosphorus oxychloride (3 g) and N-methylformanilide (3 g) was added a solution of methyl 3-(benzofuran-3-yl)benzoate (3 g) in N-methylformamide (1.5 g) at room temperature. The mixture was stirred overnight at room temperature and was poured onto aqueous sodium acetate solution. The product was extracted with ethyl acetate and the organic layer was washed with hydrochloric acid solution, water and brine. The layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1) to afford methyl 3-(2-formylbenzofuran-3-yl)benzoate (2.39 g).
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7](P(OCC)(OCC)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)[C:29]([O:38][CH3:39])=[CH:28][C:25]=1[CH:26]=O.O>C1COCC1.C(OCC)(=O)C>[Cl:3][CH2:4][CH2:5][CH2:6]/[C:7](=[CH:26]\[C:25]1[CH:28]=[C:29]([O:38][CH3:39])[C:30]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[CH:31][C:24]=1[F:23])/[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: COc1cc(C=O)c(F)cc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C(CCCCl)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C(\CCCCl)C(=O)OC(C)(C)C)c(F)cc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
Sodium hydride (containing mineral oil at 40%, 0.68 g) was added to a solution of tert-butyl 5-chloro-2-(diethoxyphosphoryl)valerate (5.59 g) in THF (50 mL) in a nitrogen atmosphere at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. A solution of 2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.19 g) in THF (10 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate (5.93 g). A solution of tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate in trifluoroacetic acid (30 mL) was stirred while cooling with ice. After 2 hours, the reaction solution was concentrated under reduced pressure. Tert-butyl methyl ether was added to the resulting residue, and the resulting deposited solid was filtered to obtain 3 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]1[CH2:12][NH:11][CH2:10][CH:9]([CH3:13])[NH:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:6][CH:7]1[NH:8][CH:9]([CH3:13])[CH2:10][N:11]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1CNCC(C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(S(C)(=O)=O)CC(C)N1
Reaction time: 0.5 h

Procedure:
A solution of methanesulfonyl chloride (1.42 mL, 18.4 mmol) in DCM (10 mL) was added dropwise to a solution of 2,6-dimethylpiperazine (2 g, 17.5 mmol) and triethylamine (2.56 mL, 18.4 mmol) in DCM (10 mL) under nitrogen. The mixture was stirred for 30 min. The solvent was removed and the residue was applied to a 5 g aminopropyl SPE cartridge to give the product as a yellow solid (2.3 g), ˜10:1 mixture of cis and trans isomers by NMR.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9]([CH2:12][C:13](=O)[CH3:14])(=[O:11])C.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:4]([C:3]1[CH:2]([C:7]#[N:8])[NH:1][C:9]([OH:11])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13]([CH3:14])[N:6]=1)#[N:5]
Reactant: CC(=O)CC(C)=O
Reactant: N#C/C(N)=C(/N)C#N
Reactant: c1ccccc1
Product: CC1=CC(O)(c2ccccc2)NC(C#N)C(C#N)=N1

Procedure:
In the presence of a catalytic amount of acetic acid, 2,3-dicyano-5-hydroxy-5-phenyl-7-methyl-4H-1,4-diazepine (compound 5a) was obtained by reacting 1 mol of diaminomaleonitrile with 1 mol of acetylacetone in a solvent (benzene) at 45° C. for 6 hours. The diazepine compound (5a) thus obtained was dehydrated in the presence of phosphorus pentoxide. The object compound 2,3-dicyano-5-phenyl-7-(2-(4-methoxyphenyl)vinyl-1-yl)-6H-1,4-diazepine (compound 5) was obtained by reacting the diazepine compound (5b) thus obtained with 4-methoxybenzaldehyde in the presence of piperidine.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[CH:5]=1
Reactant: Cc1sccc1C1OCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1sc(Br)cc1C1OCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.9 %

Procedure:
To a solution of 2-(2-methylthiophen-3-yl)-1,3-dioxolane (2.30 g) synthesized above in acetonitrile (25 mL) was added N-bromosuccinimide (2.65 g), and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title compound (2.15 g, 64%) as a pale-yellow oil.
Reaction SMILES: [Ca].F[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:3]1([C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCCCC1
Agent: [Ca]
Product: OC1(c2ccccc2)CCCCC1
Yield: 85 %

Procedure:
Reactions of aryl halides with reactive calcium required slightly higher temperatures, up to -30° C. for aryl bromides and up to -20° C. for aryl chlorides. The aryl calcium compounds are very stable at room temperature. Reactions of m-bromotoluene, m-bromoanisole, and p-chlorotoluene with the soluble highly reactive calcium complex gave the corresponding arylcalcium reagents in quantitative yields based on the GC analyses of reaction quenches. The 1,2-addition of these arylcalcium compounds with ketones gave the alcohols in excellent yields (76%, 79% and 86%, respectively). The soluble highly reactive calcium readily reacted with fluorobenzene at room temperature to form the corresponding organometalic compound which underwent an addition reaction with cyclohexanone to give 1-phenylcyclohexanol in 85% yield.