Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCCCCCC1CCCC1=O.OCCCCCC1CCCC1=O.C(OCCCCCC1CCCC1=O)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C.[CH3:59][C:60]([O:62][CH2:63][C:64]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:71]([CH2:78][O:79][C:80]([CH3:82])=[O:81])=C2C=1C=CC=C2)=[O:61]>>[C:80]([O:79][C:78]1[CH2:71][CH2:72][CH2:73][C:74]=1[CH2:75][CH2:76][CH2:77][CH2:64][CH2:63][O:62][C:60](=[O:61])[CH3:59])(=[O:81])[CH3:82]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)OCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCCC1CCCCCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1

Procedure:
A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 11 l. of acetic anhydride is refluxed acetic a rate to maintain a steady distillation of acetic acid from the reaction through a relix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 452 g. of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1/[CH:33]=[CH:34]/[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1/[CH:33]=[CH:34]/[CH2:35][N:19]1[CH2:20][CH2:21][C:16]([CH2:15][CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:27])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: O=C/C=C/c1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(C/C=C/c2ccco2)CC1
Reaction time: 0.67 h
Yield: 93.4 %

Procedure:
To 2 mL of a dichloromethane solution containing 50 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 18 mg of (2E)-3-(2-furyl)acrolein and 20 μL of acetic acid were added, and stirred for 40 min. To the reaction mixture, 43 mg of sodium triacetoxyborohydride was added, stirred for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1], to give 60 mg of ethyl 1-((2E)-3-(2-furyl)-2-propen-1-yl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate as a brown solid.
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4]N.Cl[C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:27](F)(F)[C:28]([OH:30])=[O:29]>ClCCl>[C:8]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:2][C:3]2[CH:4]=[CH:9][C:8]([CH2:27][C:28]([OH:30])=[O:29])=[CH:7][CH:14]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCS
Reactant: O=C(O)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)Cc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 85 %

Procedure:
2-Mercaptoethylamine hydrochloride (261.4 mg, 2.3 mmol) was added to the solution of chloro triphenylmethane (557.6 mg, 2 mmol) in 1.0 mL of anhydrous dichloromethane. Then trifluoroacetic acid (TFA, 0.4 mL) was added to afford dark brown solution. The solution was stirred for 2 hrs under nitrogen. The reaction was quenched by 1N NaOH (3 mL). The suspension was extracted with 10 mL of ethyl acetate, and the organic phase was washed with brine (5 mL×3) and dried over anhydrous magnesium sulfate. The solvent was removed and residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/hexane=⅓) to afford 543 mg of the desired product (85%). 1H NMR (400 MHz, CDCl3) δ 7.50-7.48 (m, 6H), 7.34-7.26 (m, 6H), 7.25-7.23 (m, 3H), 2.63 (t, J=6.5 Hz, 2H), 2.36 (t, J=6.5 Hz, 2H), ESI-MS: observed [M+Na]+: 342.5, calculated: 319.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.IC[CH:9]=[CH:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:34]([NH:35][C:36](=[O:66])/[C:37](=[N:63]\[O:64][CH3:65])/[C:38]3[N:39]=[C:40]([NH:43]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:41][CH:42]=3)[C:33](=[O:67])[N:15]2[C:16]=1[C:17]([O:19]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:18].[CH3:68]COCC>>[NH2:43][C:40]1[S:41][CH:42]=[C:38](/[C:37](=[N:63]/[O:64][CH3:65])/[C:36]([NH:35][CH:34]2[C:33](=[O:67])[N:15]3[C:16]([C:17]([O-:19])=[O:18])=[C:11](/[CH:10]=[CH:9]/[CH2:1][N+:2]4([CH3:68])[CH2:6][CH2:5][CH2:4][CH2:3]4)[CH2:12][S:13][C@H:14]23)=[O:66])[N:39]=1
Reactant: CCOCC
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CN1CCCC1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[N+]3(C)CCCC3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methylpyrrolidine (0.2 ml, 2 mmole) was added to a suspension of diphenylmethyl 3-(3-iodo-1-propen-1-yl)-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (X-1, 958 mg, 1 mmole) in ether (100 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, the filter cake was treated with 90% trifluoroacetic acid (5 ml) at room temperature for 1 hour, and the resulting mixture was concentrated under reduced pressure to give a light yellow powder (500 mg). The crude product was dissolved in formic acid (2 ml) and placed on a column of HP-20 resin (40 ml). The column was washed with water (about 500 ml) until the pH of the eluate became 7 and then was eluted with 30% aqueous CH3OH. The eluate was monitored by UV absorption at 254 nm. The fractions containing the desired product were combined, concentrated and lyophilized to give 185 mg of light yellow powder. It was purified by HPLC (Lichrosorb RP-18; 20% methanol) to give 101 mg (20%) of the title compound I-1A. M.p. >160° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH2:14][CH2:2][CH2:3][CH3:4])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(Br)ccc1-2

Procedure:
As shown in Scheme 1, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11). Then, (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a). Finally, in acetonitrile, 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-cyano-3-[5-(7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (13a).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>CC(O)C>[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][NH:30][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:27][CH2:28]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (15.2 g, 73.3 mmol) and trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (14.8 g, 61.0 mmol) in 2-propanol (80 mL) was stirred at reflux for 4 days, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (20.4 g, 81%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:20][OH:21])[CH:8]=[C:9]([O:16][CH2:17][O:18][CH3:19])[C:10]=1[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].C(N(CC)CC)C.[Cl-].[S:30]([O-])(=[O:33])(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:19][O:18][CH2:17][O:16][C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]=1[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:20][O:21][S:30]([CH3:31])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)[O-]
Reactant: COCOc1cc(CO)cc(OCOC)c1CC=C(C)C
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1cc(COS(C)(=O)=O)cc(OCOC)c1CC=C(C)C
Temperature: 0 °C

Procedure:
[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-methanol (2.0 g, 6.75 mmol) was dissolved in CH2Cl2 and placed in an ice bath. Triethylamine (1.2 ml, 8.92 mmol) was added and stirred until the reaction solution was at 0° C., followed by the dropwise addition of mesylate chloride (900 ul, 8.92 mmol). After stirring in the ice bath for 1 hour, the reaction was quenched with water, extracted with EtOAc, washed with brine, dried with MgSO4, filtered and evaporated yielding methanesulfonic acid 3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-benzyl ester as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.82 (s, 2H), 5.20 (t, 1H), 5.16 (s, 4H), 4.13 (s, 2H), 3.48 (s, 6H), 3.39 (d, 2H) 2.96 (s, 3H), 1.78 (s, 3H), 1.65 (s, 3H). MS (ESI) m/z: 375 (M+H)+, 397 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCCc2ccc(F)cc2)cc1
Yield: 86.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.031 g, 0.051 mmol) and LiOH (0.012 g, 0.513 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 4 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0254 g, 0.044 mmol, 86% yield) as solid. 1H NMR (500 MHz, CDCl3) δ 7.18-7.22 (m, 2H), 7.13-7.17 (m, 1H), 7.04-7.08 (m, 1H), 6.95-7.03 (m, 4H), 5.95 (br. s., 1H), 3.98-4.07 (m, 2H), 3.43-3.78 (m, 1H), 2.87-3.06 (m, 1H), 2.84 (t, J=7.7 Hz, 2H), 2.67 (s, 3H), 2.36 (br. s., 1H), 2.24 (s, 3H), 2.10-2.18 (m, 2H), 1.93-2.09 (m, 1H), 1.48-1.68 (m, 1H), 1.28-1.40 (m, 2H), 1.25 (s, 9H), 1.10-1.22 (m, 1H), 0.88 (br.s., 3H), 0.69 (br.s., 3H). LCMS (M+H)=577.3.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH3:21])=[C:11]([CH2:13][OH:14])[CH:12]=1.[CH3:22]CN(C(C)C)C(C)C.CCOCC>C(Cl)Cl.CO>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH3:21])=[C:11]([CH2:13][O:14][CH3:22])[CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1CCCCN1c1ccc(Br)cc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COCc1cc(Br)ccc1N1CCCCC1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Methanesulfonyl chloride (4.0 mL, 51.6 mmol) was added into a solution of [5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol (13.43 g, 47.3 mmol) and DIEA (17.7 mL, 104 mmol) in anhydrous DCM (130 mL) cooled at 0° C. After 1 hour, the reaction mixture was diluted with MeOH (150 mL) and heated at 50° C. for 3 hours. The solvents were removed under reduced pressure to give a brown oil. The residue was taken up with Et2O (450 mL), and then washed with water (150 mL, pH 8 adjusted with a 5N aqueous solution of NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL). The aqueous layers were extracted with Et2O (150 mL). The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a brown yellow oil (13.0 g, 92%) used without further purification in the next step. HPLC (Method A), Rt 2.9 min (Purity: 97.1%). HPLC/MS, M+(ESI): 298.1, 300.1. 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J=2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 4.60 (d, J=12.8 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.44 (s, 3H), 2.96-2.81 (m, 2H), 2.51 (m, 1H), 1.77 (m, 2H), 1.64 (m, 2H), 1.50-1.30 (m, 2H), 0.79 (d, J=6.1 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([N:16]2[CH2:27][CH2:26][C:19]3([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[C:9]=1[Cl:28])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[C:12]([CH:11]=[C:10]([N:16]2[CH2:27][CH2:26][C:19]3([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[C:9]=1[Cl:28])[C:14]#[N:15]
Reactant: CN1CCC2(CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC2(CCN(c3cc(C#N)cc(N)c3Cl)CC2)C1=O
Yield: 70 %

Procedure:
tert-butyl-(2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)carbamate (336 mg, 0.802 mmol) in DCM (3 mL) was treated with TFA (1.174 mL, 15.24 mmol) at room temperature for 2 h. Solvent was evaporated and the residue was redissolved in DCM and concentrated again. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-10% methanol/dichloromethane). 3-amino-4-chloro-5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzonitrile (179 mg) was obtained as alight yellow oil.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([Cl:25])=[O:24])([O-:19])=[O:18]>>[ClH:25].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)cc1)c1cccc([N+](=O)[O-])c1

Procedure:
Was prepared by Method G from 4-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 3-nitrobenzoyl chloride. Mp. >280° C.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].ClC([O:11][CH2:12][CH3:13])=O.[CH2:14]([N:16](CC)CC)C>C(Cl)(Cl)Cl>[CH:12]([O:11][CH:4]([CH3:3])[CH3:5])([CH3:13])[CH3:14].[C:1]([NH2:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: CCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)OC(C)C
Product: CCCCC(N)=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 124.9 %

Procedure:
Valeric acid (10.86 mL, 100 mmol, 1.0 eq) was dissolved in chloroform (100 mL, 0.1 M) and cooled to -20° C. Ethyl chloroformate (9.52 mL, 100 mmol, 1 eq) was added. Triethylamine (14.0 mL, 100 mmol, 1.0 eq) was then added dropwise over 5 minutes. The mixture was stirred at -20° C. for 30 minutes. Ammonia was bubbled through the mixture 10 minutes at -20° C. and 20 minutes at 0° C. The mixture was then allowed to warm to room temperature and stirred for 90 minutes. Chloroform (100 mL) and 1 N hydrochloric acid (50 mL) were added. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and freed of solvent in vacuo. Trituration with isopropyl ether gave the title compound (6.315 g, 62%) as a white solid.
Reaction SMILES: [S:1]([O:6][CH3:7])([O:4][CH3:5])(=[O:3])=[O:2].C([C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)C.[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]O>>[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:7][O:6][S:1]([O-:4])(=[O:2])=[O:3].[CH3:5][N+:14]1[CH:13]=[CH:12][N:11]([CH2:20][CH3:21])[CH:10]=1
Reactant: CCc1ncc[nH]1
Reactant: COS(=O)(=O)OC
Reactant: COCCOCCO
Product: CCn1cc[n+](C)c1
Product: COCCOCCOS(=O)(=O)[O-]

Procedure:
In a 100 ml Schlenk flask, 16.27 g (0.129 moles) of dimethyl sulfate was slowly added dropwise to 12.40 g (0.129 moles) of ethylimidazole with ice cooling and under a blanket gas. Stirring of the mixture was continued at room temperature over night. After the addition of 30.92 g (0.258 moles; 2 equ.) of diethylene glycol monomethyl ether, the volatile fractions were removed in a distillation apparatus at 160° C. for 5 hours. After drying the mixture in a high vacuum, 1-methyl-3-ethylimidazolium 2-(2-methoxyethoxy)ethyl sulfate was obtained as a low-viscous, slightly yellow liquid in quantitative yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1F>CN(C=O)C.O>[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1[NH:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: NCC(N)=O
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CNc1c(F)cc([N+](=O)[O-])cc1F
Temperature: 80 °C
Yield: 65.9 %

Procedure:
To a stirred solution of glycinamide hydrochloride (45 g, 407 mmol) in DMF (500 mL) was added successively triethylamine (197 mL, 1.43 mol) followed by 3,4,5-trifluronitrobenzene (72 g, 407 mmol) at room temperature over 15 min. The reaction mixture was heated to 80° C. overnight and then allowed to cool to room temperature. Ice pieces suspended in water were added to the reaction mixture and the solid obtained was filtered. The solid was dried to afford title compound (62 g, 67%) that was taken up directly for the next step without further purification. Mp 160–162° C.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH3:3].[CH:31](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[CH:31]=[N:12][N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:18][CH:19]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCOC(OCC)OCC
Product: CCCc1nc(C)n2cnnc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
4.8 g of 6-n-propyl-2-methyl-4-hydrazino-5-{[2'(5-tetrazolyl)-4-biphenylyl]methyl}pyrimidine, prepared in Example 67, are heated to reflux for 4 hours in 40 ml of triethyl orthoformate. The mixture is evaporated under vacuum and the residue is crystallised in an ethyl acetate/isopropyl ether mixture to give 1 g of 7-n-propyl-5-methyl-8-{[2'-(5-tetrazolyl)-4biphenylyl]methyl}-1,2,4-triazolo[4,3-c]pyrimidine in the form of crystals of melting point 182°-184° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: OCCO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(C2OCCO2)cc1
Yield: 51.1 %

Procedure:
To a solution of 4-cyanobenzaldehyde (25 g, 0.190 mol) in dry toluene (300 mL) was added ethyleneglycol (15 g, 0.228 mol) and PTSA (0.5 g) and allowed to reflux at 130° C. with azeotropic removal of water for 12 h. The reaction mixture was cooled, washed with 10% aqueous NaHCO3 (100 mL), dried and concentrated under vacuum. The crude solid was recrystallised from PetEther/EtOAc to give the 4-(1,3-dioxolan-2-yl)benzonitrile (17 g, 51%) as white solid. TLC (PetEther/EtOAc 4/1), Rf=0.6
Reaction SMILES: [Cl:1]Cl.C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=O.CO>C(Cl)(Cl)Cl>[ClH:1].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:1])=[CH:8][C:7]=1[CH3:12]
Reactant: ClCl
Reactant: Cc1ccccc1NC=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(Cl)ccc1N
Product: Cl
Reaction time: 2 h
Yield: 132.7 %

Procedure:
79 g (1.1 moles) of chlorine is introduced into a solution of 135 g (1 mole) of 2 -formylaminotoluene in 500 ml of chloroform at 20° to 25° C. in the course of 2 to 3 hours. After the addition of 28 g (0.88 mole) of methanol, the mixture obtained is stirred for 2 hours at 25° to 30° C., and the formed 2 -amino-5 -chlorotoluene hydrochloride is subsequently filtered off. There is obtained 130 g (73% of theory relative to 2 -formylaminotoluene) of 2 -amino-5 -chlorotoluene hydrochloride. The content of 2 -amino-5 -chlorotoluene hydrochloride in the product is 98 to 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.Cl.ClC1C=CC(NC(C2C=CC(C(=N)OCC)=CC=2)=O)=CC=1C1C=CC=CN=1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:11]=[CH:12][C:13]([C:16](=[NH:17])[N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: C1COCCN1
Agent: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: Cl
Solvent: CCO
Product: N=C(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)N1CCOCC1
Temperature: 75 °C
Reaction time: 72 h
Yield: 7.9 %

Procedure:
N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide (300 mg, 0.899 mmol) was slurried in 45 ml ethanol and treated with 10 ml of ethanol saturated with HCl. The reaction was stored at 0° C. for 3 days, then heated to 75° C. for 3.0 hours, and cooled to room temperature for 18 hours. The reaction was cooled in an ice bath, and saturated with HCl gas. After storing at 0° C. for an additional 3 days, N2 gas was bubbled through the solution for 1.0 hour, and the solution was diluted with enough ethanol to make a 0.0155 M solution of ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate. Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (17.5 ml of a 0.0155 M ethanol solution, 0.27 mmol) was treated with morpholine (1.0 ml, 11.4 mmol) for 3 days. The ethanol was evaporated, and the residue purified by reverse phase HPLC to afford 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(morpholino)methyl)benzamide. MS (Q1) 421 (M)+.