Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[NH:21]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10]([OH:12])=[O:11])=[CH:17][CH:18]=2)=[N:2][N:23]=[N:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Oc2ncccc2C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1Oc1ccc(-c2nnn[nH]2)cc1
Reaction time: 24 h
Yield: 29.2 %

Procedure:
A mixture of 14.5 g of 2-(4-cyanophenoxy)nicotinic acid, 3.97 g of ammonium chloride, 4.96 g of sodium azide and 120 ml of dimethylformamide is allowed to stand at 100° C to 110° C for 24 hours. After cooling, the reaction mixture is filtered, and the filtrate is concentrated. To the residue is added a dilute hydrochloric acid, and the crystals are filtered off and recrystallized from methanol to give 5 g of 2-[4-(5-1H-tetrazolyl)phenoxy]-nicotinic acid melting at 225° C to 230° C with decomposition.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][CH:33]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:34]([OH:39])[C:35]([F:38])([F:37])[F:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:32][CH:33]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:34]([OH:39])[C:35]([F:36])([F:37])[F:38])=[O:22])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:32][CH:33]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])=[O:21])[C:15]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc([N+](=O)[O-])cc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1c(-c2ccc([N+](=O)[O-])cc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-nitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-2-(4-nitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 15, 14.2 g, 33.5 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 8.08 g, 36.9 mmol), WSCI hydrochloride (7.71 g, 40.2 mmol) and HOBT (9.05 g, 67.0 mmol) in DMF (120 mL) to give 19.4 g (93%) of the target compound as colorless crystals.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:45])[CH2:42][CH:43]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:40][CH:41]([CH3:45])[CH2:42][CH2:43][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)CC=O
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CCN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 23.3 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol), 3-methylbutanal (20 μl, 0.186 mmol), acetic acid (11 μl, 0.181 mmol), and sodium triacetoxyborohydride (53 mg, 0.248 mmol) were processed as described in Example 27 to provide the title compound (23 mg, 23%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.79 (s, 2H), 7.29-7.07 (m, 10H), 5.20 (s, 4H), 4.79 (br s, 2H), 3.85 (m, 2H), 2.83 (dd, 2H), 2.73 (m, 2H), 2.43 (m, 5H), 1.46 (m, 2H), 1.17 (m, 2H), 0.82 (d, 6H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])=[CH:19][CH:18]=1
Reactant: CCCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 3 h
Yield: 58.1 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-undecadienoic acid methyl ester (5.9 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 3 hours the reaction was worked up in the usual way and the crude acid was crystallized from hexane to give 3.27 g of (E,E)-5-(4-methoxyphenyl)-2,4-undecadienoic acid, mp 8°-89.5° C.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.Cl.[CH3:30][O:31][C:32]([CH:34]1[NH:39][CH2:38][C:37]2[N:40]([CH2:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:41]=[N:42][C:36]=2[CH2:35]1)=[O:33].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:30][O:31][C:32]([CH:34]1[N:39]([C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:38][C:37]2[N:40]([CH2:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:41][NH:42][C:36]=2[CH2:35]1)=[O:33]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1Cc2ncn(CC(=O)c3ccccc3)c2CN1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9.3 g dicyclohexycarbodiimide, 6.1 g hydroxybenzotriazole hydrate, 9.5 g diphenylacetic acid and 100 mL acetonitrile is stirred at 25° C. for 15 min (suspension A). A mixture of 15.8 g methyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-3H-imidazo-[4,5-c]pyridine-6-carboxylate dihydrochloride, 14.8 mL diisopropylethylamine and 100 mL acetonitrile is stirred 10 min at 25° C. then treated with suspension A, using 100 mL acetonitrile to complete the transfer. The resulting suspension is stirred 48 hr, filtered and the filtrate is evaporated, dissolved in dichloromethane, washed with 10% Na2CO3, dried and evaporated. Chromatography on silica gel (chloroform-methanol, 99:1) gives methyl-5-diphenylacetyl-3-(2-oxo-2-phenyl-ethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate as foam. MS (FAB) 494 (M+1).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([S:38]([C:35]5[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=5)(=[O:40])=[O:39])[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (35 mg, 0.108 mmol, 1.0 equivalent, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. Triethylamine (32.7 mg, 0.323 mmol, 3.0 equivalents) was added followed by the addition of 4-(trifluoromethyl)benzene-1-sulfonyl chloride (34.3 mg, 0.140 mmol, 1.3 equivalents). The resulting solution was allowed to stir for 30 minutes at room temperature. The reaction solution was loaded directly onto a 4 g silica gel column and eluted with 0:100 to 50:50 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (30 mg, 56%). 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J=1.3 Hz, 1H), 7.91 (dd, J=9.0, 4.9 Hz, 3H), 7.82 (d, J=8.4 Hz, 2H), 5.43 (t, J=3.9 Hz, 1H), 4.25 (dd, J=16.5, 9.6 Hz, 1H), 4.16-3.95 (m, 3H), 3.57 (dd, J=13.7, 4.0 Hz, 1H), 2.96-2.83 (m, 1H), 2.82-2.64 (m, 2H), 2.65-2.52 (m, 1H), 2.47 (dd, J=13.4, 9.3 Hz, 1H), 2.04-1.84 (m, 2H), 1.08-0.77 (m, 4H); MS (ESI+) m/z 497.0 (M+H)+; [α]D23.8=−0.15 (c=0.13, CH3OH).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-:25].[Na+].[O:27]1[CH2:41][CH:28]1[CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].Cl>O.O1CCOCC1>[C:31]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[C:34](=[O:35])[NH:30][CH2:29][CH:28]([OH:27])[CH2:41][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1)([OH:40])=[O:25]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)CNC(=O)c2ccccc2C(=O)O)CCN(CC(=O)O)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
50 g (144.3 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A) is dissolved in 250 ml of water, and the pH is set at 13 with 5N sodium hydroxide solution. Then, a solution of 38.12 g (187.6 mmol) of N(2,3-epoxypropyl)-phthalimide (Aldrich) in 100 ml of dioxane is added in drops within one hour, stirred for 24 hours at 50° C., and the pH is kept at 13 by adding 5N sodium hydroxide solution. The solution is set at pH 2 with 10% hydrochloric acid and evaporated to the dry state in a vacuum. The residue is dissolved in some water and purified on an ion exchange column (Reillex(R) =poly-(4-vinyl)-pyridine) (it is eluted with water). The main fractions are concentrated by evaporation in a vacuum, and final purification of the residue is achieved by chromatography on RP-18 (LiChroPrep(R) /mobile solvent: gradient that consists of tetrahydrofuran/methanol/water). After the main fractions are concentrated by evaporation, 63.57 g (71% of theory) of an amorphous solid is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:11]C)[C:6]([O:9]C)=[CH:7][CH:8]=1)[CH3:2].C(O)(=O)C.Br.O>CCOCC>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:7][CH:8]=1)[OH:9])[CH3:2]
Reactant: CCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(O)c(O)c1
Yield: 89 %

Procedure:
A mixture of 10.0 g (60.2 mM) of 4-ethylveratrole, 38.4 g (639 mM) of acetic acid and 115.0 g (668 mM) of 47% hydrobromic acid was heated under reflux for 4 hours with stirring After cooling to the room temperature, 100 ml of water was added and the resultant mixture was extractbd three times with each 110 ml of ether. The ether extract was successively washed with 110 ml of water, 150 g of 5% aqueous sodium thiosulfate solution and further twice with each 110 ml of water. The resulting ether solution was dried with anhydrous sodium sulfate, filtered, concentrated and distilled under vacuum to obtain 7.4 g (53.6 mM) of 4-ethylcatechol as a light yellow liquid having a boiling point of 111°-112 ° C./4 mmHg.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[S:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[N:15]=1.C(O)(C(F)(F)F)=O.CO>C([SiH](CC)CC)C.C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:4]1[S:5][C:6]([C:7]2[S:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[N:15]=2)=[C:2]([Br:1])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nc(Br)c(-c2nc3ccncc3s2)s1)Cc1ccc(C(F)(F)F)cc1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CNc1nc(Br)c(-c2nc3ccncc3s2)s1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
To a 150 mL round-bottomed flask was added tert-butyl (S)-1-(4-bromo-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.157 g, 0.26 mmol), DCM (25.00 mL, 389 mmol) and TFA (5.00 mL, 65 mmol) with a few drops of triethylsilane, and the resulting solution was stirred for about 15 minutes and followed by LCMS. LCMS showed conversion to product so the solvent was removed, and the oil was dissolved in 2 N ammonia in MeOH and adsorbed on to a plug of silica gel. Chromatography through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% 2 M ammonia.MeOH in DCM, provided N—((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-bromo-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine (0.086 g, 65% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:6]12.[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[C:28]([O:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][C:9]=1[CH3:12])[N:6]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:5]1=[C:4]2[C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)([CH3:30])[CH3:29])[CH3:25]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc2c(c(C)c1O)c(-c1ccncc1)c1n2CCCCC1
Product: CCOC(=O)C(C)(C)Oc1c(C)cc2c(c1C)c(-c1ccncc1)c1n2CCCCC1

Procedure:
The above compound was prepared from 7,8,9,10-tetrahydro-1,3-dimethyl-11-(4-pyridyl)-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19](N)=[O:20])=[CH:17][C:10]=3[C:9](=[O:23])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([OH:26])C.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:26])=[O:20])=[CH:17][C:10]=3[C:9](=[O:23])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1Sc1ccc(C(C)C(N)=O)cc1C(=O)C2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1Sc1ccc(C(C)C(=O)O)cc1C(=O)C2
Reaction time: 6 h
Yield: 60 %

Procedure:
To a mixture of 273 mg of 2-(10,11-dihydro-6-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 8 ml of ethanol was added 800 mg of potassium hydroxide in 2 ml of water, and the resulting mixture was refluxed with stirring for 6 hours. The solvent or ethanol was distilled off to obtain a residue, to which was added water, and the mixture was washed with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a yellowish-brown oil, which was chromatographed over 9 g silica gel and eluted with chloroform to obtain light yellow crystals. The crystals were recrystallized from benzene-n-hexane to obtain 165 mg (yield: 60%) of 2-(10,11-dihydro-6-methoxy-11-oxodibenzo-[b,f]thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 176°-178° C.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.C[Cl:9].[C:10]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])(=[O:14])[C:11]([CH3:13])=[CH2:12]>>[C:10]([O:15][CH2:16][CH2:17][N+:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH3:5])(=[O:14])[C:11]([CH3:13])=[CH2:12].[Cl-:9].[C:10]([O:15][CH2:16][CH2:17][N+:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH3:5])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: COS(=O)(=O)OC
Reactant: C=C(C)C(=O)OCCN(CC)CC
Reactant: CCl
Product: C=C(C)C(=O)OCC[N+](C)(CC)CC
Product: [Cl-]

Procedure:
Alternatively, the objective mono- or co-polymers are obtained by the following procedure. As an example, dimethyl sulfate or methyl chloride was added to an ethereal β-diethylaminoethyl methacrylate solution and then the resulting solution was kept in an ice-water bath for several hours to yield a viscous quaternary ammonium salt compound, β-methacryloxyethyl diethylmethyl ammonium methosulfate or β-methacryloxyethyl diethylmethyl ammonium chloride. The thus produced quaternary ammonium salt monomer or its mixture with other co-polymerizable vinyl monomer was subjected to a further reaction at about 60° C. overnight after addition of a polymerization initiator such as hydrogen peroxide to yield the desired mono- or co-polymers.
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl.ClCCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[N+:1]([C:4]1[CH:48]=[CH:47][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the compound (2.50 g), which had been obtained in (1), in anhydrous dichloromethane (25 ml), trifluoroacetic acid (15 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 15 minutes and at room temperature for 15 minutes. The reaction mixture was diluted with 1,2-dichioroethane and concentrated by evaporation under reduced pressure. The residue was washed successively with hexane and diethyl ether by decantation and then the solvent was distilled off, whereby crude (3S)-3-[4-[2,3,-di(4-nitrobenzyloxycarbonyl)guanidino]butanoylamino]pyrrolidine trifluoroacetate (2.55 g) was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[C:7]([NH:8][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1cncnc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2N)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4,5-diaminopyrimidine (1.0 g, 9.1 mmol), N-(tert-butoxycarbonyl)-4-piperidone (3.0 g, 15 mmol) and sodium triacetoxyborohydride (1.2 g, 5.6 mmol) in dichloroethane (60 mL) was stirred at room temperature for 3 d. The reaction was partitioned between chloroform (200 mL) and 3 N sodium hydroxide (30 mL). After drying over magnesium sulfate, the organic phase was concentrated to give the title compound as a tan gum. MS 294 (M+1)
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[Cl:60][C:61]1[CH:66]=[CH:65][C:64]([CH:67]([NH2:73])[CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:63][CH:62]=1>CN1C(=O)CCC1.CO>[Cl:60][C:61]1[CH:62]=[CH:63][C:64]([CH:67]([NH:73][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:49])[CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:65][CH:66]=1
Reactant: CN(C)CCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
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: CN1CCCC1=O
Solvent: CO
Product: CN(C)CCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.044 g, 0.12 mmol) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.040 g, 0.11 mmol) and N,N-diisopropylethylamine (0.023 mL, 0.13 mmol) in NMP (5 mL) at 22° C. The resulting suspension was stirred at 50° C. for 10 minutes. The mixture was cooled to ambient temperature and 1-(4-chlorophenyl)-N3,N3-dimethylpropane-1,3-diamine (Intermediate 33) (0.023 g, 0.11 mmol) was added as a solution in NMP (2 mL). The mixture was stirred at 22° C. for 3 days. The mixture was diluted with methanol and purified by ion exchange chromatography using an SCX column; the desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and product-containing fractions were evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-(dimethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.047 g, 76%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>CC(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(COc2cccc(F)c2)cc1
Yield: 87.2 %

Procedure:
A mixture of 4-(bromomethyl)benzonitrile (23.50 g, 120.0 mmol), K2CO3 (55.20 g, 400.0 mmol) and 3-fluorophenol (11.21 g, 100.0 mmol) were heated at reflux in acetone (400 mL) (16 h). The volatiles were evaporated and the residue was diluted with CH2Cl2 (300 mL). The organic layer was washed with H2O (300 mL), dried (MgSO4) and concentrated in vacuo to give white needles (19.81 g, 87%): Rf=0.40 (9/1 hexanes/ethyl acetate); mp 69-70° C.; 1H NMR (CDCl3) δ 5.02 (s, CH2O), 6.56-6.67 (m, 3 ArH), 7.16 (q, J=7.7 Hz, 1 ArH), 7.45 (d, J=7.1 Hz, 2 ArH), 7.59 (d, J=8.1 Hz, 2 ArH); 13C NMR (CDCl3) δ 60.1 (CH2O), 102.8 (d, J=24.4 Hz, C2′ or C4′), 108.3 (d, J=21.1 Hz, C4′ or C2′), 110.4 (d, J=2.8 Hz, C6′), 111.9 (Are), 118.6 (CN), 127.5 (ArC), 130.4 (d, J=9.7 Hz, C5′), 132.4, 141.9 (2 Are), 159.4 (d, J=10.8 Hz, C1′), 163.6 (d, J=244.2 Hz, C3′); LRMS (M+Na+) (ESI+) 250.0 [M+Na+] (calcd for C14H10NONa+ 250.0).