Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:36]1[CH2:37][CH2:38][CH:33]([C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=2)[CH2:34][CH2:35]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(Cl)cc4)CC3)cnc12
Yield: 79.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 21, step 4 and 4-(4-chlorophenyl)piperidine (0.14 g, 0.70 mmol), the title compound (0.24 g, 81%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(OC(=O)C)(=O)C>>[C:30]([O:34][C:35](=[O:36])[NH:37][CH2:38][C:39]([N:25]1[CH2:26][CH2:27][CH:23]([N:6]2[C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]2)[CH2:24]1)=[O:40])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC2)c2cnccc12
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
(2-{3-[5-Chloro-2-(3-methanesulfonyl-pyrazolo[3,4-c]pyridin-1-ylmethyl)-benzoimidazol-1-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester was prepared in analogy to Example 2-16 by using 1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-(tert-butoxycarbonylamino)acetic acid (14 mg) instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and acetic anhydride, MS obsd. (ESI+) [(M+H)+] 588.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13][F:14])=[CH:4][C:3]=1[F:19].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:25]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]1)[N:9]([CH2:12][CH2:13][F:14])[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cn(CCF)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CCN1
Yield: 33.8 %

Procedure:
A mixture of 1.50 g of 7-chloro-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.60 g of 2-methylpiperazine and 8 ml of pyridine was heated for 11 hours under reflux. The solvent of the reaction mixture was evaporated and the residue was dissolved in hot water. After cooling of the solution, the precipitate was filtered and recrystallized from ethanol to give 0.62 g of the title compound as colorless needles, M.p. 226°-227° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:9]=1.P(=O)(O)O.[CH3:31]CC.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:31][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:11]=[C:10]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:9]=1
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)nc(-c2ccccc2O)n1
Reactant: CCC
Agent: O=C([O-])[O-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc(-c2ccccc2)nc(-c2ccccc2O)n1
Temperature: 150 °C
Yield: 94.5 %

Procedure:
9.6 g (0.028 mol) of 2,4-bis(2'-hydroxyphenyl)-6-phenyl-s-triazine, 25 ml (0.234 mol) of dimethylmethane phosphonate and 4.0 g (0.028 mol) of sodium carbonate are mixed and the mixture is heated to 150° C. After 2 hours the clear, pale red reaction solution is stirred into 150 ml of ethanol. The precipitate is filtered with suction, rinsed with 20 ml of ethanol and water and dried in an exsiccator, giving 9.4 g (94.1%) of the compound of formula ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17](O)=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:20][C:21]1[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[CH:25][CH:26]=1>C(O)CO>[F:20][C:21]1[CH:26]=[CH:25][C:24]2[N:27]=[C:17](/[CH:16]=[CH:15]/[C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:28][C:23]=2[CH:22]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(F)cc1N
Solvent: OCCO
Product: COc1cc(/C=C/c2nc3ccc(F)cc3[nH]2)ccc1-n1cnc(C)c1
Temperature: 100 °C

Procedure:
(E)-3-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-acrylic acid (100 mg, 0.39 mmol) and 4-fluorobenzene-1,2-diamine (49 mg, 0.39 mmol) were placed in a 4-mL vial. Ethylene glycol (1 ml) was added and the reaction mixture heated to 100° C. for 16 h and then to 165° C. overnight.
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10].[OH-].[Na+]>C(O)C.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: N[n+]1ccccc1
Reactant: N#Cc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2nc3ccccn3n2)nc1
Reaction time: 72 h
Yield: 36.5 %

Procedure:
To a stirred and cooled solution of N-amino-pyridinium chloride (26.1 g) and 2-cyanopyridine (31.2 g) in ethanol (100 ml) was added a solution of sodium hydroxide (8.0 g) in water (50 ml) over a period of one hour. The mixture was then left at room temperature for 72 hours, after which time the ethanol was removed in vacuo and the residue extracted with chloroform. The chloroform extract was dried and evaporated. The residue, on recrystallisation from acetone, yielded 14.3 g of 2-(2-pyridyl)-s-triazolo[1,5-a]pyridine.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Product: CC(C)NC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Yield: 75 %

Procedure:
As described for example 13 g, 5-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (81 mg, 75%) which was obtained as a light yellow solid. MS: m/e=415.1 [M+OAc]+.
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21]C3CCCCO3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O>[OH:21][NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:13]1[CH:14]=[CH:15][N:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1)NOC1CCCCO1
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccn(S(=O)(=O)Cc2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 91 h
Yield: 97.1 %

Procedure:
0.189 g of (E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylamide (compound A2) are dissolved in 50 ml of a methanol/water (3/2) solution. Then 0.102 g of the acidic ion exchange resin amberlyst IR15 are added and the mixture is stirred for 91 hours at ambient temperature. The mixture is filtered. The filtrate is evaporated. The residue is crystallized from methanol to give 0.144 g of the title compound as white crystals.
Reaction SMILES: O(CCCC(O)=O)C1C=CC=CC=1.[N:14]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18][C:17]=2[S:16][C:15]=1[C:28]([OH:30])=O.[OH-].[Na+].[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[NH:36][CH3:37]>C1COCC1.O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[N:36]([CH3:37])[C:28]([C:15]1[S:16][C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[C:23]=2[N:14]=1)=[O:30]
Reactant: O=C(O)c1nc2c(s1)CCOc1ccccc1-2
Reactant: CNc1ccccc1Cl
Agent: O=C(O)CCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1nc2c(s1)CCOc1ccccc1-2)c1ccccc1Cl

Procedure:
To a solution of 4-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (4.0 g, 12.4 mmol) in ethanol, was added ethyl thiooxamate (5.0 g, 37.4 mmol) and the reaction mixture was heated to reflux for 3 days. Purification on silica gave 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester, which was hydrolyzed to the carboxylic acid, 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid, in THF, sodium hydroxide, and water. 4,5-Dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid was coupled with 2-chloro-N-methylaniline using General Procedure B. Purification on silica gave 226. 1H NMR (400 MHz, CDCl3): 3.24 (2H, t), 3.37 (3H, s), 4.17-4.25 (2H, m), 6.74-6.79 (1H, m), 6.85 (1H, dd), 7.02-7.07 (1H, m), 7.11 (1H, dd), 7.27-7.33 (3H, m), 7.42-7.45 (1H, m). MS: (ESI+) MH 371
Reaction SMILES: C[Si](C)([CH2:9][CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CN=1.[F-].[K+].C(=O)([O-])[OH:22].[K+].OO>CO.O>[C:11]1([CH:10]([OH:17])[CH2:9][OH:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(CC(O)c1ccccc1)c1ccccn1
Reactant: O=C([O-])O
Agent: OO
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OCC(O)c1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 95.5 %

Procedure:
To 129 mg (0.5 mmol) of the (2-hydroxy-2-phenylethyl)(2-pyridyl)silane obtained in Example 6, a solution of 58 mg (1.0 mmol) of potassium fluoride and 100 mg(1.0 mmol) of potassium hydrogencarbonate in methanol(1 ml)tetrahydrofuran(1 ml) was added, followed by 1.71 g (15 mmol) of 30% aqueous hydrogen peroxide. The mixture was continued to be stirred at an inner temperature of 50° C. for 6 hours, and then cooled to room temperature. After addition of 10 ml of water, the mixture was extracted with four portions of 10 ml of diethyl ether. The separated organic layers were combined together and washed with 10 ml of a 15% aqueous sodium thiosulfate solution. After drying over magnesium sulfate, the residue after the evaporation of the solvent was purified with silica gel chromatograph to give 66 mg of phenyl-1,2-ethanediol. Yield: 96%
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:68][C:69]([N:71]1[CH2:76][CH2:75][N:74]([C:77](=[O:87])[C@@H:78]([NH2:86])[CH2:79][CH2:80][C:81]2[N:82]=[N:83][NH:84][N:85]=2)[CH2:73][CH2:72]1)=[O:70])[CH2:65][CH2:66][CH3:67]>CN(C=O)C>[CH2:64]([O:68][C:69]([N:71]1[CH2:72][CH2:73][N:74]([C:77](=[O:87])[C@@H:78]([NH:86][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:29])[CH2:79][CH2:80][C:81]2[N:85]=[N:84][NH:83][N:82]=2)[CH2:75][CH2:76]1)=[O:70])[CH2:65][CH2:66][CH3:67]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 327 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 415 μl DIPEA, 302 mg HATU and 360 mg 4-[(S)-2-amino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate. After 30 minutes the reaction mixture was concentrated and the crude product obtained purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 180 mg
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:12]([O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)[CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC)c(OCc2nc(C)c(C)nc2C)c1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.768 g, 0.003 mol), 3-hydroxy-4-methoxybenzoic acid ethyl ester (0.954 g, 0.005 mol), anhydrous potassium carbonate (1.1 g, 0.008 mol), and DMF (60 mL) into a 100 mL three-necked bottle in turn, wherein the solution appears orange, heating to 90° C. with oil bath, stirring to react for 12 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.4), and the reaction solution appears orange, filtering to obtain orange filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain light yellow solid, recrystallizing with anhydrous alcohol to obtain 0.71 g 3-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-4-methoxybenzoic acid ethyl ester, a yield is 60.7%, m.p. 129.8-130.4° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15]Br)=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]([CH:18]([CH3:20])[CH3:19])[N:6]=1>C1COCC1>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][S:2][CH3:1])=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]([CH:18]([CH3:20])[CH3:19])[N:6]=1
Reactant: C[S-]
Reactant: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
Sodium methanethiolate (0.23 g, 3.33 mmol) was dissolved in THF (1 ml) and added dropwise to a solution of 4-bromo-7-bromomethyl-2-isopropyl-2H-phthalazin-1-one (0.4 g, 1.11 mmol) in THF (10 ml). The mixture was stirred at RT for 3 hours whereupon LC-MS indicated complete consumption of starting material. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The residue was subjected to flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.29 g, 79% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[N:10]=1.C(=O)([O-])[O-].[K+].[K+].N1C=NC=NC=1.Br[CH2:49][CH2:50][CH2:51][CH3:52]>O.CN(C)C=O>[CH2:49]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:7][CH2:2][CH2:3][CH3:4])=[CH:17][C:16]=3[OH:22])[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:10]=2)=[C:2]([OH:1])[CH:7]=1)[CH2:50][CH2:51][CH3:52]
Reactant: Oc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ncncn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(OCCCC)cc3O)n2)c(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a 500 mL round bottomed flask equipped with a magnetic stirrer, condenser and nitrogen atmosphere are charged 2.0 g (4.2 mmol) of 2,4-bis-(2,4-dihydroxyphenyl)-6-[4-(phenylthio)phenyl]-s-triazine, 0.58 g (4.2 mmol) of potassium carbonate and 30 mL of N,N-dimethylformamide. The mixture is heated to 90° C., and the s-triazine compound dissolves readily. Bromobutane (4.5 mL, 42.0 mmol) is added all at once. The reaction mixture is heated at 90° C. for 2.5 hours and then stirred at room temperature overnight yielding a yellow precipitate. Chilled water is added and the yellow precipitate is isolated by vacuum filtration to give 2.74 g of crude product. The crude product is purified by flash chromatography with 1:1 heptane:ethyl acetate to afford 0.26 g (10%) yield of the title compound as a yellow solid; mp>250°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([CH:20]=[O:21])=[CH:5][CH:4]=1.S(=O)(=O)([OH:24])N.Cl([O-])=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([C:20]([OH:24])=[O:21])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)c2sc3c(NC(C)=O)cccc3c12
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c2sc3c(NC(C)=O)cccc3c12
Temperature: 10 °C

Procedure:
To a solution of 1-methoxy-6-acetamido dibenzo[b,d]thiophene-4-carbaldehyde (800 mg, 0.00266 mol) in THF(15 ml) and water(2 ml) was added sulfamic acid (387 mg, 0.004 mmol) while stirring at 10° C. A solution of 80% sodium chlorite (360 mg, 0.004 mmol) in water (2.0 mL) was added drop wise to the above reaction mixture over a period of 5 min and was allowed to stir at 110° C. for additional 30 min. Water (150 ml) was added to obtain a precipitate which filtered and dried under vacuum (350 mg).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25](=[NH:28])[NH:26]O)=[CH:20][C:19]=1[CH2:29][CH3:30])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]2[N:28]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=3)[O:10][N:26]=2)=[CH:20][C:19]=1[CH2:29][CH3:30])[CH3:13]
Reactant: CCOC(=O)CCc1c(C)cc(C(=N)NO)cc1CC
Reactant: Cc1cc(C(=O)O)sc1C=O
Product: CCOC(=O)CCc1c(C)cc(-c2noc(-c3cc(C)c(C=O)s3)n2)cc1CC

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid ethyl ester; LC-MS: tR=1.19 min; [M+1]+=413.15; 1H NMR (D6-DMSO) δ 1.20 (t, J=7.5 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.44-2.50 (m, 2H), 2.65 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 2.93-3.00 (m, 2H), 4.11 (q, J=7.0 Hz, 2H), 7.71 (s, 1H), 7.72 (s, 1H), 8.07 (s, 1H), 10.17 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Reaction time: 8 h

Procedure:
3-Nitrobenzaldehyde (2.04 g, 13.5 mmol) was dissolved in 50 ml 1,2-dichloroethane. 1-Acetylpiperazine 1.90 g, 14.9 mmol) and sodium triacetoxyborohydride (3.15 g, 14.9 mmol) were added followed by the addition of 0.100 ml of acetic acid. The reaction was allowed to proceed overnight (18 hours) and was then quenched with half-saturated NaHCO3 (aq). The mixture was extracted 3× with DCM and the organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluting with 95:5 DCM/MeOH) to afford 1-acetyl-4-(3-nitrobenzyl)piperazine (5-2). 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 8.13 (dd, J=1.2, 8.3 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 3.63 (t, J=5.2 Hz, 2H), 3.61 (s, 2H), 3.48 (t, J=4.8 Hz, 2H), 2.44 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: [ClH:1].Cl.NC1CCN([CH2:10][CH:11](C2(O)CCCCC2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[C:14]([Cl:30])[CH:13]=2)CC1.[Cl:38]C1C=[C:41]([CH:57](C2(O)CCCCC2)[C:58]([N:60]2[CH2:65][CH2:64][CH:63]([NH:66]C(=O)OC(C)(C)C)[CH2:62][CH2:61]2)=O)[CH:42]=[CH:43][C:44]=1[O:45]CC1C=CC2C(=CC=CC=2)C=1>>[ClH:30].[ClH:38].[NH2:66][CH:63]1[CH2:62][CH2:61][N:60]([CH:58]2[CH2:57][CH2:41][CH2:42][CH2:43][C:44]2([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[C:14]([Cl:1])[CH:13]=2)[OH:45])[CH2:65][CH2:64]1
Reactant: NC1CCN(CC(c2ccc(OCc3ccc4ccccc4c3)c(Cl)c2)C2(O)CCCCC2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2ccc(OCc3ccc4ccccc4c3)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: NC1CCN(C2CCCCC2(O)CCc2ccc(OCc3ccc4ccccc4c3)c(Cl)c2)CC1

Procedure:
In an analogous manner to Example 1, step 2 1-{2-(4-aminopiperidin-1-yl)-1-[3-chloro-4-(2-naphthylmethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl {1-[[3-chloro-4-(2-naphthylmethoxy)phenyl](1-hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate. MS (ESI) m/z 493; HRMS: calcd for C30H37ClN2O2+H+, 493.26163; found (ESI, [M+H]+), 493.2599.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+]([C:13]1[CH:18]=CC(O)=C[CH:14]=1)([O-])=O.OCC(CO)O.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[CH:18][CH:13]=[CH:14]2
Reactant: Nc1cc(F)ccc1Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: OCC(O)CO
Product: Fc1ccc(Br)c2ncccc12

Procedure:
Alternatively, 8-bromo-5-fluoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (100 g, 1.0 eq), 4-nitrophenol (40 g, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 ml) and water (114 mL) at 140-150° C. The initial mixture showed 37.8% 4-nitrophenol by relative HPLC area %. Samples showed 4.7% 4-nitrophenol immediately after adding 50% of mixed starting materials and 5.0% immediately after adding all of the materials. The yield upon workup was 87.5%, with total impurities 0.29%. Addition of less (0.46 eq, 34 g) 4-nitrophenol also successfully produced the intermediate of interest at acceptable yield.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12](O)=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[N:8][CH:7]=3.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc2nnnn2c2cnccc12
Product: Clc1cc2nnnn2c2cnccc12
Temperature: 90 °C

Procedure:
A suspension of tetrazolo[1,5-a][1,7]naphthyridin-5-ol (3.5 g) in phosphorous oxychloride (15 mL) was heated at 90° C. for 2 hours. The reaction mixture was concentrated under vacuum. The residue was poured into ice water, dichloromethane was added followed by the addition of 10% sodium hydroxide to neutral pH. The product was partitioned into dichloromethane. The dichloromethane layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide 3.8 g of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine as a solid, m.p. 176-177° C. Analysis: Calculated for C8H4ClN5: %C, 46.73; %H, 1.96; %N, 34.06; Found: %C, 46.80; %H, 2.16; %N, 34.45.