Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.N1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].[CH2:31](O)CCC>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:27]3[CH2:28][CH2:29][CH2:31][C:25](=[O:30])[CH2:26]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: O=C1CNCCN1
Reactant: CCCCO
Product: O=C1CCCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)C1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 29 mg of piperazin-2-one in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-oxopiperidin-1-yl)nicotinamide. MS (Q1) 408.3 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24].C([O-])([O-])=O.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2; 1.5 g; 5.0 mmol) was dissolved in toluene (35 mL) an DMF (2 mL). To this solution was added 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (204 mg, 250 μmol), followed by 3-chloro-4-fluorophenylboronic acid (CAN 144432-85-9; 959 mg, 5.5 mmol) and 2M-Na2CO3 (20.0 mL 40.0 mmol). The reaction mixture was heated to 90° C. and stirred for 4 h, cooled and poured into 100 mL ice water, acidified with 45 mL 2N—HCl and extracted ethyl acetate. The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The crude material was crystallized from heptane:ethyl acetate (5:1) to yield 1.1 g (63%) of the title compound as light grey solid; LC-MS (UV peak area/ESI): 97%, 348.0066 (M−H)−.
Reaction SMILES: [CH2:1]([C@@](C(O)=O)(CO)N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(=N)(OCC)C1C=CC=CC=1.Cl.[C:35]([O:39][C:40](=[O:45])[C@H:41]([CH2:43][OH:44])[NH2:42])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([O:39][C:40]([CH:41]1[CH2:43][O:44][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:42]1)=[O:45])([CH3:38])([CH3:37])[CH3:36]
Reactant: N[C@](CO)(Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)CO
Agent: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1COC(c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
In order to synthesize α-benzyl-L-serine (Angew. Chem. Int. Ed. 2004, 43, 2382-2385), 1.41 ml of triethylamine was added to a methylene chloride solution in which 939.2 mg of ethyl benzimidate hydrochloride and 1 g of L-serine-tert-butyl ester hydrochloride had been dissolved. The mixture was heated and refluxed for 2.5 hours, and stirred at room temperature for 19 hours. 50 ml of methylene chloride was added to the reaction mixture, which was then washed twice with 20 mL of water, and dried on magnesium sulfate. Magnesium sulfate was removed, and then the solvent was evaporated. A residue was purified by silica gel chromatography (hexane/ethyl acetate, 5/1 to 4/1). After evaporating the solvent, 759 mg of 2-phenyl-2-oxazoline-4-carboxylate tert-butyl ester was yielded. 0.12 ml of benzyl bromide was added to a toluene solution in which 52.4 mg of 2-phenyl-2-oxazoline-4-carboxylate tert-butyl ester, 56.1 mg of potassium hydroxide and 9.55 mg of (S,S)-3,4,5-trifluorophenyl-NAS bromide (Wako Pure Chemical Industries Ltd., code number: 201-16401) had been suspended. The resulting mixture was stirred at 0° C. for 8 hours. 20 ml of ethyl acetate was added to the reaction mixture, which was then washed twice with 5 mL of water, and dried on magnesium sulfate. Magnesium sulfate was removed, and then the solvent was evaporated. A residue was purified by silica gel chromatography (hexane/ethyl acetate, 8/1 to 5/1). After evaporating the solvent, 51 mg of 4-benzyl 2-phenyl-2-oxazoline-4-carboxylate tert-butyl ester was obtained. This was analyzed by HPLC using CHIRALPAK OD-H (4.6×250 mm) (Mobile phase: hexane/isopropyl alcohol=99/1, column temperature: room temperature, flow rate: 1 ml/minute, detection: UV 210 nm), and its optical purity was 98.4% e.e. 1 ml of ethanol and 0.5 ml of a 6 N sodium hydroxide solution were added to 42 mg of 4-benzyl 2-phenyl-2-oxazoline-4-carboxylic acid tert-butyl ester, which was then heated and refluxed for 1 hour. Then 1 ml of 6 N HCl was added, and the reaction mixture was heated and refluxed for 2 hours. The reaction mixture was neutralized and impurities were removed to obtain a solution containing α-benzyl-L-serine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](I)[N:11]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>C(NC(C)C)(C)C.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:32]#[C:31][CH2:30][CH2:29][OH:33])[N:11]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Fc1ccc(-c2nc(I)n(CCCc3ccccc3)c2-c2ccncc2)cc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: OCCC#Cc1nc(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-(4-fluorophenyl)-2-iodo-1-(3-phenylpropyl)-5-(4-pyridyl)imidazole (1.42 g, 2.74 mmol) and 3-butyn-1-ol (0.289 g,4.1 mmol) in diisopropylamine (10 mL) was added bis(acetato)-bis(triphenylphosphine) palladium (0.102 g, 0.14 mmol), followed by the addition of copper(I) iodide (0.052 g, 0.274 mmol). The mixture was stirred at 75° C. for 4 h. The reaction mixture was then cooled to room temperature and quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extract was washed with water (2×30 mL), brine (30 mL), and dried with Na2SO4. After removal of solvents, the crude product was obtained as a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[CH2:9]=O.[In+3]>C(#N)C>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:9][C:3]=2[CH:4]=[CH:5]1
Reactant: OCCc1cccs1
Reactant: C=O
Agent: [In+3]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Yield: 43 %

Procedure:
10.0 g of 2-thiopheneethanol, 2.8 g of paraformaldehyde, and 2.2 g of indium(III) triplate were added to 780 mL of acetonitrile, and the resulting mixture was refluxed for 12 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was distilled under reduced pressure to obtain 4.7 g (yield of 43%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: [CH2:1]([C:8]1(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:16].[Na+].CCCCCC.CCO[C:27](C)=[O:28]>>[CH2:1]([C:8]1([NH:16][CH:27]=[O:28])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: OC1(Cc2ccccc2)CCOCC1
Reactant: CCOC(C)=O
Agent: [Na+]
Solvent: CCCCCC
Product: O=CNC1(Cc2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 11 %

Procedure:
Tertiary alcohol 17 (13.9 g, 72.4 mmol) is treated with NaCN according to general procedure B. TLC analysis (1:1 hexane/EtOAc) indicates that 17 is completely converted into a high Rf product within a few hours. Prolonged stirring of the reaction mixture first at rt(5 days), then at 50° C. (16 h), gives only a small amount of a lower Rf product. The reaction is worked up by the general method, and the mixture is purified by filtration through silica gel with 1:1 hexane/EtOAc. The material (8.0 g, 64%) proves to be (1H NMR) a ca. 1:1 mixture of olefin isomers formed by simple elimination of water from 17. Further elution of the silica gel with 10:1 CH2Cl2 /MeOH yields a small amount of the formamide (19, 1.8 g, 11%). The mixture of olefins is resubmitted to the general Ritter reaction conditions (but at rt for 5 days, then at 45-50° C. for 16 h) to give 5.5 g of 19 as a yellow oil after FC (10:1 CH2Cl2 /MeOH). The total yield of 19 from 17 is therefore 7.3 g(46%). The following NMR spectra are for a a. 75:25 mixture of amide rotamers. Signals for the major rotamer are designated A, and those for the minor rotamer re designated B. 1H NMR (CDCl3) 8.13(s,0.75,A), 7.80(d,0.25, J=12.3,B), 7.45-7.00(m,5 total), 6.02(br d,0.25,J=12.3,B), 5.25 (br s,0.75,A), 3.90-3.50(m,4 total), 3.08 (s,0.75, A), 2.85(s,0.25, B), 2.15-1.65 (m, 4 total); 13C NMR (CDCl3) 163.76 (B), 161.29 (A), 136.13 (A), 134.52 (B), 131.30 (B), 130.82 (A), 130.70 (B), 130.56 (A), 128.36 (A), 128.14 (B), 127.99 (A), 127.84 (B), 127.11 (B), 126.54 (A), 63.19 (A), 62.76 (B), 54.38 (A), 52.93 (B), 49.60 (B), 43.87 (A), 36.11 (B), 34.98 (A); MS(MW=219.3, EI,eE=70 eV) m/z 220 (M+H)+, 201, 174, 141, 128(base peak), 115, 100, 98, 91, 82, 70, 65, 53, 42.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16])([O-:7])=[O:6]>C1COCC1>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][O:16][C:1]([Cl:4])=[O:2])([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1ccccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 94 %

Procedure:
Phosgene was introduced into a solution of 2-(2-nitrophenyl)ethanol (5.2 g, 31 mmol) in THF (20 ml, dist. over CaH2) at room temperature under stirring. After 1.5 h, the excess phosgene and the solvent were removed by distillation in a high vacuum. 2-(2-nitrophenyl)ethoxycarbonyl chloride (6.69 g, 94%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15](Cl)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])=[CH:31][CH:30]=1.N1C=CC=CC=1.C(Cl)(Cl)Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O:38][CH2:37][C:36]([O:35][C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=3)([CH3:40])[CH3:39])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)Oc1ccc(Cl)cc1
Reactant: O=C(Cl)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(COC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (3.16 g.) in 1,2-dichloroethane (10 ml.) is added, dropwise and below 10° C., to a stirred mixture of 2-(4-chlorophenyloxy)-2-methylpropanol (1.40 g.), pyridine (4.0 ml.), and 1,2-dichloroethane (10 ml.). The mixture is stirred at ambient temperature for 20 hours, then mixed with ice-water and chloroform. The organic phase is separated, and washed with 3N-hydrochloric acid and water. 0.4N-Aqueous potassium hydroxide (5 ml.) and ice are added, the mixture is shaken, and enough ether is added to cause the resulting emulsion to separate into two layers. The organic layer is washed with water, dried and evaporated. The residual oil (3.6 g.) is chromatographed in light petroleum (b.p. 60°-80° C.) on a column of silica gel (45 g.). The column is washed portionwise the solvent (2 l ) until no more material is eluted, and then with a mixture of light petroleum and ether (10:1, 200 ml.). This eluate is evaporated to give 2-(4-chlorophenyloxy)-2-methylpropyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (2.6 g.) as a syrup.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:31]=[N:32][N:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:34]=34)[N:25]=2)[CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]4[CH:31]=[N:32][N:33]5[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:34]=45)[N:25]=3)[CH2:18]2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(N2CCC[C@@H](Nc3ccnc(-c4cnn5ccc(C#N)cc45)n3)C2)nc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 69.2 %

Procedure:
6-Chloronicotinonitrile (0.04 g, 0.29 mmol) and triethylamine (0.15 mL, 1.08 mmol) were added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 0.11 g, 0.24 mmol) in dichloromethane (3.3 mL) and the resulting mixture was stirred at 50° C. for 20 hours. The reaction mixture was then cooled to ambient temperature and dichloromethane and 4% aqueous sodium hydrogencarbonate solution were added. The organic layer was separated, washed with water and brine, dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography (200:1 to 60:1 chloroform/methanol) to give the title compound (0.07 g, 71%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][CH3:22])=[C:10]([CH2:19]O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.S(Cl)(Cl)=O>[N:23]([CH2:19][C:10]1[C:9]([CH2:21][CH3:22])=[N:8][C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[C:11]=1[NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 218.1 %

Procedure:
To [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (24.9 g, 82 mmol) was added thionyl chloride (90 mL, 1.23 mmol) and the mixture was heated to 80° C. under an atmosphere of nitrogen. After 2 h the mixture was cooled, evaporated and the residue azeotroped with toluene. The residue was then dissolved in a solution of sodium azide (7.98 g, 123 mmol) in DMSO (120 mL). The mixture was stirred for 16 h. The above procedure was repeated on the same scale and the 2 reactions combined for work-up. The combined DMSO mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was extracted thoroughly with ethyl acetate and the combined organics were washed with water, then brine, dried and evaporated to afford 58.9 g of a brown solid. The product was purified by flash chomatography on 1.5 kg of silica using a step gradient from 3:1 to 2:1 cyclohexane/ethyl acetate to afford 39.94 g of the title compound. LC-MS m/z 330 (M+H)+, 2.21 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]3[O:20][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[O:13]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Yield: 69.7 %

Procedure:
A mixture of 4-(4-chlorophenyl)benzaldehyde (15.0 g.), 2-hydroxy-2-methylpropionic acid (10.0 g.) and p-toluenesulphonic acid monohydrate (0.2 g.) was heated in toluene (200 ml.) under reflux for 6 hours with continuous removal of water by azeotropic distillation. The solution was then cooled, washed with 10% w/v sodium hydrogen carbonate solution (100 ml.) and then with water (2×100 ml.) before it was dried (Na2SO4). The dried toluene solution was filtered and evaporated to give 2-[4-(4-chlorophenyl)phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (14.6 g.), m.p. 108°-110° C. (after recrystallisation from cyclohexane and then from toluene).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[Cl:17]C1C2C(=CC=CC=2)C(O)=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[C:9]([Cl:17])[CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1
Reactant: O=c1cc(O)c2ccc3ccccc3c2o1
Reactant: Oc1ccc(Cl)c2ccccc12
Product: O=c1cc(O)c2cc(Cl)c3ccccc3c2o1
Yield: 30 %

Procedure:
The procedure was identical to that used for the preparation of 10a: 30% yield (starting with 4-chloro-1-naphthol 9d); 1H NMR (DMSO) δ 5.90 (1H, s, H-3), 7.81 (2H, m, H-8, 9), 7.90 (1H, s, H-5), 8.25 (1H, d, J=7.8 Hz, H-7), 8.43 (1H, d, J=7.5 Hz, H-10).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH:2]12.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11].C(O)=O>>[OH:23][C:22]1[N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][CH2:9][CH:2]4[CH2:1]3)=[O:29])=[CH:26][N:25]=2)[N:20]=[CH:19][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][C:14]=1[CH3:33]
Reactant: C1CC2CNCCN2C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN4CCCC4C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using octahydropyrrolo[1,2-a]pyrazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (47 mg, 0.099 mmol, 79%) as a white solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.52 (m, 1H) 1.72 (br. s., 3H) 2.09 (br. s., 1H) 2.21 (d, J=8.8 Hz, 2H) 2.43 (s, 3H) 2.54-2.61 (m, 1H) 2.87-3.15 (m, 3H) 3.50-3.88 (m, 1H) 4.30-4.68 (m, 1H) 7.63 (d, J=8.1 Hz, 1H) 7.69 (s, 1H) 7.88 (d, J=8.1 Hz, 1H) 8.03 (dd, J=8.6, 2.0 Hz, 1H) 8.09 (s, 1H) 8.42 (d, J=8.3 Hz, 1H) 8.52 (d, J=2.0 Hz, 1H) 12.77 (br. s., 1H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1.[C:18]([Cu])#[N:19]>CN(C=O)C.O.C(OCC)(=O)C>[C:18]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1)#[N:19]
Reactant: N#C[Cu]
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C#N)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Temperature: 115 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
To a solution of 4-bromo-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (450 mg, 1.42 mmol) in dry DMF (14 mL) under argon was added CuCN (178 mg, 1.99 mmol). The resulting mixture was heated to 115° C. and stirred for 4 h. The reaction was cooled and diluted with water and ethyl acetate. The layers were separated, and the organics were washed once with water. The organics were then dried, concentrated, and purified by flash chromatography (35% ethyl acetate/hexanes) to provide 4-cyano-2-methyl-5-nitro-(N,N-dimethyl)benzenesulfonamide (249 mg, 65%) as pale yellow crystals. IR (thin film): 2240 cm−1. 1H NMR (400 MHz, CDCl3): δ2.78 (s, 3), 2.94 (s, 6), 7.87 (s, 1), 8.74 (s, 1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CCO>[CH2:16]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCBr
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: CCCCCCCCSc1nnc(-c2ccc3[nH]cnc3c2)o1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and octylbromide (0.258 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1Cl)C(C)CNCC2
Temperature: 20 °C
Reaction time: 8 h
Yield: 109.3 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.399 g, 1.24 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20° C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.306 g of a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 3.0-2.8 (m, 6H), 2.62 (m, 1H), 2.16 (bs, 1H), 1.24 (d, J=7 Hz, 3H). MS calculated for C12H16ClNO+H: 226, observed: 226.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.Cl>N1C=CC=CC=1>[NH2:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1.[C:15]([NH:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1
Product: O=C(Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1)c1cccnc1
Temperature: 60 °C

Procedure:
1.9 g of benzoguanamine and 3.6 g of nicotinic acid chloride (or an equivalent amount of the hydrochloride) are dissolved in 70 ml of pyridine and heated at 60° C for 6 hours. The reaction mixture is processed as described in Example 4 to yield 0.17 g of 2-amino-4-nicotinamido-6-phenyl-s-triazine [mononicotinoylbenzoguanamine] and 1.2 g of 2,4-bis(nicotinamido)-6-phenyl-s-triazine [dinicotinoylbenzoguanamine].