Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.COCCN(S(F)(F)F)CCOC.Cl.[CH3:42][NH:43][O:44][CH3:45]>C(Cl)Cl>[CH3:45][O:44][N:43]([CH3:42])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: COC(C(=O)O)c1ccc(-c2nnc(C)o2)cc1
Agent: COCCN(CCOC)S(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 26 %

Procedure:
To an ice-cold solution of 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid (6.8 g, 27.4 mmol) in anhydrous CH2Cl2 (270 mL) and diisopropylethylamine (17 mL, 97 mmol) under argon was added bis(2-methoxyethyl)aminosulfur trifluoride (5.6 mL, 30.3 mmol) dropwise. After stirring over an ice bath for 45 min, N,O-dimethylhydroxylamine hydrochloride (3.40 g, 34.8 mmol) was added in three aliquots over a period of 15 min. The mixture was stirred for 15 min then the ice bath was removed. After 3 hrs, saturated aqueous NaHCO3 was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, H2O and brine, dried over MgSO4, filtered through Celite and concentrated in vacuo. Purification by chromatography (75-100% EtOAc-hexanes then 0-5% EtOH-EtOAc) gave N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide as an oil that solidified upon standing (2.06 g, 26% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([CH:23]=1)[NH2:22]>C(O)(C)C.CO>[ClH:1].[NH2:22][C:21]1[CH:23]=[C:17]([NH:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:18]=[C:19]([Cl:24])[CH:20]=1
Reactant: Nc1cc(N)cc(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(N)cc(Cl)c3)c2cc1OC
Product: Cl
Temperature: 20 °C
Yield: 77.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) and 5-amino-3-chloroaniline (253 mg, 1.78 mmol) were combined in isopropanol (3 mL) and heated to reflux for 16 hours under an atmosphere of dry nitrogen. After cooling to 20° C. the mixture was diluted with methanol (5 mL) and the resulting precipitate was filtered and dried, in vacuo, to afford 252 mg (77%) of (3-amino-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine hydrochloride (mp. 298°-301° C.; LC-MS: 331 (MH+)). A portion of this product (175 mg, 0.476 mmol) was dissolved in 80% acetic acid/H2O (12 mL), cooled to 0° C., and a solution of NaNO2 (36 mg, 0.516 mmol) in H2O (300 μL) was added. The solution was stirred for 10 minutes at 0° C. and NaN3 (33 mg, 0.50 mmol) in H2O (300 μL) was added. The reaction mixture was allowed to warm to 20° C. and stirred 16 hours. The resulting precipitate was filtered and dissolved in 10% methanol in CHCl3 and the solution was washed with saturated aqueous NaHCO3, and brine, dried over Na2 SO4, filtered and concentrated in vacuo to yield 59 mg (35%) of the title product as a yellow solid; mp 205°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[CH2:28]([O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34])[CH3:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[O:30][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)NCC2
Reactant: CCOc1ccccc1CN
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(F)cc1

Procedure:
prepared by reaction of 1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzylamine
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.ClCCl>S(Cl)(Cl)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: Nc1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloropicolinic acid (0.50 g, 3.17 mmol) was dissolved in thionyl chloride (5.0 mL) and stirred at 25° C. for 1 hour. The thionyl chloride was evaporated, and 4-aminopyridine (0.28 g, 2.98 mmol), triethylamine (0.415 mL, 2.98 mmol) and dichloromethane (50 mL) were added. The solution was stirred at 25° C. for 18 hours. The reaction mixture was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was dried (sodium sulfate) and concentrated, and the residue was purified by silica gel flash column chromatography to afford the titled compound: 1H NMR (500 MHz, methanol-D4) δ ppm 7.71 (dd, J=7.9, 0.9 Hz, 1H), 7.91-7.95 (m, 2H), 8.05 (t, J=7.8 Hz, 1), 8.20 (dd, J=7.6, 0.6 Hz, 1H), 8.43-8.52 (m, 2H) MS (ESI) m/z=335 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=O)[CH2:13][CH2:14][N:3]1[C:4]=23.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>CO>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([NH:30][CH2:27][CH:28]=[CH2:29])[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: C=CCN
Reactant: O=C1CCN2C(=O)OCc3cccc1c32
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=CCNC1CCN2C(=O)OCc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6,7-dihydro-3,7-dioxo-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (6.10 g) in methanol (100 ml) were added molecular sieve 3A (12 g), p-toluenesulfonic acid (catalytic amount) and allylamine (50 ml), and the mixture was refluxed overnight. After cooling the reaction mixture, molecular sieve 3A was filtered off and sodium borohydride (1.70 g) was added to the filtrate under ice-cooling, then the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added a small amount of water, and methanol was distilled off. The residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3:1)]to give 6,7-dihydro-3-oxo-7-allylamino-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5.89 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:31]4[NH:30][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=4)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc3ccccc3[nH]2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-benzo[d]imidazole-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[CH3:3][C:1]([C:5]1[CH:11]=[C:10]([O:12][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])[CH:9]=[CH:8][C:6]=1[O:7][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([CH3:4])[CH3:2]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(OCCCC(C)(C)C(=O)OC)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 3.32 g of t-butylhydroquinone in 15 ml of dimethylformamide is added dropwise to a suspension of 2.4 g of 50% sodium hydride in 25 ml of dimethylformamide, and allowed to stir for 1/2 an hour at room temperature. 11.2 g of methyl 5-bromo-2,2-dimethylpentanoate is added followed by heating the mixture at 60°-70° C. for 6 hrs. Dimethylformamide is distilled off, the residue is poured into water and the organic material is extracted with ether. The ether extract is washed with water until neutral, dried over anhydrous magnesium sulfate and the ether is evaporated. The residue is purified by distillation yielding the product, dimethyl 5,5'-[[2-(1,1-dimethylethyl)1,4-phenylene]bis(oxy)]bis[2,2-dimethylpentanoate] b.p. 200° C. at 0.5 mm of Hg; yield 4 g.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][C:27](CC)=[O:28]>>[C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6]2([O:28][CH2:27][CH2:26][O:9]2)[CH:5]1[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14])#[N:2]
Reactant: CCC(C)=O
Reactant: CC/C=C\CC1C(=O)CCC1CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC/C=C\CC1C(CC#N)CCC12OCCO2
Reaction time: 9 h

Procedure:
Into a 2 liter flask fitted with a 1 meter adiabatic column provided with a metallic lining, are placed: 212 g of 3-cyanomethyl-2-(cis-2-n-pentenyl)-1-cyclopentanone, 512 g of the glycoketal of methylethyl ketone and 2.1 g of para-toluenesulphonic acid. The mass is progressively heated in order to slowly distil the methyl ethyl ketone from the head of the column (temperature of the mass 120°-140°C; temperature of the vapour 77°-79°C). The operation lasts about 9 hours. The mass is then cooled, 10 g of dry sodium carbonate added thereto, stirred for a half-hour and the mass washed to neutrality after diluting with 200 ml of ethyl ether. After distillation of the solvent and rectification of the crude product, there is obtained 229.2 g of 3-cyanomethyl-1,1-ethylenedioxy-2-(cis-2-n-pentenyl)-cyclopentane. The product exhibits the following constants: b.p.0.5 = 130°C, nD15 = 1.4862. The infra-red spectrum had principal bands at: 2240, 1650, 730, 1150, 1115 and 1040 cm-1. NMR Spectrum: 0.95, 4.82, 5.36.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:28][CH2:29][CH2:30]O)[C:20]4=[O:32])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1.[S:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:22]=[CH:27][CH:26]=[CH:25][C:24]=5[N:21]([CH2:28][CH2:29][CH2:30][N:35]5[C:36](=[O:38])[CH2:37][S:33][C:34]5=[O:39])[C:20]4=[O:32])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=c1n(CCCO)c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Reactant: O=C1CSC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CSC(=O)N1CCCn1c(=O)n(C2CCN(C3CCC4CCc5cccc3c54)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-[1-(1,2,2a,3,4,5-Hexahydroacenaphthylen-5-yl)piperidin-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one and 2,4-thiazolidinedione (314 mg) were dissolved in THF (25 ml), 40% solution (1.22 ml) of triphenylphosphine (702 mg) and diethyl azodicarboxylate (DEAD) in toluene was added, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (160 mg).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].ClC(N(C)C)=C(C)C.Cl.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([CH2:25][N:26]2[C:34]3[C:29](=[C:30]([O:35][CH3:36])[CH:31]=[CH:32][CH:33]=3)[C:28]([NH:37][S:38]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)(=[O:40])=[O:39])=[N:27]2)[CH:22]=[CH:23][CH:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:46][C:43]1[S:42][C:41]([S:38]([NH:37][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH2:18][NH:17][C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH:24]=[CH:23][CH:22]=3)[N:27]=2)(=[O:39])=[O:40])=[CH:45][CH:44]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(C)(O)C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 2-hydroxy-2-methylpropanoic acid (Aldrich) (20.84 mg, 0.200 mmol) in THF (2 mL) was added dropwise at room temperature 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.026 mL, 0.200 mmol). The resulting mixture was stirred at room temperature for 30 min. To this were successively added N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (50 mg, 0.100 mmol) and DIPEA (0.052 mL, 0.300 mmol). After 1 hour of stirring at room temperature LCMS showed product as the major peak. The reaction mixture was concentrated under a stream of nitrogen in the Radleys blowdown apparatus, the residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (48.5 mg, 88%). LCMS (System A) RT=1.05 min, ES+ve m/z 549/551 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][OH:14]>C(O)CCC>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][OH:14])([O-:10])=[O:9]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1NCCO
Yield: 74.6 %

Procedure:
According to the procedure of B. Agai, et al., Tetrahedron, 32, 839, (1976), a solution of 1-chloro-2-nitrobenzene (50.0 g, 0.317 mol) and 2-aminoethanol (116.3 g, 1.904 mol) in nBuOH (400 mL) was heated under reflux for 6 hours. The mixture was concentrated, taken up in H2O, and extracted with ether. The organic phase was washed with brine, dried, and concentrated to give 43.1 g (75%) of an orange solid m.p. 78° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[CH:3][C:4]=4[F:25])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:24][CH2:23]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C4CC4)cn3)CC2)c(F)c1
Yield: 89.3 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl]methanone (404 mg) described in Preparation Example 188 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (379 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[N:16][CH:15]=[C:14]([CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)[N:13]=1)[C:5]2([CH3:25])[CH3:24].CCN(CC)CC.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([C:14]2[N:13]=[C:12]([N:6]3[C:5]([CH3:25])([CH3:24])[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:11])[CH:17]=[N:16][CH:15]=2)[CH2:19]1)(=[O:35])[CH3:34]
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(C2CCCNC2)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(c2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)n2)C1
Yield: 34.9 %

Procedure:
To a mixture of 5-chloro-3,3-dimethyl-2-(6-piperidin-3-yl-pyrazin-2-yl)-2,3-dihydro-isoindol-1-one (80 mg, 0.22 mmol) and Et3N (44.4 mg, 0.44 mmol) in DCM (2 mL) was added acetyl chloride (26.4 mg, 0.34 mmol) at 0° C. After removal of solvent, the residue was purified by prep-HPLC to yield the title compound (30.6 mg, 35%) as a white solid. MS: 399.2 (M+H+).
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[C:20]([CH3:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>CS(C)=O>[Cl:18][C:19]1[C:20]([CH3:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Cc1c(N)cccc1Cl
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: Cc1c(Cl)cccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 3-chloro-2-methylaniline (0.026 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 329 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[C:5]2[N:6]=[C:7]([CH3:33])[C:8]([C@H:22]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])=[C:9]([C:10]3[C:11]([CH3:21])=[C:12]4[C:17](=[C:18]([F:20])[CH:19]=3)[O:16][CH2:15][CH2:14][CH2:13]4)[N:4]2[N:3]=1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[CH:34]=[C:5]2[N:6]=[C:7]([CH3:33])[C:8]([C@H:22]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[C:23]([OH:25])=[O:24])=[C:9]([C:10]3[C:11]([CH3:21])=[C:12]4[C:17](=[C:18]([F:20])[CH:19]=3)[O:16][CH2:15][CH2:14][CH2:13]4)[N:4]2[N:3]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(N)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
A mixture of (2S)-ethyl 2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (1.20 g, 2.55 mmol), 1N NaOH (3.83 mL, 3.83 mmol) in EtOH (20 mL) was stirred at rt for 16 h. LCMS indicated a small amount of starting material remaining, therefore, the reaction mixture washeated at 60° C. for 2 h. At this time, LCMS indicated that the ester hydrolysis was complete. The reaction mixture was then concentrated in vacuo, and the residue was adjusted to pH=4 using 1N HCl. A white precipitate formed and was collected by filtration, washed with water, and dried in vacuo to obtain (2S)-2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (1.06 g, 2.16 mmol, 85% yield) as a off-white solid. 1H NMR (500 MHz, CDCl3) δ 6.90 (d, J=10.56 Hz, 1H), 5.91 (s, 1H), 4.97 (s, 1H), 4.26-4.35 (m, 2H), 2.74 (m, 2H), 2.65 (s, 3H), 2.11-2.18 (m, 2H), 1.95 (s, 3H), 1.21 (s, 9H). LCMS (M+H)=443.23.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20].[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[K+].[CH2:30](Br)[CH:31]=[CH2:32].ClOC(C)(C)C>ClCCl>[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[CH3:21][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH+:9]1[CH:30]=[C:31]([CH3:32])[N:11]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[NH:10]1
Reactant: C=CCBr
Reactant: Cc1cc(C)c(N=NNc2c(C)cc(C)cc2C)c(C)c1
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: CC1=C[NH+](c2c(C)cc(C)cc2C)NN1c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8b (1.70 g, 6 mmol) and anhydrous potassium hexafluorophosphate (1.10 g, 6 mmol) and allyl bromide 12 (1.04 mL, 12 mmol) in dry dichloromethane (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (1.0 mL, 9 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether affords the crude dihydrotriazolium salt 13 as a beige solid (3.02 g, ˜92%), which is contaminated by ca. 30% of the aromatized triazolium salt 10bi. 1H-NMR (CDCl3, 300 MHz): δ=7.07 (s, 2H), 7.06 (s, 2H), 6.03 (t, J=12.7 Hz), 5.20 (t, J=14.9 Hz, 1H), 4.85 (t, J=12.5 Hz, 1H), 3.91 (dd, J=12.8, 2.5 Hz, 1H), 3.68 (d, J=12.6 Hz, 1H), 2.45-2.36 (m, 18H). 13C-NMR (CDCl3, 75 MHz): δ=142.8, 142.6, 135.9, 134.8, 134.3, 134.1, 132.2, 131.2, 130.5, 128.8, 68.3, 59.1, 30.1, 21.3, 21.2, 19.0, 18.7, 17.8. Calcd. for C21H27BrN3 [M+]: 400.1383. found 400.1400.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@@H:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][OH:31]>>[OH:31][CH2:30][C@@H:29]([NH:28][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: N[C@H](CO)c1ccccc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](CO)c3ccccc3)cc2)CC1
Yield: 77 %

Procedure:
By the same procedure as described in the example 30, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using (S)-(+)-2-amino-2-phenylethanol. Then, the product was recrystallized using ethanol and petroleum ether to give the desired compound.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#N.[CH2:20]([OH:23])[CH2:21]O.[OH-:24].[Na+]>O>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:21]([C:20]([OH:23])=[O:24])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: OCCO
Reactant: [OH-]
Reactant: CCCCCc1ccc(-c2ccc(C#N)cc2)cc1
Agent: [Na+]
Solvent: O
Product: CCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 125 °C
Reaction time: 8 h

Procedure:
5 g. 4-cyano-4'-n-pentylbiphenyl in a mixture of 90 ml. ethylene glycol, 18 ml. water and 3.2 g. sodium hydroxide are heated while stirring to 125° C. for 8 hours. After cooling, the reaction mixture is filtered, the residue suspended in 50 ml. ethanol and acidified with 5% hydrochloric acid to a pH of about 2. The reaction mixture is further stirred for 4 hours at room temperature, then filtered and the residue washed with ethanol. The 4-(4-n-pentylphenyl)-benzoic acid obtained is recrystallized from chloroform; m.p. 174° C., S/N 200° C., K. 254° C.