Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[S:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10][C:11](=[O:12])[CH:2]21)=[O:9].Cl.[OH2:14]>>[CH:1]12[S:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([OH:14])=[O:9])[CH:2]2[C:11]([OH:10])=[O:12]
Reactant: O=C1OC(=O)C2C3C=CC(S3)C12
Reactant: O
Agent: Cl
Product: O=C(O)C1C2C=CC(S2)C1C(=O)O
Temperature: 700 °C

Procedure:
The compound of Chemical Formula 201, that is 7-thiabicyclo[2.2.1]hept-5ene-2,3-dicarboxylic anhydride (50 g) is well mixed with water (200 ml), and 1 g of hydrochloric acid is added thereto. The resultant mixture is heated under reflux at 700° C. for 20 hours. Upon cooling the mixture to room temperature, crystals are formed. The crystals are dried in vacuo to obtain 7-thiabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid represented by Chemical Formula 167 (yield: 70%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][N:17]=[C:18]=[O:19])[CH3:14]>O.O1CCOCC1>[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][NH:17][C:18]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:19])[CH3:14]
Reactant: CCCCC(CC)CN=C=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCC(CC)CNC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 24 h
Yield: 88.2 %

Procedure:
At 5° C., a suspension of L-(+)-glutamine (23.1 g, 158 mmol) in 1:1 water/dioxane (300 ml) was treated successively with a solution of 2N aq. NaOH (79 ml) and with 2-ethylhexyl isocyanate (25 g, 158 mmol). The resulting mixture was stirred for 24 h while its temperature rose to 20° C. (final pH value: 6) and filtered. The filtrate was washed twice with ethyl acetate (200 ml) and the combined organic phases were acidify with a 2N aq. HCl solution to pH 1. Filtration of the resulting precipitate and drying under vacuum gave N2-[(2-ethylhexylamino)carbonyl]-L-glutamine (42 g, 88%, white solid).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1.[C:25]1([CH3:34])[C:26]([C:31](Cl)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.C1(C2C=CC=CC=2C(Cl)=O)C=CC=CC=1>>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:31](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:34])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1

Procedure:
Compound 4 as prepared in Example 25 (0.55 g, 1.5 mM) was treated as described in Example 26 with 2-toluoyl chloride (0.3 ml) substituted for 2-phenylbenzoyl chloride to give the desired product m/z (MH+)483
Reaction SMILES: C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+].[H-].[Na+].[Br:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:26][NH:27]2)=[CH:23][CH:22]=1.C([Li])(C)(C)C.CCCCC.[O:47]1[CH2:52][CH2:51][C:50](=[O:53])[CH2:49][CH2:48]1>O1CCCC1>[Br:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:26][NH:27]2)=[CH:23][CH:22]=1.[C:33]([O:32][C:30]([C:25]1[C:24]2[C:28](=[CH:29][C:21]([C:50]3([OH:53])[CH2:51][CH2:52][O:47][CH2:48][CH2:49]3)=[CH:22][CH:23]=2)[NH:27][N:26]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C1CCOCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)c1n[nH]c2cc(Br)ccc12
Agent: [H-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1n[nH]c2cc(C3(O)CCOCC3)ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid by reaction with a 2-fold excess of di-tert-butyldicarbonate followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% mineral oil dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) at 0° C. was slowly added a solution of tert-butyl 6-bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL). After stifling for 0.5 h at 0° C., the mixture was cooled to −78° C. and a 1.7 M solution of tert-butyllithium in pentane (5.1 mmol) was added. After 0.5 h at −78° C., a solution of tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h and warmed to 0° C. The reaction mixture was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine (50 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (70/30 ethyl acetate/hexanes) to yield 6-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (68%) as a colorless solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:10]=3)=[CH:20][CH:21]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles) the title compound was isolated as a white solid. Yield; 60 mg (30%); (M+H)=496.3
Reaction SMILES: [CH3:1][Si:2]([CH2:5][Mg]Cl)([CH3:4])[CH3:3].[O:8]1[CH2:13][CH2:12][CH2:11][O:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]([CH:31]2[CH2:34][C:33]([F:36])([F:35])[CH2:32]2)=[O:30])[N:23]=3)=[C:16]([F:37])[CH:15]=1>C1COCC1>[O:10]1[CH2:11][CH2:12][CH2:13][O:8][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]([CH:31]2[CH2:32][C:33]([F:36])([F:35])[CH2:34]2)([OH:30])[CH2:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[N:23]=3)=[C:16]([F:37])[CH:15]=1
Reactant: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)CC(O)(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilylmethylmagnesium chloride (1.1M solution in THF; 2.24 mL, 2.47 mmol) was added to a solution of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)(3,3-difluorocyclobutyl)methanone (630 mg, 1.450 mmol) in THF (30.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 10 min. Excess Grignard reagent was quenched by the careful addition of sat. aq. NH4Cl (10 mL), water was added to dissolve the precipitated salts, and THF was then removed in vacuo. The resulting mixture was partitioned between EtOAc (250 mL) and sat. aq. NH4Cl (50 mL), and the organic layer was separated and washed with brine (50 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-(2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)-1-(3,3-difluoro-cyclobutyl)-2-(trimethylsilyl)ethanol as a yellow foam. MS (ESI) m/z: Calculated: 522.2; Observed: 522.8 (M++1).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:16](OC)[CH2:17][Cl:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][CH:16]([CH2:17][Cl:18])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: COC(CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: ClCC1OCC(OCc2ccccc2)CO1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 5.0 g of 2-benzyloxy-1,3-propanediol, 3.5 g of chloroacetaldehyde dimethyl acetal and 0.3 g of p-toluenesulfonic acid was heated via oil bath through the temperature range 25° to 130° C in a three-necked, round-bottomed flask equipped with stirrer, thermometer and condenser. The by-product methanol, removed by distillation during the course of reaction, amounted to 63% of theory. The reaction mixture was cooled to room temperature and dissolved in ether. The ether solution was washed with 10% sodium carbonate and then with water. After drying over anhydrous sodium sulfate, the ether was removed under reduced pressure. Distillation of the crude oil gave 3.3 g of 5-benzyloxy-2-chloromethyl-1,3-dioxane; b.p. 100°-105° C/0.025 mm Hg; nD25 1.5228. The nmr spectrum was consistent with the assigned structure and showed the cis isomer content to be 30 ± 5%, the remainder being the trans isomer.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[C:9]([NH:13][NH2:14])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([N:13]1[C:6]([NH2:7])=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: N#CCC(=O)C1CC1
Reactant: CC(C)(C)NN
Solvent: CCO
Product: CC(C)(C)n1nc(C2CC2)cc1N

Procedure:
1-tert-Butyl-3-cyclopropyl-1H-pyrazol-5-amine was prepared by reacting 3-cyclopropyl-3-oxopropanenitrile (5.0 mmol, 545 mg) and tert-butylhydrazine (3.5 mmol, 440 mg) in ethanol under reflux conditions for 6 h. Solvent was removed in vacuo. 1H NMR (400 MHz) CDCl3: 5.36 (s, 1H), 3.61 (s, 1H), 2.51-2.45 (m, 1H), 1.75 (s, 9H, t-Bu), 1.107-1.104 (m, 2H), 0.73-0.72 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=[O:12].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][OH:12]
Reactant: Cn1c(C=O)nc2ccccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cn1c(CO)nc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a 0° C. solution of 1-methyl-1H-benzimidazole-2-carbaldehyde (1.1 g, 6.8 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (350 mg, 9.3 mmol). The reaction mixture was stirred at room temperature for 5 hours. Saturated ammonium chloride solution (20 mL) was added. Methanol was evaporated. The resultant mixture was extracted with EtOAc (3×50 mL) and CH2Cl2 (1×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. (1-methyl-1H-benzimidazol-2-yl)methanol was obtained (1.1 g, 99% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6](=O)[CH2:5]2.Cl.[CH3:13][NH2:14]>>[CH3:13][NH:14][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1
Reactant: O=C1Cc2ccc(Cl)cc2C1
Reactant: CN
Agent: Cl
Product: CNC1Cc2ccc(Cl)cc2C1

Procedure:
Following the procedure of Example 5, 5-chloro-2-indanone and methylamine hydrochloride gave N-methyl-5-chloro-2-indanamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][CH3:25])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH2:24]([O:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:35](=[O:36])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:37])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH3:25]
Reactant: CCOc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCOc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-ethoxyphenyl)-5-phenylbenzoxazole (157 mg, 0.44 mmol) and 1,2,4-benzenetricarboxylic anhydride (84 mg, 0.44 mmol) the title compound was obtained (133 mg, 60%). 1H NMR (DMSO) δ 8.50(dd, 1H), 8.40(s, 1H), 8.25(d, 1H), 8.17(m, 2H), 7.93(d, 1H), 7.80(m, 4H), 7.50(m, 4H), 4.41(q, 2H), 1.52(t, 3H). MS 505 m/z (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[CH3:17])[CH:2]=[CH2:3].C1(C)C(C)=CC=CC=1.O.[CH3:27][CH2:28][CH:29]([NH2:33])[CH2:30][CH2:31][CH3:32]>>[CH3:27][CH2:28][CH:29]([NH:33][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([CH3:17])[C:6]=1[N+:14]([O-:16])=[O:15])[CH2:30][CH2:31][CH3:32]
Reactant: C=CCc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CCCC(N)CC
Solvent: O
Solvent: Cc1ccccc1C
Product: C=CCc1cc([N+](=O)[O-])c(NC(CC)CCC)c([N+](=O)[O-])c1C

Procedure:
One equivalent of 4-allyl-3-methyl-2,6-dinitrochlorobenzene is dissolved in three volumes of xylene containing two equivalents of 3-hexylamine. The mixture is refluxed for 5 hours and then poured into water. The organic phase is washed with 5% hydrochloric acid and then water, dried over calcium sulfate, and removed in vacuo to leave the above-named product.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]#[C:15][Si](C)(C)C)=[CH:8][CH:7]=1>O.C1COCC1>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]([OH:20])=[O:4])=[CH:11][CH:10]=1)#[C:13][C:14]#[CH:15]
Reactant: COC(=O)c1ccc(C#CC#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC#Cc1ccc(C(=O)O)cc1
Reaction time: 16 h
Yield: 91.4 %

Procedure:
Potassium hydroxide (3.700 g, 65.9 mmol) was dissolved in H2O (10 mL) and added to a solution of 4-(4-trimethylsilanyl-buta-1,3-diynyl)-benzoic acid methyl ester 3 (3.420 g, 13.5 mmol) in THF (26 mL) in the absence of light. After stirring 16 h, the reaction was quenched with 1.0 M HCl (120 mL) and the resulting precipitate was filtered, washed with 1:1 hexanes/benzene (150 mL) and dried in vacuo to afford 2.100 g (91% yield, 98% pure) of 4-(buta-1,3-diynyl)-benzoic acid 4 as a brown solid, mp>230° C. Although diyne 4 was found to be unstable at room temperature it could be stored for several weeks at 0° C. with only small amounts of decomposition observed by TLC. Rf=0.2 (4:1 Hexanes/EtOAc); HPLC (300 nm, 28 min run) 16.0 min; LRMS (ES+) m/z 171.0 (C11H6O2+H requires 171.04).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([NH:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)=[O:18])=[CH:5]1)([CH3:2])[CH3:3]
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(C(C)C)c2n1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,4-Dihydro-1-isopropyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (Example 3b, 0.9 g) was warmed in dimethylformamide (70 ml) and triethylamine (0.7 ml) was added. The solution was cooled to 0° and ethyl chloroformate (0.4 ml) was added and the mixture was kept for 30 minutes. 5-Amino-1H-tetrazol (3.6 g) was added and the mixture was stirred at room temperature for 18 hours and filtered. The filtrate was evaporated and the residue was crystallised from a mixture of dimethylforamido and isopropanol. The product had m.p. >300° (d) (36%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)=[N+:2]=[N-:3].Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[OH:15][NH:14][C:9]([C:8]1[CH:7]=[N:6][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:12][CH:11]=1)=[NH:10]
Reactant: N#Cc1ccc(CN=[N+]=[N-])nc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: [N-]=[N+]=NCc1ccc(C(=N)NO)cn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a solution of the azide of Example 51 (11-3) (6.46 g, 40.6 mmol) in methanol (100 ml) was added hydroxylamine hydrochloride (3.95 g, 56.84 mmol), followed by triethylamine (9.6 ml). The solution was heated to 65° C. for four hours. The solvent was removed under reduced pressure and the remaining residue was extracted with ethylacetate (300 ml) and water (100 ml). The water layer was re-extracted with ethylacetate (2×200 ml). The combined organic extracts were washed with brine (2×100 ml), dried over MgSO4 and evaporated to yield the title product (11-4) (7.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.S(Cl)([Cl:15])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][Cl:15])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)cc(CCl)c1
Reaction time: 1 h

Procedure:
To a stirring solution of (3-bromo-5-nitrophenyl)methanol (5.00 g; 21.5 mmol; Biogene Organics Inc) in DCM (65 mL) and NMP (9 mL) at RT was added dropwise thionylchloride (3.9 mL; 53.9 mmol). The mixture was allowed to react at RT overnight. Then, the mixture was poured into aqueous sodium bicarbonate solution/saturated aqueous sodium chloride solution/ice. The batch was stirred for one hour before it was extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give crude 1-bromo-3-(chloromethyl)-5-nitrobenzene, that was used without further purification.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:19]([O:21][P:22]([C:27]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH2:28])(=[O:26])[O:23][CH2:24][CH3:25])[CH3:20]>C1COCC1>[CH2:31]([O:30][P:29]([CH:27]([P:22](=[O:26])([O:21][CH2:19][CH3:20])[O:23][CH2:24][CH3:25])[CH2:28][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:36])[O:33][CH2:34][CH3:35])[CH3:32]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: C#Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CC#Cc1ccccc1)P(=O)(OCC)OCC
Reaction time: 0.5 h

Procedure:
Phenylacetylene (IX, 4.4 g) is dissolved in THF (43 ml), cooled to -78°, and treated with lithium hexamethyldisilazide (1M in THF, 43 ml). The reaction is stirred for 30 min, then a solution of ethenylidenebisphosphonic acid tetraethyl ester (10.7 g) in THF (36 ml) is added and the reaction warmed to 22° for 1 hour. The reaction is quenched with water, extracted thrice with ethyl acetate. The organics were then washed with water, hydrochloric acid (10%), saturated sodium bicarbonate, and saline, dried with magnesium sulfate, and concentrated. The concentrate is purified by distillation, bp 0.1 195°-200°.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17](C)[C:18](=O)OC(C)(C)C)[CH2:13]2)[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3([CH2:29][CH2:28][CH2:27][CH2:26]3)[C:4]=2[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:18][NH:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5]4([CH2:29][CH2:28][CH2:27][CH2:26]4)[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2nc(N)nc3c2CCCC32CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCN(c2nc(N)nc3c2CCCC32CCCC2)C1
Reaction time: 16 h

Procedure:
A solution of Example 1G (38 mg, 0.09 mmol) in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.1 mL) at ambient temperature, and the reaction was stirred for 16 hours. The mixture was diluted with CH2Cl2 (20 mL) and washed with 1N NaOH and water. The organic layer was dried (MgSO4) and concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel (0.8:7.2:92 NH4OH/MeOH/CH2Cl2, eluant) to provide the title product. 1H NMR (300 MHz, CD3OD) δ 3.55-3.78 (m, 3 H), 3.37-3.44 (m, 1 H), 3.22 (t, 1 H), 2.57-2.65 (m, 2 H), 2.38-2.41 (m, 3 H), 2.02-2.17 (m, 3 H), 1.51-1.91 (m, 11 H). MS (DCI+) m/z 302 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].O>C1COCC1>[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])([OH:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: COc1ccccc1Br
Reactant: CC(C)C(=O)c1ccc(C(C)C)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(O)(c1ccc(C(C)C)cc1)C(C)C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution of 2-bromoanisole (5.0 g, 26.7 mmol) in THF (50 mL) was added n-butyllithium (1.6 M, 18 mL, 29 mmol) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 1-(4-isopropylphenyl)-2-methylpropan-1-one (5.70 g, 30.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture which was extracted with ethyl acetate, and the combined organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 3.4 g (yield 43%) of the title compound. Melting point: 85-86° C. (methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3=[N:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])[C:19](=[O:20])[C:9]3=[CH:8]2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37].[Cl-].[NH4+]>ClCCl>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[C:19](=[O:20])[C:9]2=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:29][CH:28]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]2=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(N)cc3)cc-2c1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(NS(C)(=O)=O)cc3)cc-2c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-(4-Aminobenzyl)-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 756, 35 mg, 0.092 mmol) and sodium bicarbonate (23 mg, 0.28 mmol, 3 equiv) were combined in dichloromethane (2 mL) and cooled to 0° C. The mixture was treated with methanesulfonyl chloride (0.071 mL, 0.92 mmol, 10 equiv), stirred for 4 hours and treated with ammonium chloride (0.2 mL, aqueous saturated). The mixture was diluted with dichloromethane (15 mL) and washed with brine (15 mL). The organic extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound: 1H-NMR (400 MHz, CD3OD) δ 8.95 (1H, s), 8.34 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=8.5 Hz), 7.70-7.66 (1H, m), 7.62-7.58 (1H, m), 7.47-7.38 (4H, m), 7.33-7.26 (4H, m), 5.76 (2H, s), 2.94 (3H, s), 2.27 (3H, s), ppm; low resolution mass spectrometry (ES+) m/z 458.9 [(M+H)+; calculated for C23H22N4O3S: 459.1].