Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: CCOC(=O)C(F)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 200 mg, 0.49 mmol) in tetrahydrofuran (4 mL) is cooled in an ice bath. Lithium diisopropylamide (2 M in tetrahydrofuran, 270 μL, 0.54 mmol) is added, and the mixture is stirred for 15 min. Ethyl 2-bromo-2-fluoroacetate (135 mg, 0.73 mmol) is added, and the mixture is warmed at room temperature and stirred over night. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 70 mg; ESI mass spectrum [M+H]+=516; Retention time HPLC: 0.67 min (X012_S01).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH3:17][CH:18]([CH3:21])[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:17][CH:18]([CH3:21])[CH3:19]
Reactant: CC(C)CO
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OCC(C)C)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.9 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 3.1 mmol 2-methyl-1-propanol and 3.3 mmol triphenylphosphine in 10 ml THF was added 3.1 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 2:3) to afford the title compound. MS (m/e): 300.2 ([M−H]−, 100%)
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([S:14]N2C(=O)C=CC2=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:1]1([S:7][S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C1C=CC(=O)N1Sc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(SSc2ccccc2)cc1
Yield: 84.3 %

Procedure:
5.5 Grams (0.05 mole) of thiophenol are stirred with 10.2 grams (0.05 mole) of N-(phenylthio)maleimide in 150 ml of benzene at room temperature for one hour. The benzene is removed from the reaction mixture by evaporation and the residue is added to 200 ml of methanol. A white solid forms upon contact with the methanol which is recovered by filtration. The solid recovered is 9.2 grams (84% yield) of phenyl disulfide. Recrystallized from methanol, the product melts sharply at 60° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[Cl:26])(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1)[C:21]([OH:23])=[O:22]
Reactant: Oc1ccc2nc(Cl)ccc2c1F
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3n2)c(Cl)c1
Temperature: 95 °C
Yield: 15.7 %

Procedure:
2-Chloro-5-fluoroquinolin-6-ol (Intermediate 16, 1.0 mmol) and 4-borono-3-chlorobenzoic acid (1.1 mmol) were mixed with 5% (Ph3P)4Pd and 4.0 mmol of NaHCO3 in 20 ml 50% dioxane/water. The mixture was degassed three times by evacuation and argon filling and heated at 95° C. overnight. The reaction was diluted with 20 ml of water and filtered. The filtrate was acidified with 1N HCl to pH=4. The precipitate was filtered and washed with water, dried. The crude was purified by column using AcOH/MeOH/EtOAC (1/5/94) as solvent B and hexanes as solvent A with gradient 2 to 100%. The fractions with compound were pooled and evaporated to obtain white solid. The solid was triturated with diisopropyl ether. 50 mg of final product was obtained. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 10.55 (b, 1H), 8.47 (d, 1H), 8.01-8.03 (m, 2H), 7.79 (m, 3H), 7.56 (t, 1H). MS (ESI): m/z=316.3 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C=O)C>[C:17]([NH:21][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1
Yield: 83.8 %

Procedure:
To a stirred suspension of 4-chlorobenzoic acid (31.3 g, 200 mmol) in toluene (200 mL) was added oxalyl chloride (30 mL, 350 mmol) followed by DMF (0.1 mL). The resulting suspension was heated at reflux until all solids dissolved. The solvent was removed under reduced pressure by rotary evaporation. The resulting semi-solid residue was dissolved in ethyl acetate (200 mL) and cooled in an ice bath under nitrogen with mechanical stirring. A solution of tert-butylamine (53 mL, 500 mmol) in ethyl acetate (50 mL) was carefully added to the mixture dropwise keeping the internal temperature below 10° C. During addition the initially clear solution became thick colorless slurry. Ethyl acetate (50 mL) was added followed by sat. aq. NaHCO3 (300 mL) and the resulting mixture was stirred until two clear layers resulted. The biphasic mixture was transferred into a separatory funnel, and the organic layer was separated. The organic layer was then washed with water (100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Recrystallization from ethyl acetate/hexanes afforded N-tert-butyl-4-chlorobenzamide (35.5 g, 84% yield) as colorless needles (mp 136-137° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F>ClCCl.CO>[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1[NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2]
Reactant: CCN(CC)CCN
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1Cl

Procedure:
Prepared analogously to Example 4.25.a. from N1,N1-diethylethane-1,2-diamine and 3-chloro-4-fluoronitrobenzene. Yield: 9.2 g (99.1% of theory); C12H18ClN3O2 (M=271.74); calc.: molecular ion peak (M+H)+: 272/274; found: molecular ion peak (M+H)+: 272/274; Rf value: 0.72 (Alox, dichloromethane/methanol (49:1)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[CH:17]([NH:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH2:8][CH2:9][C:10]([N:20]([CH:17]([CH3:19])[CH3:18])[NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:12])[CH:7]=1
Reactant: CCCOc1ccc(F)cc1CCC(=O)O
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(F)cc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 36.2 %

Procedure:
A solution of 3-(5-fluoro-2-propoxy-phenyl)-propionic acid (160 mg, 0.71 mmoles) and benzoic acid N′-isopropyl-hydrazide (106 mg, 0.60 mmoles) in DMF (3 mL) was treated with diisopropylethylamine (0.26 mL, 1.49 mmoles), and PyBroP (416 mg, 0.89 mmoles) at room temperature for 16 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (84 mg, 30%). LC-MS m/e 387.26 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:20])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:20])=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2ccc[n+]([O-])c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2oc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide in 100 mL of toluene at 0° C. was added dropwise phosphorus oxychloride (35.8 mL, 391 mmol) followed by 2 mL of DMF and the mixture was stirred at RT overnight. The solvent was evaporated under vacuum and the residue which crashed out of water, was filtered and washed with water, methanol and acetone in sequence. The solid was air dried to give 8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one as a tan solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:16]2[CH:17]=[CH:18][C:13]([O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=3)=[CH:14][CH:15]=2)=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(Br)cc2)cc1C
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Product: Cc1cc(Oc2ccc(Oc3ccc(Cl)cc3Oc3ccccc3)cc2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(4-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.133 g (19%). 1H NMR (400 MHz, CDCl3); MS (ES−) m/z mass calculated for C28H23O5Cl 474, found 473 and 475 (M−1, and M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[N:23]=[N:24][N:25]([CH2:27][C:28](OC)=[O:29])[N:26]=2)=[C:9]1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[OH-].[NH4+:38]>O1CCOCC1>[C:28]([CH2:27][N:25]1[N:24]=[N:23][C:22]([CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:26]1)(=[O:29])[NH2:38]
Reactant: CCOC(=O)C1=C(COCc2nnn(CC(=O)OC)n2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCc2nnn(CC(N)=O)n2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2-methoxycarbonylmethyl-(2H)-tetrazole (0.52 g), dioxane (15 ml) and 0.880 aqueous ammonium hydroxide solution (10 ml) was stirred at room temperature for 2.5 hours and then evaporated. The residual oil was partitioned between water and ethyl acetate and the organic layer washed with water, dried (Na2SO4) and evaporated. The residual oil was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.31 g), m.p. 101°-103° decomp.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:20].[K+]>O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([I:20])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)c1ccc(N)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)c1ccc(I)cc1
Temperature: 2 °C
Reaction time: 0.33 h

Procedure:
4-Isopropylaniline (49.5 g, 366 mmol) is suspended in 200 ml of dist. water and admixed gradually under ice cooling with 200 ml of semiconcentrated sulphuric acid. Subsequently, a solution of sodium nitrite (25.5 g, 370 mmol) in 200 ml dist. water is added dropwise at such a rate that the temperature does not rise above 20° C. On completion of the dropwise addition, the mixture is stirred at 2° C. for another 20 min. The resulting clear reddish diazonium salt solution is now added through a filter to a solution of potassium iodide (135.0 g, 813 mmol) in 200 ml of dist. water. The reaction mixture is stirred at 80° C. for 1 h. In the course of this, the solution becomes black with vigorous gas evolution and an oily organic phase separates out. After cooling, the organic phase is removed and the aqueous phase is extracted four times more with 100 ml of ether. The combined organic phases are washed with dilute sodium hydroxide solution and dist. water, and dried over sodium sulphate. After the solvent has been removed, the crude product is distilled in a membrane-pump vacuum. The slightly reddish target product distils over at a temperature of 100-105° C. (15 mbar).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:23]([N+:24]([O-])=O)=[CH:22][N:21]=[C:20]3[N:27]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:28]=[CH:29][C:19]=23)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]3[N:27]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:28]=[CH:29][C:19]=23)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Yield: 72.7 %

Procedure:
Zinc (24 g) was added to a solution of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid benzyl ester (21.3 g, 40 mmol) in acetic acid (150 mL) and heated to 60° C. for 30 minutes. After cooling the mixture was filtered and the filtrate concentrated to dryness under vacuum. The resulting residue was partitioned between ethyl acetate and sodium hydrogen carbonate (sat. aq.), the organics layer dried with sodium sulphate and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 100% ethyl acetate) afforded 14.7 g (75%) of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid benzyl ester as a purple residue. 1H NMR (400 MHz, CDCl3) δ: 8.16-8.11 (m, 2H), 7.87 (s, 1H), 7.58-7.41 (m, 4H), 7.35 (m, 5H), 6.52 (d, 1H), 5.13 (s, 2H), 4.89 (br s, 1H), 4.11 (m, 2H), 3.95-3.84 (m, 1H), 3.10-2.96 (m, 2H), 2.10-2.05 (m, 1H), 1.54-1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=O)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].O.[NH2:20][NH2:21]>C(O)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]([CH3:13])[CH2:9][C:10](=[O:11])[NH:20][N:21]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
920 g of 3-(4-chloro-3-nitrobenzoyl)-butyric acid are added to a mixture of 6.8 1 of acetic acid and 499 g of hydrazine hydrate, and the mixture is stirred for 2 hours at 95°-100°. It is poured into ice water, and filtration gives 6-(4-chloro-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, m.p. 186°-188°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])/[C:11](=[CH:20]/[CH3:21])/[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:22][NH2:23].[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]([OH:19])[CH:11]([CH:20]([NH:23][CH3:22])[CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN
Reactant: C/C=C1\C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(C)C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1O
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To a solution of 42 (0.80 g, 2.52 mmol) in THF (10 mL) at ambient temperature was added methylamine solution (2.0 M in THF, 3.78 mL, 7.56 mmol). The reaction mixture was stirred for 4 h before NaBH4 (0.44 g, 11.49) was added. The reaction mixture was stirred for 3 h before being quenched by a saturated solution of NH4Cl (10 mL). The product was extracted with diethyl ether, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/0.1% DEA=1 :7 to 1:5) to give (4S)-4-(3,4-dichlorophenyl)-2-(1-(methylamino)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (44) (493 mg, 56%).
Reaction SMILES: C1(N(CC2C=C(C=CC=2)C(NC2SC3CCCCC=3C=2C(NC2C=CC(CC[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=3)=CC=2)=O)=O)CCNCC(OCC)=O)CC1.[OH-].[Na+].CO.Cl>C1COCC1>[C:41]([OH:43])(=[O:42])[C:40]1[CH:45]=[CH:46][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 140 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropyl {2-[(2-ethoxy-2-oxoethyl)amino]ethyl}amino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 1.0 mL of a 1.0M aqueous sodium hydroxide solution, 1.0 mL of methanol, and 2.0 mL of THF was stirred overnight at room temperature. To the reaction mixture was added 1.0 mL of 1.0 M hydrochloric acid. The precipitated solid was collected by filtration, thereby obtaining 113 mg of 4-(2-{4-[({2-[(3-{[{2-[(carboxymethyl)amino]ethyl}(cyclopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl)}ethyl)benzoic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N+:18]([C:21]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](F)=[CH:24][C:22]=1[NH2:23])([O-:20])=[O:19]>O.C(O)C>[N+:28]([C:26]1[CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[C:22]([NH2:23])=[CH:24][C:25]=1[NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O-:30])=[O:29]
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(NCCc2c[nH]c3ccccc23)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroaniline in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.57) which is well resolved from the starting materials under the same conditions
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:30](B(O)O)=[C:29]([CH3:34])[O:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:26]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:9]3[CH2:10][C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14]3)=[CH:6][CH:7]=2)=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
An round-bottomed flask was charged with 16 (192 mg, 0.5 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (141 mg, 1.0 mmol), 2 N aqueous Na2CO3 (0.5 mL, 1 mmol), and THF (5 mL). The reaction mixture was refluxed for 18 h. The mixture was cooled to RT, diluted with EtOAc (100 mL), and then the mixture was washed with H2O (1×25 mL), brine (1×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography to give 136 mg (68%) of the title product 22 as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.94 (s, 6H), 0.97 (s, 6H), 1.31 (s, 2H), 1.97 (s, 2H), 2.01 (s, 2H), 2.28 (s, 3H), 2.41 (s, 3H), 7.32-7.14 (m, 9H). LCMS (APCI): m/z 400 (M+H)+.
Reaction SMILES: [Br:1][C:2]([Br:30])=[CH:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.Cl>>[Br:30][C:2]([Br:1])=[CH:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1
Reactant: BrC(Br)=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: BrC(Br)=CCCc1c[nH]cn1

Procedure:
4-(4,4-dibromobut-3-enyl)imidazole was prepared by deprotection of 4-(4,4-dibromobut-3-enyl)-1-(triphenylmethyl)imidazole by HCl.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([NH:8][C:9](=[O:33])[CH2:10][N:11]([CH2:19][C:20](=[O:32])[NH:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)=[O:24])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]([CH3:7])[CH3:6].COC(N1CC(=O)N2C(C(OCC)=O)CCC2C1)=O>>[Br:31][C:28]1[CH:27]=[CH:26][C:25]([C:23](=[O:24])[CH2:22][NH:21][C:20]([CH2:19][N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C:9]([NH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:34])=[O:2])=[O:33])=[O:32])=[CH:30][CH:29]=1
Reactant: COC(=O)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(C)C
Agent: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Product: CC(C)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(=O)O

Procedure:
2-[2-({[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid was prepared using method 801 substituting 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethyl carbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid methyl ester for 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester. C22H30BrN3O7 calculated 527.1 observed [M+1]+528.1; rt=2.39 min.