Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[Na+].[Na+].C(O)C.FC1C=C([C:29]2[C:34](=[O:35])[N:33]3[CH:36]=[CH:37][S:38][C:32]3=[N:31][C:30]=2[CH3:39])C=C(F)C=1.[C:40]1(C)[CH:45]=CC=[CH:42][CH:41]=1>O>[CH3:39][C:30]1[N:31]=[C:32]2[N:33]([C:34](=[O:35])[C:29]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:36]1[CH:45]=[CH:40][CH:41]=[CH:42][C:37]=1[S:38]2
Reactant: Cc1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C#N)cc1

Procedure:
This compound was prepared from Step 2 intermediate (800 mg, 2.331 mmol), 4-cyanophenylboronic acid (480 mg, 8.271 mmol), Pd[(C6H5)3P]4 (108 mg, 0.093 mmol) and Na2CO3 (1.48 g, 14.023 mol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, Step 3 to afford the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.49 (s, 3H), 7.53-7.59 (m, 4H), 7.91 (d, J=7.8 Hz, 2H), 8.03-8.10 (m, 1H), 8.80-8.90 (m, 1H); ESI-MS (m/z) 318.30 (M+H)+.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1([CH3:23])[CH2:22][CH2:21]1)=O)(=O)OC.O.[NH2:25][NH2:26]>>[CH3:23][C:20]1([C:18]2[N:26]=[N:25][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=3[CH:17]=2)[CH2:22][CH2:21]1
Reactant: COP(=O)(CC(=O)C1(C)CC1)OC
Reactant: NN
Reactant: O=C1CCCCCCC1=O
Solvent: O
Product: CC1(c2cc3c(nn2)CCCCCC3)CC1

Procedure:
light yellow oil. MS (EI): 216.3 (M+). Prepared from cyclooctane-1,2-dione, [2-(1-Methyl-cyclopropyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29](Br)=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:28]=[CH:27][C:26]([NH2:25])=[N:31][C:30]=3[CH3:32])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)ccc1Br
Product: Cc1nc(N)ccc1C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 6-amino-3-bromo-2-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (65 mg, 15%). MS (ISP) 444.3 [(M+H)+]; mp 243-246° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:23]([C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[CH2:22][CH:21]=[CH2:20]
Reactant: C=CCCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.4 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.4 g of 4-bromo-1-butene were dissolved in 10 ml of dimethyl sulfoxide, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.09 g of 2-(3-butenyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (73)).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8][C:7]=12)[CH3:24]
Reactant: CCN1CCCC1CN
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Product: CCN1CCCC1CNc1nnc(C)c2c1cc1ccccn12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 2-(aminomethyl)-1-ethylpyrrolidine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 128° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Nc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Nc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1
Yield: 32 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC to give the title product (32%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 4.72 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][CH2:27][C@H:28]([OH:41])[C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:30]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11])=[O:4].[OH-].[Na+]>>[OH:41][C@H:28]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:30]=1)[CH2:27][NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][S:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:4])=[O:2])(=[O:12])=[O:11])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccsc4C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from methyl 3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylate (which was obtained in Example 320) by NaOH hydrolysis as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.50–1.70 (m, 2 H), 1.95–2.10 (m, 2 H), 2.50–2.70 (m, 2 H), 2.95 (s, 3 H), 3.00–3.30 (m, 3 H), 3.60–3.70 (m, 2 H), 4.75–4.85 (m, 1 H), 6.10 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.85–6.95(m, 3 H) 7.04 (d, J=5.4 Hz, 1 H), 7.08 (dd, J=8.4, 1.8 Hz, 1 H), 7.26 (d, J=1.8 Hz, 1 H), 7.39 (d, J=5.4 Hz, 1 H), 8.73 (brs, 1 H), 9.96 (brs, 1 H); MS (ES) m/z: 610.7 (MH+); HRMS Calcd. for C25H31N4O8S3 (MH+): 611.1299. Found: 611.1284.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.05 g, 0.13 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.04 mL, 0.52 mmol) and benzoyl chloride (0.03 mL, 0.26 mmol). After stirring for twelve hours and room temperature, the reaction was quenched with a saturated, aqueous sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient), followed by re-crystallization from a mixture of ethyl acetate-hexane, to yield the title compound as a white solid (0.04 g, 59%);
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][C:18]([F:21])([F:20])[F:19])[C:7]=2[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[C:26]([CH3:32])[CH:25]=2)[CH2:5][CH2:4]1.[CH3:33][O:34][C:35](=[O:46])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][C:37]=1[O:44][CH3:45]>CN(C=O)C.O>[CH3:33][O:34][C:35](=[O:46])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][N:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][C:18]([F:20])([F:21])[F:19])[N:9]=[CH:10][C:6]=3[CH:3]3[CH2:4][CH2:5]3)=[CH:25][C:26]=2[CH3:32])[CH3:31])=[CH:38][C:37]=1[O:44][CH3:45]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Reactant: CNc1ccc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)cc1OC
Temperature: 40 °C
Yield: 67.8 %

Procedure:
Sodium hydride (60% in mineral oil, 30 mg, 0.75 mmol) is added to a solution of {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amine (0.31 g, 0.75 mmol) and 4-bromomethyl-2-methoxy-benzoic acid methyl ester (0.320 g, 1.23 mmol) in DMF (3 mL) at room temperature. The reaction is heated to 40° C. for 2 h. The mixture is diluted with water and is extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The crude residue is purified via radial chromatography (2 mm plate, 20 to 40 THF-heptane) to afford 4-[({4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methoxy-benzoic acid methyl ester (303 mg, 68%). ES/MS m/e 596.0 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([N+:7]([O-])=O)[C:4](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)=[CH:3][CH:2]=1.O[CH:23]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H:24]1O>>[NH:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH:24]=[CH:23]1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: c1ccc2[nH]ccc2c1

Procedure:
Principle of Step 1: ONPG substituting for lactose is metabolized with β-galactosidase. At 44.5° C. E. coli grow and utilize ONPG and produce indole. β-galactoside turns the medium yellow. In the yellow colored medium, both fecal coliforms and E. coli are present. In samples which do not have a yellow color, there are no fecal coliforms and E. coli.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][C:9]1[C:18]2[O:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([CH3:25])[C:14](=[O:26])[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>ClCCCl>[CH3:6][N:7]([CH2:8][C:9]1[C:18]2[O:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([CH3:25])[C:14](=[O:26])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: CNCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1c(-c2ccccc2)oc2c(CN(C)C(=O)CCl)cccc2c1=O
Reaction time: 2 h

Procedure:
A solution of 6 ml of chloroacetyl chloride in 60 ml of 1,2-dichloroethane was added dropwise at -5°/0° C. to a solution of 20 g of Intermediate XI and 10 ml of triethylamine in 200 ml of 1,2-dichloroethane. After stirring at 20°-25° C. for 2 hours, 150 ml of water was added to the reaction mixture and the phases were separated. The organic phase was washed with water and dried on anhydrous sodium sulphate. The solvent was removed in vacuo, and the residue was crystallized from ethanol to give 22.5 g of the title compound, melting point 146°-148° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1([CH3:17])[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:18][NH:19][CH3:20]>CO>[ClH:1].[CH3:18][N:19]([CH3:20])[CH2:2][CH2:3][C:4]1([CH3:17])[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1
Reactant: CN1CC(C)(CCCl)Oc2ncccc2C1=S
Reactant: CNC
Solvent: CO
Product: CN(C)CCC1(C)CN(C)C(=S)c2cccnc2O1
Product: Cl
Reaction time: 240 h
Yield: 76 %

Procedure:
To a suspension of 4.5 g (0.017 mole) of 2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione in 20 ml of methanol, cooled in an ice bath, was added 40 ml of dimethylamine. The flask was sealed tightly and left standing at room temperature for 10 days. The dimethylamine and methanol were removed by rotary evaporation (60° C.; 30 mm). The residue was taken up in 150 ml of chloroform, washed with 3×50 ml dil sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70° C.; 30 mm). The crude oil was dissolved in isopropyl alcohol and treated with ethereal hydrogen chloride, which yielded 4.0 g (76%) of yellow crystals, m.p. 255° C. with decomposition.
Reaction SMILES: CON(C)[C:4](=[O:16])[CH2:5][CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].Br[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1>>[Cl:25][C:22]1[N:23]=[CH:24][C:19]([C:4](=[O:16])[CH2:5][CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH3:7])=[CH:20][CH:21]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CON(C)C(=O)CC(C)NC(=O)OC(C)(C)C
Product: CC(CC(=O)c1ccc(Cl)nc1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl {3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate and 5-bromo-2-chloropyridine, and in the same manner as in Example 24, step E, the title compound was obtained.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:21])[CH2:16][CH:15]([NH:17][CH3:18])[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1>[Cl:3][C:2]1[N:1]=[C:8]([N:17]([CH3:18])[CH:15]2[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12][C:11]([CH3:21])([CH3:10])[CH2:16]2)[N:7]=[C:5]([N:17]([CH:15]2[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12][C:11]([CH3:21])([CH3:10])[CH2:16]2)[CH3:18])[N:4]=1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(c1nc(Cl)nc(N(C)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
18.4 g of cyanuric chloride and 34.0 g of 2,2,6,6-tetramethyl-4-(methylamino)piperidine were dissolved in 250 ml of xylene, and the solution was stirred at a temperature of 90°-110° C. for 3 hours. 30 ml of a saturated aqueous solution of potassium carbonate were then added and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was poured into water and extracted with benzene. The extract was dried over anhydrous potassium carbonate and then the benzene was distilled off. The residue was recrystallized from ethyl acetate, giving the title compound in the form of crystals melting at 179°-180° C.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:34][CH2:35][O:36][CH3:37])[CH:4]=[CH:5]2>CO.[Pd]>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:34][CH2:35][O:36][CH3:37])[CH:4]=[CH:5]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCc4ccc(OC)cc4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCc4ccc(OC)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 1.5 h

Procedure:
A solution of 4,5α-epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-7-ene (1.01 g, 2 mmol) in MeOH (40 ml) is mixed with 10% Pd/C (650 mg) and agitated for 1.5 hours under 1 bar of H2 pressure. The catalyst is removed by filtering through Celite and the filtrate is evaporated down. The residue is pure 4,5α-epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinane (0.87 g, 85.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:12]Cl)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:12][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:5][CH:4]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(COc2ccc(CCl)cc2OCc2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(CN3CCN(C)CC3)cc2OCc2ccc(OC)cc2)cc1

Procedure:
A solution of 3,4-bis(p-methoxybenzyloxy)benzyl chloride (2.58 g: 6.47 mMol.), N-methylpiperazine (777 mg: 1.2 Eq.), and potassium carbonate (893 mg; 1 Eq.) in dimethylformamide (7 ml) is stirred at room temperature for 3 hours. The reaction mixture is filtered to remove solid and concentrated under reduced pressure. The residue is washed with n-hexane to give 1-(3,4-bis(p-methoxybenzyloxy)benzyl)-4-methylpiperazine. Yield: nearly quantitative.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[N:6]([N:14]=[CH:15][C:16]=2[C:17]([O:19]CC)=[O:18])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:5]2[N:6]([N:14]=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1cnn2c1c(OCC)nc1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2ccccc2n2ncc(C(=O)O)c12

Procedure:
To a solution of 2.85 g. of 4-ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester in hot ethanol, there is added 10 ml. of 10% aqueous sodium hydroxide and the mixture refluxed for 2 hours. The mixture is concentrated under reduced pressure and the residue dissolved in water. The solution is filtered and neutralized with dilute hydrochloric acid. The precipitated 4-ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid is filtered and washed with a small amount of cold water. The product is crystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:17][C:18]([OH:20])=[O:19].C(O)(=[O:23])C.O=[O+][O-].[OH2:28]>>[C:2]([NH:3][C:4]1[C:9]([C:10](=[O:23])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:17][C:18]([OH:20])=[O:19])(=[O:28])[CH3:1]
Reactant: O
Reactant: CC(=O)O
Reactant: Cc1[nH]c2c(CC(=O)O)cccc2c1-c1ccccc1
Agent: O=[O+][O-]
Product: CC(=O)Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1

Procedure:
A solution of 2 g. of α-(2-methyl-3-phenylindol-7-yl)acetic acid in 60 ml. of acetic acid was treated with ozone for 15 minutes. The reaction mixture was treated with 10 ml. of water and allowed to evaporate overnight. The residue (1.7 g.) was recrystallized from isopropanol; yield 1.6 g. (71%); m.p. 188°-190°C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[N:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1>>[Br-:1].[CH3:28][C:23]1[CH:22]=[N+:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[C:25]([CH3:27])[CH:24]=1
Reactant: Cc1cncc(C)c1
Reactant: BrCCCCCCCCCCCCCc1cccnc1
Product: Cc1cc(C)c[n+](CCCCCCCCCCCCCc2cccnc2)c1
Product: [Br-]
Yield: 62 %

Procedure:
3-(13-Bromo-tridecyl)-pyridine (1 mmol) was added to 3,5-lutidine (5 ml), and the mixture was heated at 50 C overnight. The excess picoline was removed in a vacuum, and the resulting residue was partitioned between water and ether. The aqueous layer was washed extensively with ether until no 3,5-lutidine was left in the aqueous layer, and then the aqueous layer was extracted with chloroform. The chloroform was removed to afford the product (62%). 1HNMR (300 MHz, CDCl3, ppm), 9.10 (s, 2H), 8.45 (br, 2H), 7.96 (s, 1H), 7.57 (d, J=7.5, 1H), 7.24-7.27 (m, 1H), 4.89 (t, J=7.5, 2H), 2.59-2.54 (m, 8H), 1.99-2.04 (m, 2H), 1.57-1.62 (m, 2H), 1.21-1.38 (m, 18H), 13CNMR, 148.07, 146.11, 145.45, 141.94, 139.01, 137.96, 124.16, 62.13, 58.74, 33.29, 32.34, 31.26, 29.76, 29.73, 29.62, 29.39, 29.30, 26.49, 18.98, 18.82.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2].[Br:22]Br>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:22])=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)Cc1ccc2[nH]c(C)c(C(=O)OCC)c2c1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc2c(C(=O)OCC)c(C)[nH]c2cc1Br
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a solution of 5-ethoxycarbonylmethyl-2-methyl-1H-indole-3-carboxylic acid ethyl ester (3 g, 10.4 mmol) in acetic acid (20 mL) is added bromine (1.65 g, 10.4 mmol) dropwise, and the reaction mixture is stirred for 10 minutes. The solution is then concentrated in vacuo and chromatographed with a gradient of hexane/ethyl acetate (5%-30%) within 30 minutes to afford a yellow solid (3.3 g, 86%). MS: 368, 370 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[NH4+].[N:13]#[C:14][S-:15].BrBr>C(O)(=O)C>[NH2:13][C:14]1[S:15][C:7]2[CH:6]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(CC(=O)O)cc2s1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
(4-Amino-phenyl)-acetic acid (20 g, 132.5 mmol) and NH4SCN (20 g, 263.2 mmol) were dissolved in 300 ml of acetic acid and the mixture was cooled to 15° C., treated with Br2 (21.2 g, 6.8 ml) in acetic acid (10 ml) and the temperature did not exceed 15° C. Then the reaction was stirred at room temperature for 4 h. The mixture was filtered and the cake was re-dissolved in water, adjusted the pH=5. The precipitate was filtered and dried to obtain 2-amino-benzothiazol-6-yl)-acetic acid as light yellow powder (24 g, 87.1%).