Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=O)=[CH:38][CH:37]=1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]([CH3:55])[CH3:54])=[CH:49][N:48]=1.C(N(C(C)C)CC)(C)C.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>CN(C=O)C>[CH3:54][N:53]([CH3:55])[C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:43](=[O:45])[CH2:42][C:39]2[CH:38]=[CH:37][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)=[CH:41][CH:40]=2)=[N:48][CH:49]=1
Reactant: CN(C)c1ccc(N)nc1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(N(C)C)cn4)cc3)c2cc1OC
Yield: 73.1 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.101 g) and 2-hydroxypyridine N-oxide (0.059 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid (0.15 g), 2-amino-5-dimethylaminopyridine (0.073 g), diisopropylethylamine (0.092 ml) and DMF (2 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The resultant reaction mixture was transferred onto a Waters ‘β Basic Hypersil’ reversed-phase preparative HPLC column (5 microns silica, 30 mm diameter, 250 mm length) that was eluted with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.148 g); 1H NMR: (DMSOd6) 2.88 (s, 6H), 3.71 (s, 2H), 3.98 (s, 3H), 3.98 (s, 3H), 7.19 (m, 1H), 7.25 (d, 2H), 7.38 (s, 1H), 7.44 (d, 2H), 7.55 (s, 1H), 7.84 (d, 1H), 7.90 (d, 1H), 8.53 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(Nc1ccccc1Br)N1CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3NS(=O)(=O)N3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(2-bromophenyl)pyrrolidine-1-sulfonamide in Step B. MS (ESI): mass calcd. for C20H20FN5O2S, 413.13; m/z found, 414.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.40 (dd, J=5.4, 1.4, 2H), 8.14 (m, 1H), 7.61 (dd, J=8.3, 1.1, 1H), 7.42-7.35 (m, 1H), 7.32 (dd, J=8.0, 1.7, 1H), 7.23 (dd, J=3.6, 1.6, 1H), 7.22-7.15 (m, 1H), 6.44 (s, 1H), 3.33-3.25 (m, 4H), 1.87 (dd, J=7.0, 0.9, 4H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Br:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Br:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Yield: 58.9 %

Procedure:
3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (2.04 g, 5.35 mmol) dissolved in THF (30 mL) was treated successively with triphenylphosphine (2.10 g, 8.02 mmol) and water (0.482 g, 26.7 mmol) at 25° C. for 16 h with stirring. The reaction mixture was concentrated to dryness and purified on silica gel (eluted successively with EtOAc (to remove triphylphosphine oxide) followed by a gradient of 100% EtOAc to 10% CH3OH/DCM) to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (1.12 g, 3.15 mmol, 58.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (t, 1H), 7.46-7.57 (m, 4H), 3.77 (s, 2H), 1.91 (br. s., 2H). LC-MS (ES+) m/z 354.92, 356.91, 358.88 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C([Mg]Br)(C)C.[CH:16]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22])([CH3:18])[CH3:17]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:21]([C:20]2[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:19]=2[CH:16]([CH3:18])[CH3:17])[OH:22])=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1ncc(I)c(Cl)n1
Reactant: COc1cc(C=O)c(C(C)C)cc1OC
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(C(O)c2cnc(SC)nc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methylsulfanyl-pyrimidine (1.10 g, 3.9 mmol) in 20 mL THF at −40° C. was added isopropyl magnesium bromide (2.3 mL, 2 M in THF)) over 5 minutes. After 30 minutes, 2-isopropyl-4,5-dimethoxy-benzaldehyde from step 3 (1.04 g, 4.6 mmol) was added and the solution was warmed to room temperature. The mixture was quenched by the addition of brine, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (ethyl acetate) afforded (4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-(2-isopropyl-4,5-dimethoxy-phenyl)-methanol (1.168 g, 82%) as a light yellow solid.
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].[OH-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[C:15](=[CH:17][CH:18]=1)[OH:16].Cl>C(OCC)(=O)C.O.CN(C)C=O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([O:16][CH:2]([F:6])[F:7])=[C:14]([OH:19])[CH:13]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Cl)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)ccc1OC(F)F
Temperature: 125 °C
Yield: 19.4 %

Procedure:
723 mg (5.0 mmol) of sodium chlorodifluoroacetate, 220 mg (5.5 mmol) of sodium hydroxide and 838 mg (5.5 mmol) of 4-chlorocatechol were successively added to a mixture of 7.0 mL of N,N-dimethylformamide and 0.1 mL of water under argon atmosphere with stirring. The mixture was slowly heated to 125° C. and allowed to react at this temperature for 1.0 h. The reaction was stopped and cooled to room temperature. To the reaction solution was added 10 mL of 1.0 mol/L hydrochloric acid until the solution turned acid, and then 50 mL of water and 20 mL of ethyl acetate were added. The organic layer was isolated, and the water layer was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, successively washed with 50 mL of water and 50 mL of saturated saline, dried over anh. MgSO4, filtered and concentrated. The residue was purified by preparative silica gel thin layer chromatography (mobile phase: petroleum ether: ethyl acetate=4:1) to obtain 189 mg of a light yellow oil. Yield 19.4%. MS([M-H]−): 193.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[Cl:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncc(Cl)cc1Cl
Temperature: 100 °C
Yield: 98.7 %

Procedure:
2,3,5-Trichloropyridine (25 g) and hydrazine monohydrate (109.8 g) were added to ethanol (20 ml), stirred at 100° C. and left to stand at room temperature. The precipitated solid was collected by filtration to give 3,5-dichloropyridin-2-ylhydrazine (24.07 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([O-:3])=[O:2].B(Br)(Br)Br>>[OH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:6]([N+:13]([O-:15])=[O:14])=[CH:7][C:8]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])c(CCCC(=O)O)c([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Product: O=C(O)CCCc1c([N+](=O)[O-])cc(O)c(O)c1[N+](=O)[O-]

Procedure:
The product from example 2 (0.5 g) was demethylated with boron tribromide according to the procedure described in example 10. Yield: 90 mg, melting point 165-170° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:16]=[C:15](Cl)[S:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19]>>[NH2:11][C:12]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:9])[F:1])=[CH:4][CH:5]=2)[S:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19]
Reactant: FC(F)(F)c1ccccc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Product: Nc1cc(-c2ccc(C(F)(F)F)cc2)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from 4-trifluoromethylbenzene boronic acide and 3b by following the procedure in example 3c. This compound is a white solid: MS (ES) 323 (M+H)+; 1H NMR (400 MHz, CD3OD)δ7.80 (d, 2 H, J=8.2 Hz), 7.72 (d, 2 H, J=8.2 Hz), 7.02 (s, 1 H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Clc1ccccn1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cccc3c2oc2ccccc23)nc1
Yield: 91.7 %

Procedure:
4-dibenzofuranboronic acid (5.0 g, 23.6 mmol), 2-chloropyridine (2.2 g, 20 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.36 g, 0.8 mmol), and potassium phosphate (11.4 g, 50 mmol) were mixed in 100 mL of toluene and 10 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.18 g, 0.2 mmol) and the mixture was heated to reflux under nitrogen for 8 h. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with dichloromethane. 4.5 g of desired product was obtained after purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[N:34]=[CH:33][C:32]([CH3:31])=[CH:37][N:36]=6)[CH2:39][CH2:40]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C2(N)CC2)nc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative TLC (Eluent Chloroform: Methanol 9.5:0.5, 200 ml). Yield: 29 mg (54%). 1H NMR (400 MHz, CD3OD): δ 8.50 (d, J=0.5 Hz, 2H), 8.03-7.94 (m, 2H), 7.89-7.82 (m, 2H), 7.69-7.64 (m, 2H), 7.47-7.37 (m, 2H), 7.33-7.24 (m, 2H), 2.96 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 1.77-1.70 (m, 2H), 1.47-1.40 (m, 2H)
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.S(Cl)(Cl)(=O)=O>C1COCC1>[CH2:2]([O:9][NH:10][S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 107.1 %

Procedure:
O-Benzylhydroxylamine hydrochloride (31.3 mmol, 5.0 g), 4-methoxybenzenesulfonyl chloride (34.5 mmol, 7.12 g) and anhydrous THF (50 mL) were combined under nitrogen. The reaction was cooled to 0° C. and dlisopropylethylamine (69.0 mmol, 12.0 mL) was injected. The reaction was allowed to warm to room temperature and continued to stir for 18 hours. An additional 0.25 equivalents of O-Benzylhydroxylamine hydrogen chloride (7.8 mmol, 1.25 g) and 0.75 equivalents of diisopropylethylamine (23.5 mmol, 4.1 mL) were added to encourage complete conversion of the remaining sulfonyl chloride. The reaction stirred for 4 additional hours at room temperature. The reaction solution was concentrated to a solid and partitioned between ethyl acetate and 1N HCl. The organic layer was dried over magnesium sulfate and concentrated under vacuum to yield 9.83 g (76%) of an off-white colored solid. Rf: 0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84 (2H,d), 7.34 (5H,s) 7.08 (2H,d), 4.92 (2H,s), 3.88 (3H,s).
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:3]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C(OCC)=O.Cl>O>[C:15]1([C:2](=[O:1])[CH2:3][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C(=O)c1ccccc1)c1cccnc1
Agent: Cl
Solvent: O
Product: O=C(Cc1cccnc1)c1ccccc1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
Ethyl 3-oxo-3-phenyl-2-(pyridin-3-yl)propanoate (1.82 g, 6.76 mmol) was dissolved in hydrogen chloride (8.11 mL, 101.0 mmol) and heated to 100° C. overnight. The reaction was then diluted with H2O (25 mL), extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a clear oil (0.894 g). LCMS m/z=198.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 4.29 (s, 2H), 7.27 (dd, J=7.07, 5.56 Hz, 1H), 7.49 (t, J=7.58 Hz, 2H), 7.55-7.64 (m, 2H), 7.99-8.05 (m, 2H), 8.49-8.56 (m, 2H).
Reaction SMILES: C(Cl)CCl.[C:5]1([CH3:14])[C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH2:25][NH:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[CH3:27][N:26]([CH2:25][C:17]1[N:16]([CH3:15])[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:11](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH3:14]
Reactant: Cc1ccccc1C(=O)O
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: Cc1ccccc1C(=O)N(C)Cc1cc2ccccc2n1C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
EDC (0.22 g, 1.15 mmole) was added to a solution of ortho-toluic acid (0.15 g, 1.10 mmole), 1-methyl-2-(methylaminomethyl)indole (0.20 g, 1.15 mmole), and HOBt.H2O (0.15 g, 1.11 mmole) in DMF at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (20% EtOAc/hexanes) gave a colorless gum, which was triturated with Et2O to afford the title compound (0.2 g, 37%) as a white solid: 1H NMR (300 MHz, CDCl3) indicated an approximately 5:1 mixture of amide rotamers; for the major rotamer: δ 7.60 (d, J=7.7 Hz, 1H), 7.05-7.40 (m, 7H), 6.52 (s, 1H), 5.01 (s, 2H), 3.85 (s, 3H), 2.71 (s, 3H), 2.30 (s, 3H); for the minor rotamer: δ 7.60 (d, J=7.7 Hz, 1H), 7.05-7.40 (m, 7H), 6.44 (s, 1H), 4.52 (s, 2H), 3.50 (s, 3H), 3.14 (s, 3H), 2.37 (s, 3H); MS (ES) m/e 293 (M+H)+. Anal. Calcd for C19H20N2O.0.35H2O: C, 76.40; H, 6.99; N, 9.38. Found: C, 76.10; H, 6.83; N, 9.33.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[OH-].[Na+].C(O)[C@H]1[O:21][C@@H:20]2[O:22][C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[OH:12][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:20]([OH:22])=[O:21]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C(O)c1ccc2ccccc2c1
Yield: 4209.8 %

Procedure:
A solution of 2-naphthaldehyde (2.0 g, 1.0 eq), benzyltriethylammonium chloride (BTEAC) (0.13 g), and 50% aqueous NaOH (2.3 mL), and β-cyclodextrin (0.10 g) in chloroform (10 mL) was heated at 55° C. for 12 hours. The mixture was then poured into water and the solution washed with EtOAc. The aqueous layer was then acidified to pH 1 by dropwise addition of HCl (conc.). This was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil (0.75 g, 29%) that was not further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:13](=[O:23])[C@@H:12]2[CH3:24])=[O:10])[CH:5]=[CH:6][CH:7]=1.ON1C=CC=CC1=O.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[CH2:51]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][O:52]1.C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([N:57]3[CH2:58][CH2:59][C:54]4([CH2:51][O:52][CH2:53]4)[CH2:55][CH2:56]3)=[O:22])[C:13](=[O:23])[C@@H:12]2[CH3:24])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C(=O)N(CCCC(=O)O)CCN1C(=O)Nc1cccc(Cl)c1
Reactant: C1CC2(CCN1)COC2
Agent: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: O=c1ccccn1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC2)COC3)CCN1C(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
A suspension of 0.035 g (0.10 mmol) of 4-[(S)-4-(3-chloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-butyric acid (intermediate 19) and 0.012 g (0.11 mmol) N-hydroxy-2-pyridon in 1.5 ml of DMF was treated at 0° C. with 0.021 g (0.11 mmol) of EDCI and was naturally warmed to RT over night. A solution of 0.035 g (0.10 mmol) of 2-oxa-7-aza-spiro[3.5]nonane trifluoro-acetic acid salt (1:2) (intermediate 20) and 0.030 ml (0.30 mmol) of triethylamine in 1.5 ml of DMF was then added and the reaction was stirred for 1 h at RT. The solution was poured on aqueous 10% KHSO4 solution and extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.013 g of the titled compound with maximal 60% purity. The aqueous phases were reextracted with EtOAc (3×), the organic phases were dried (NaSO4), evaporated and dried under reduced pressure to give 0.029 g (62%) of the titled compound as light yellow foam. MS: 463.21 (MH+, Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:21](=O)([O-])[O-].[K+].[K+].CBr>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccnc1S(=O)(=O)Nc1ccccc1
Reactant: O=C([O-])[O-]
Agent: CBr
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccnc1S(=O)(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
A mixture of 2-phenylsulfamoylnicotinic acid methyl ester (1.8 g), acetonitrile (100 mL) and potassium carbonate (1.9 g) was treated with a mixture of methyl bromide (1.5 mL) and acetonitrile (6.0 mL), and the resulting mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure, triturated with dichloromethane and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a tan oil (1.5 g).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH:17](O)[CH3:18])([CH3:9])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:1]([NH:5][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)OCCOCCNC(C)(C)C
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CC(C)(C)NCCOCCOCCNC(C)(C)C
Temperature: 200 °C
Yield: 68.2 %

Procedure:
To a 300 ml stainless steel, stirred autoclave there was added 21 g of tertiarybutylamine, 20 g of tertiarybutylaminoethoxyethoxyethanol, 0.6 g of Ni-Al2O3 -SiO2 catalyst (Harshaw NI-5132P), and 50 ml of toluene. The autoclave containing the reactants was heated to 200° C. under autogenous pressure (180 psi) for 6 hours. The contents were cooled, removed and filtered. The autoclave and filtercake were washed with additional toluene. G.C. analysis revealed that the product was comprised of about 91 wt. % 1,2-bis-(tertiarybutylaminoethoxy) ethane and less than about 5 wt. % tertiarybutylaminoethoxyethoxyethanol. Vacuum distillation gave 17.3 g of 1,2-bis-(tertiarybutylaminoethoxy) ethane, having a boiling point of 125°-128° C./3 mm.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([S:4]Cl)[CH3:3].[NH:7]1[C:11](=[O:12])[C:10](=[O:13])[NH:9][C:8]1=[O:14].[Na]>>[C:2]([S:4][N:7]1[C:11](=[O:12])[C:10](=[O:13])[NH:9][C:8]1=[O:14])([CH3:6])([CH3:3])[CH3:1]
Reactant: O=C1NC(=O)C(=O)N1
Reactant: CC(C)(C)SCl
Agent: [Na]
Product: CC(C)(C)SN1C(=O)NC(=O)C1=O

Procedure:
1-(t-Butylthio)imidazolidinetrione is prepared by adding a solution of 1,1-dimethylethane sulfenyl chloride (0.1 mole) to a stirred slurry of sodium imidazolidinetrione (0.1 mole). 1-(t-Butylthio)imidazolidinetrione, m.p. 150.5°-152° C. recrystallized from toluene, is recovered.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[N+:8]([C:16]1[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1)([O-:11])=[O:9]
Reactant: CCOC(=O)c1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])s1
Reaction time: 1 h

Procedure:
To 160 ml. of acetic anhydride cooled to -5° in an ice-salt bath is added 34 ml. of 90% nitric acid dropwise so that the temperature does not rise above 0°. To this mixture is added 62.7 g. of ethyl 2-thiophenecarboxylate dropwise so that the temperature remains below -5°. Reaction is stirred for 1 hour and poured onto ice. The product is filtered, dried, and recrystallized from hexane.