Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]4)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc(O)ccc21
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(ccn4C)c3)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a solution of 1-methyl-1H-indol-5-ol (44.0 mg, 0.30 mmol) (Example 47) and ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 100 mg, 0.29 mmol) in DMF (4.0 mL) were added Cs2CO3 (114.6 mg, 0.35 mmol) and water (3 drops). The reaction mixture was stirred at 40° C. for 16 h, then cooled to rt, and concentrated under reduced pressure. Water was added and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:13) yielded 55 mg (46%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.28 (t, 3H), 1.76 (m, 1H), 2.26 (m, 2H), 2.39 (m, 2H), 2.71 (dd, 1H), 2.88 (m, 2H), 3.50 (m, 1H), 3.78 (s, 3H), 4.18 (m, 6H), 6.38 (d, 1H), 6.72 (dd, 1H), 6.80 (s, 1H), 6.89 (d, 1H), 7.02 (s, 1H), 7.06 (d, 1H), 7.10 (s, 1H), 7.20 (d, 1H).
Reaction SMILES: [N+]([C:4]1[C:5]([N+]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[N+:14]([O-:17])(O)=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:9]1[CH:8]=[CH:7][C:6]([CH3:10])=[CH:5][CH:4]=1)([O-:17])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Described herein is a continuous process for preparing dinitrotoluene by reacting toluene with dilute nitric acid to produce mononitrotoluene, then reacting the mononitrotoluene with concentrated nitric acid to produce dinitrotoluene.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Procedure--Nonanoyl chloride (2.74 m, 14.6 mmol) was added dropwise to a cooled solution of tyramine (1 g, 7.29 mmol) and triethylamine (2.03 ml, 14.6 mmol) in THF (35 ml). The reaction mixture was stirred at room temperature for 48 hours. It was then poured into 10% HCl solution (70 ml) and the mixture was then extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (MgSO4) and concentrated under reduced pressure to give crude N-nonanoyl tyramine. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1). m.p. 65.9° to 66.7° C. IR (KBr) 3306, 2922, 2851, 1638; 1H NMR δ 6.65-6.98 (d of d, 4 H, aromatic), 7.78 (t, 1 H, NH), 9.15 (s, 1 H, OH). Analysis calculated for C17H27NO2 : C, 73.61; H, 9.81; N, 5.05. Found C, 73.49; H, 9.661; N, 5.31.
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:23][CH3:24])([CH3:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:24][O:23][C:17]([C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)([CH3:22])[C:18]([F:19])([F:20])[F:21]
Reactant: COC(C)(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(C)(c1ccc(O)cc1)C(F)(F)F

Procedure:
At 50° C. and a hydrogen pressure of 5 bar, 24.5 g of 1-benzyloxy-4-(1-methoxy-1-methyl-2,2,2-trifluoroethyl)benzene in 150 ml of glacial acetic acid were hydrogenated in the presence of 1.4 g of palladium (10% on carbon). The catalyst was filtered off and the mixture was concentrated to give the title product as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](C)(C)(C)[CH3:34].[OH-].[NH4+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:34])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC2(CC1CS(=O)(=O)c1ccc(Br)cc1)OCCO2)OCc1ccccc1
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CC2CC3(CCC2NC(=O)OCc2ccccc2)OCCO3)cc1
Temperature: 75 °C

Procedure:
[7-(4-Bromo-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester from example (3e) (1.0 g), was dissolved in DMF (10 ml) prior to the addition of PdCl2(PPh3)2 (54 mg) and Sn(Me)4 (0.32 ml), and a few crystals of 2,6-tert-butyl-4-methylphenol. The resulting solution was heated in an oil bath at 75° C. for 32 h. After cooling to rt, 10% ammonium hydroxide(aq) was added. The reaction was extracted with EtOAc twice. The combined organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (7R, 8S)-([7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (668 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:21]1[CH2:26][CH2:25][N:24]([C:12]2[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:2]([F:1])([F:19])[F:20])[C:4]([F:7])([F:5])[F:6])=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:23][CH2:22]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1F
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2[N+](=O)[O-])CC1

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-fluoro-3-nitrophenyl)propan-2-ol and tert-butyl piperazine-1-carboxylate were used for a similar reaction and treatment as Example 6-b), and the title compound was obtained as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:43]=[C:44]([NH2:57])[C:45]4[C:49]([CH:50]=3)=[N:48][N:47](C3CCCCO3)[CH:46]=4)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:50]=[C:49]4[C:45]([CH:46]=[N:47][NH:48]4)=[C:44]([NH:57][C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[O:8])[CH:43]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1ncc[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1H-Imidazole-2-carboxylic acid (17 mg) (available from Maybridge), HATU (63 mg) and 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg) were dissolved in anhydrous DMF (3 ml) and then treated with DIPEA (0.052 ml) and stirred at RT for 15 h. The mixture was treated with methanol (3 ml) and then macroporous-tosic acid resin (170 mg; 4.4 mmol/g) then stirred for 15 h. The mixture was then treated with 0.88 ammonia solution (0.600 ml), stirred for 10 min, then filtered and solvent blown off under a stream of nitrogen. The crude residue was purified by mass directed preparative HPLC (Method A) to give the title compound.
Reaction SMILES: CN.[C:3]([O:6][C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])(=O)[OH:4].[CH2:14]([N:16](CC)CC)C.Cl>C(Cl)Cl>[CH3:14][NH:16][C:3]([O:6][C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])=[O:4]
Reactant: CCN(CC)CC
Reactant: O=C(O)Oc1ccccc1O
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)Oc1ccccc1O

Procedure:
155 g of gaseous methylamine were fed into a solution of 680 g of pyrocatechol carbonate and 555 g of triethylamine in 2.5 liters of methylene chloride at 5° C., with vigorous stirring. 500 g of 36% strength hydrochloric acid were then added and the product was filtered off with suction and washed with water. 801 g (96% of the expected amount) of pyrocatechol methylcarbamate of melting point 125° C. were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[C:33]1([CH2:32][CH2:31][CH2:30][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCc3ccccc3)CC1)O2
Temperature: 70 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.566 g, 1.88 mmol) in acetonitrile (30 mL) was added triethylamine (0.80 mL, 5.64 mmol) followed by (3-bromopropyl)benzene (0.747 g, 3.76 mmol). The reaction was stirred at 70° C. for 3 hours. The solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and the organic layer was washed with water (30 mL). The organic extract was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatorgraphy (SiO2, 8% CH3OH in dichloromethane). The product obtained after the chromatography was further purified by crystallization from hexanes and dichloromethane to give the desired product as a purple solid (0.405 g, 51%). M.p.=112-114° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=7.6 Hz, 1H), 7.78 (d, J=3.2 Hz, 2H), 7.58-7.54 (m, 1H), 7.29-7.22 (m, 2H), 7.21-7.14 (m, 3H), 3.07 (s, 2H), 2.74 (m, 2H), 2.60 (t, J=7.6 Hz 2H), 2.37-2.27 (m, 4H), 2.05-1-97 (m, 2H), 1.85-1.71 (m, 4H); LCMS: 420 [M+H]; Calc. for C25H25NO3S: C 71.51, H 6.005, N 3.338; Found C 72.08, H 5.35, N 3.43.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:26]2[CH2:27][CH2:28][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25]2)[CH2:32][CH2:31]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.403 mmol), 1-methyl-4-piperidone (0.099 mL, 0.806 mmol), sodium triacetoxyborohydride (113 mg, 0.537 mmol) and glacial acetic acid (48 mg, 0.806 mmol) were mixed with 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (85:15) as mobile phase to give 1-[1-(1-methyl-4-piperidyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (148 mg, 78%). 1H NMR (DMSO-d6) δ 1.42 (m, 2H), 1.81 (m, 2H), 1.92 (m, 2H), 2.15 (m, 1H), 2.26 (m, 2, 3H), 2.28 (m, 2H), 2.75 (m, 4H), 2.86 (m, 1H), 3.22 (m, 1H), 5.36 (m, 1H), 7.16 (m, 5H), 7.44 (m, 2H), 7.67 (m, 2H), 8.24 (s, 1H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+=470.4, Rt=2.01
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([C:39]([O:41]C)=[O:40])=[CH:36][C:35]=3[CH:43]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([C:39]([OH:41])=[O:40])=[CH:36][C:35]=3[CH:43]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3oc(C(=O)O)cc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate (80.7 mg, 0.126 mmol) in THF (6 ml) was reacted with LITHIUM HYDROXIDE MONOHYDRATE (222.3 mg, 0.531 mmol) in water (3 ml) and stirred at rt for 3 hrs. The reaction treated with 1 N HCl (pH 3-4) and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried with sodium sulfate, filtered and lyophilized to give chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylic acid (74.3 mg, 94.1%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 626.13. found: 626.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:14][NH:13][C:12]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:27][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:26]
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccccc1)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 70 %

Procedure:
A mixture of 25 g of benzyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 29.3 g of anhydrous potassium carbonate, 50 g of methyl iodide and 200 ml of acetone is vigorously stirred at room temperature for 5 days. The mixture is concentrated under reduced pressure to remove solvent. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is collected therefrom. The ethyl acetate solution is dried and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography and then triturated with ether. 18.2 g of benzyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 60.7%
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C=O.C(OCC)(=O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
In 5.0 mL of N,N-dimethylformamide was dissolved 611 mg (5.00 mmol) of 4-hydroxybenzaldehyde. To this solution were added 3.26 g (10.0 mol) of cesium carbonate and 0.98 g (6.0 mmol) of 2-chloromethylpyridine hydrochloride at room temperature and the mixture was stirred at 50° C. overnight. The resulting reaction mixture was diluted with ethyl acetate (100 mL), washed with water and then with saturated brine (each in an amount of 30 mL), and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 50/50) to give 821 mg (77% yield) of the title compound as a light green crystal.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:20])([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[CH2:6][CH2:5]2.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:22][C:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: CON(C)C(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: [Ce+4]
Agent: [NH4+]
Product: CON(C)C(=O)C(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 73.1 %

Procedure:
Oxidation as described in protocol B, using 155 mg (0.528 mmol) of 6-hydroxy-N-methoxy-N,2,5,7,8-pentamethylchroman-2-carboxamide and 637 mg CAN (1.16 mmol) yielding 119.4 mg of 2-hydroxy-N-methoxy-N,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=[O:4].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=C2.Cl.[OH-].[Na+]>CN(C)C=O.O>[CH2:6]([O:5][C:3]([C:2]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([Br:14])[CH:16]=2)[NH:20][CH:19]=1)=[O:4])[CH3:7]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic anhydride (8.5 ml) was added to a solution of 5-bromoindole (10.0 g) in N,N-dimethylformamide (50 ml) at 0° C., and stirred at the same temperature for three hours. After completion of the reaction, water was added to the reaction solution and the precipitated crystalline was collected by filtration. Water (250 ml) and sodium hydroxide (50 g) were added to a solution of the resulting residue in ethanol (50 ml) and the mixture was stirred at 120° C. for eight hours. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated hydrochloric acid was added and the precipitated solid was collected by filtration. To a solution of the resulting residue in ethanol (250 ml), was added concentrated sulfuric acid (5.0 ml) and the mixture was stirred at 90° C. for three hours. Concentrated sulfuric acid (5.0 ml) was further added and stirred at the same temperature for four hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 4N aqueous solution of sodium hydroxide was added until the solution becomes pH 7. Ethanol was evaporated, the precipitated solid was collected and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-bromo-1H-indole-3-carboxylic acid ethyl ester (5.40 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:23]([CH2:24][CH2:25][CH2:26]Br)[N:22]=[N:21][N:20]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[CH3:32][NH:33][CH3:34]>C(#N)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:23]([CH2:24][CH2:25][CH2:26][N:33]([CH3:34])[CH3:32])[N:22]=[N:21][N:20]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc(Cc3nnnn3CCCBr)cc2)ccc(C(C)=O)c1O
Reactant: CNC
Solvent: CC#N
Product: CCCc1c(COc2ccc(Cc3nnnn3CCCN(C)C)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-1-(3-bromopropyl)-1H-tetrazole (2.0 g, 0.004 mol) was added to acetonitrile (40 ml). Dimethylamine (large excess) was cooled in the unopened reagent bottle then added to the acetonitrile solution. The mixture was cooled and stirred at 0° C. for 5 hours then concentrated in vacuo. Water was added to the concentrate and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted isocratically with a mixture of 9.5:0.5% methylene chloride:methanol plus 0.5% diethylamine added) to yield 1.4 g, 77.8% yield of the title product as a yellow oil; n.m.r. (300 MHz, CDCl3) δ: 1.0 (t, 3H); 1.6 (m, 2H); 1.9 (m, 2H); 2.1 (s, 6H; m, 2H); 2.6 (s, 3H); 2.65 (t, 2H); 4.2 (t, 2H); 4.3 (s, 2H); 5.1 (s, 2H); 6.9 (d, 2H); 7.0 (d, 1H); 7.15 (d, 2H); 7.6 (d, 1H); 12.7 (s, 1H).
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][O:20][C:21](=[O:24])[NH:22][CH3:23])[CH:16]=[CH:15][C:14]=1[Cl:25])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C>C(Cl)Cl>[Cl:25][C:14]1[CH:15]=[CH:16][C:17]([CH2:19][O:20][C:21](=[O:24])[NH:22][CH3:23])=[CH:18][C:13]=1[CH2:12][NH:8][CH:9]1[CH2:11][CH2:10]1
Reactant: CNC(=O)OCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)OCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
HCl (4M in dioxane, 35 mL) was added to a sol. of (2-chloro-5-methylcarbamoyloxymethyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (3.48 g, 9.43 mmol) in CH2Cl2 (35 mL) at 0° C. The mixture was stirred for 2 h at 0° C., and more CH2Cl2 was added. The mixture was washed with aq. 1M NaOH and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (2.48 g, 98%) that was used further without purification. LC-MS: tR=0.61 min; ES+: 310.38.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].[S][Cl:13].O>S(Cl)(Cl)(=O)=O.[Cl-].[Cl-].[Cl-].[Al+3]>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([Cl:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: [S]Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Cl
Temperature: 60 °C
Yield: 991.6 %

Procedure:
A mixture of 2,5-dichlorothiophene-3-sulfonyl chloride (1.2 g, 5 mmol) and sulfur monochloride (10 mg) in sulfuryl chloride (500 mg) was heated at 60° C. for 30 min, at which time was added dropwise a mixture of aluminum trichloride (10 mg) in sulfuryl chloride (500 mg). The reaction was heated at 60° C. for an additional 3 hours, at which time it was allowed to cool to ambient temperature. Cold water (20 mL) was added and the reaction extracted with dichloromethane (2×20 mL). The combined organic layers were washed with saturated sodium bicarbonate solution, dried (Mg2SO4) and concentrated to furnish a tan solid (420 mg, 33%).