Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[C:20]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]3[N:1]=[C:3]2[CH2:2][CH2:7][CH3:6])=[CH:12][CH:13]=1)(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(=O)Cl
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Product: CCCC(=O)OCCc1ccc(-n2c(CCC)nc3c(C)cc(C)nc32)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and butyryl chloride.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1>C(OCC)C>[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([CH3:1])([OH:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Methylmagnesium bromide (3M solution in diethylether, 51.6 ml, 155 mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0 g, 70 mmol) in dry diethylether (200 ml) at 0° C. The resulting mixture was left for 3 hours, then cooled to 0° C. and slowly quenched with saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried (sodium sulfate). The yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane:pentane:methanol (90:5:5 by volume to afford a pale yellow oil (13.26 g). 1H NMR (400 MHz, CDCl3) δ=7.40 (2H, m), 7.15 (2H, m), 2.74 (2H, s), 1.42 (1H, bs), 1.22 (6H, s).
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CS(C)=O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH2:19][C:1]#[CH:2])[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: [C-]#[C-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)CCC2C)cc1
Agent: [Li+]
Solvent: CS(C)=O
Product: C#CCC1CN(C(=O)OC(C)(C)C)CCC1C
Temperature: 8 °C
Reaction time: 4.5 h

Procedure:
A flask containing lithium acetylide, ethylene diamine complex (3.82 g, 37.4 mmol) was taken up in dry DMSO (50 mL) and cooled to approximately 8° C. (dilute ice bath) under argon atmosphere. To the cooled mixture was added a solution of (+/−)-4-methyl-3-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (6.91 g, 17.79 mmol) in dry DMSO (40 mL), via slow drop-wise addition. The dark brown-black mixture was stirred vigorously to ambient temperature for 4.5 hours. The reaction was carefully quenched via the addition of a saturated solution of aqueous ammonium chloride (60 mL), followed by the addition of diethyl ether (120 mL) and water (50 mL). The mixture was transferred to a separatory funnel and shaken. The ether phase was collected and shaken with an equal volume of brine. The aqueous phases were back extracted with diethyl ether (2×100 mL). The crude was taken up in methylene chloride (40 mL) and adsorbed onto 25 g of silica gel. The solvent was stripped and the crude material was purified by silica gel chromatography, eluting with 4% to 20% ethyl acetate in hexanes, providing 2.21 g of (+/−)-4-methyl-3-prop-2-ynyl-piperidine-1-carboxylic acid tert-butyl ester as a clear mobile oil. MS (M+Na)+=260.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][N:7]=1)=[CH2:5])C.Cl>CC(C)=O>[C:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][N:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cc(C(F)(F)F)ccn1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1cc(C(F)(F)F)ccn1
Reaction time: 16 h
Yield: 98.4 %

Procedure:
A solution of 1-ethoxy-1-(4-trifluoromethylpyrid-2-yl)-ethylene (1.4 g) in acetone (15 ml) was treated with hydrochloric acid (5 ml of a 2M solution). The reaction mixture was allowed to stand for 16 hours then concentrated, diluted with water and neutralised with sodium bicarbonate. The aqueous phase was extracted with ether (×2) and the combined extracts were washed with brine, dried and concentrated to give 2-acetyl-4-trifluoromethylpyridine (1.2 g, 99% yield) as a pale yellow liquid. IR maximum (film): 1705 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccn2C)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccn2C)=NC1c1ccc(F)cc1Br
Yield: 44.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellowish solid (0.49 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O[CH:13](OCC)[N:14]([CH3:16])[CH3:15])C>CN(C=O)C>[CH3:13][N:14]([CH3:16])/[CH:15]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
Acetophenone (1.18 mL) and N,N-dimethylformamide diethyl acetal (1.71 mL) were dissolved in DMF (4 mL) and the resulting mixture was stirred at 120° C. for 20 h. The solvent was removed in vacuo and the residue was crystallized in Et2O. The mother liquors were cooled to 0° C. and precipitation occurred. The solid was filtered off and combined with the first batch to afford (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (1.02 g of yellow solid).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)(=[O:10])=[O:9].[Cl:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[Cl:40])[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[Cl:40])[O:24][CH:25]1[CH2:26][CH2:27][N:28]([CH:31]2[CH2:32][CH2:33][N:34]([C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:8]([CH3:7])(=[O:9])=[O:10])=[O:15])[CH2:35][CH2:36]2)[CH2:29][CH2:30]1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccccc1C(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Oxalyl chloride (55 ml, 0.63 mol) was added dropwise over 10 minutes to a stirred suspension of 2-methanesulfonyl-benzoic acid (7.1 g, 0.036) in DCM (550 ml) containing DMF (0.5 ml). The solution was then stirred for 2 hours at room temperature. The solution was then evaporated to give a solid that was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (275 ml) and was added over 10 minutes to a stirred solution of the product of Step 3 (11.0 g, 0.033 mol) and triethylamine (15.4 ml, 0.11 mol) in dichloromethane (125 ml). The resultant solution was stirred at room temperature for 16 hours. The solution was then washed with water (500 ml), 1M aq NaOH (500 ml) and water (2×500 ml). The organic phase was dried (MgSO4), filterered and the solvent removed to give a pale yellow foam. The foam was triturated with diethyl ether to give the title compound (12.96 g, 76%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>O1CCOCC1>[ClH:30].[CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
N-t-butyloxycarbonyl-L-prolyl-L-proline benzylester (60.70 g, 150 mmole) was dissolved in 4N hydrochloric acid in dioxane (350 ml) solution, and stirred for 1 hour at room temperature. The solution was concentrated under reduced pressure, and diethyl ether was added to the solution while cooling with ice and stirring to obtain L-prolyl-L-proline benzylester hydrochloride (47.80 g, 94.1%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([NH:17][CH2:18][CH3:19])(=[O:16])=[O:15])[N:11]([CH2:20][CH3:21])[C:10]=2[CH:22]=1)([O-:5])=[O:4].[CH2:23](Br)[CH3:24].O>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([N:17]([CH2:23][CH3:24])[CH2:18][CH3:19])(=[O:16])=[O:15])[N:11]([CH2:20][CH3:21])[C:10]=2[CH:22]=1)([O-:5])=[O:4]
Reactant: CCBr
Reactant: CCNS(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2n1CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)S(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2n1CC
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
2.6 g (0.11 mol) of sodium hydride are added to a solution of 29.8 g (0.1 mol) of 6-nitro-1,N-diethyl-1H-benzimidazole-2-sulfonamide in 100 ml of dimethylformamide. The solution is stirred for one hour at 40° C., 10.8 g (0.1 mol) of ethyl bromide are added and the mixture is stirred for 12 hours at 50° C. It is poured into water and the product is filtered off and washed with water. The precipitate is recrystallized from ethanol to give 25.6 g (78%) of 6-nitro-1,N,N-triethyl-1H-benzimidazole-2-sulfonamide melting at 90°-1° C.
Reaction SMILES: C(NC([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=O)C>CN(C=O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:13]2[CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]3[S:8][C:7]([NH2:6])=[N:11][C:10]=3[CH:12]=2)[CH:23]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccccn3)c2s1
Solvent: CN(C)C=O
Product: Nc1nc2cc(-c3cccnc3)cc(-c3ccccn3)c2s1

Procedure:
1-Ethyl-3-(5-pyridin-3-yl-7-pyridin-2-yl-benzothiazol-2-yl)-urea (0.19 g, 0.53 mmol) in DMF (10 mL), was heated at 120° C. for 10 h in pressure vessel. After the completion of the reaction (TLC monitoring), DMF was distilled off, added water and extracted with ethyl acetate. The crude solid (0.14 g, 90%) was used as such for the next step.
Reaction SMILES: C(OC1C=CC(C2N3C(N=C4CCCCCC=24)=CC=N3)=CC=1)C1C=CC=CC=1.Cl[C:30]1[N:41]2[C:37](=[CH:38][CH:39]=[N:40]2)[N:36]=[C:35]2[C:31]=1[CH2:32][O:33][CH2:34]2.[O:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>>[O:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:48][C:49]1[CH:54]=[CH:53][C:52]([C:30]2[N:41]3[C:37](=[CH:38][CH:39]=[N:40]3)[N:36]=[C:35]3[C:31]=2[CH2:32][O:33][CH2:34]3)=[CH:51][CH:50]=1
Reactant: Clc1c2c(nc3ccnn13)COC2
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Agent: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCCCC4)cc2)cc1
Product: c1cc2nc3c(c(-c4ccc(OC5CCCCO5)cc4)n2n1)COC3

Procedure:
Using the method described for the preparation of 10-(4-benzyloxy-phenyl)-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-Chloro-5H,7H-6-oxa-1,4,8a-triaza-s-indacene and 4-(Tetrahydro-pyran-2-yloxy)-phenyl boronic acid provided the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=O.[S:11]1[CH:15]=[CH:14][C:13]2[C:16](=[O:25])[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][CH2:20][C:12]1=2.[Cl-].[Al+3].[Cl-].[Cl-].[Sn](Cl)(Cl)(Cl)Cl.Cl>C(=S)=S>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([C:15]1[S:11][C:12]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[C:16](=[O:25])[C:13]=2[CH:14]=1)=[O:9]
Reactant: COC(=O)CCC(=O)O
Reactant: O=C1c2ccccc2CCc2sccc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Al+3]
Solvent: S=C=S
Product: COC(=O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 6.3 cc of succinic acid monomethyl ester chloride in 100 cc of anhydrous carbon disulphide is added dropwise at 0° to a suspension of 10.0 g of 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one and 30.0 g of anhydrous aluminium chloride in 200 cc of anhydrous carbon disulphide, the reaction mixture is stirred for a further 6 hours at room temperature, 23.3 g of tin tetrachloride are added dropwise thereto at 20° to 25° and stirring is continued at room temperature for 15 hours. The reaction mixture is subsequently heated to 50° for 2 hours, cooled, poured on 500 cc of 5 N hydrochloric acid and extracted with chloroform. The organic phases are washed with 5 N hydrochloric acid and with water, dried over magnesium sulphate and concentrated by evaporation. The evaporation residue is dissolved in 300 cc of methylene chloride, filtered through silica gel and evaporated to dryness. The title compound crystallizes from benzene/petroleum ether and is recrystallized once from ether. M.P. 97°-98°.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12].C([BH3-])#N.[Na+]>>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(F)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)cc1F
Yield: 72 %

Procedure:
Reduction of 2,4-difluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (72% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.51 (3H, s, OCH3), 4.07 (2H, s, NCH2), 6.78–6.88 (2H, m, aromatics), 7.32–7.38 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 154–158° C. (dec.). Anal. calcd. for C8H9NO2—HCl: C, 45.83; H, 4.80; N, 6.68. Found: C, 45.81; H, 4.84; N, 6.59.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][Si:5](Cl)([CH3:7])[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].[OH2:15]>>[Cl:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:7])([CH3:6])[O:15][Si:5]([CH2:4][CH2:3][CH2:2][Cl:1])([CH3:7])[CH3:6]
Reactant: O
Reactant: C[Si](C)(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[Si](C)(CCCCl)O[Si](C)(C)CCCCl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a triangular flask of 2 l containing 1200 ml of water was added dropwise 342 g of 3-chloropropylchlorodimethylsilane (hereinafter referred to as "CPCDMSi") in an hour while stirring with a magnetic stirrer at a room temperature. After completion of the addition, the reaction mixture was neutralized with sodium carbonate and then extracted three times with each 500 ml of n-hexane. After drying the n-hexane layer with anhydrous magnesium sulfate, n-hexane was removed under reduced pressure. The obtained residue was distilled under reduced pressure, and then the distillate obtained at 103° C./1.5 mmHg was collected to give 255 g (Yield 89%) of 1,3-bis(3-chloropropyl)-1,1,3,3-tetramethyldisiloxane (hereinafter referred to as "BCPSi").
Reaction SMILES: C[O:2][C:3]1[C:12]([CH:13]=[O:14])=[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]2=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:12]([CH:13]=[O:14])=[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1C=O)CCCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)ccc2c1CCCO2
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A solution of 6-methoxy-3,4-dihydrobenzopyran-5-carboxaldehyde (30.00 g, 156 mmol) in dry methylene chloride (625 mL) was cooled to an internal temperature of -67°. A solution of boron tribromide (1M in methylene chloride, 67.5 mL, 67.5 mmol) was added dropwise. The cooling bath was removed and the mixture allowed to stir under nitrogen for three hours. The reaction was then quenched by the dropwise addition of methanol (75 mL) and the resulting mixture poured into satureated aqueous sodium chloride (1200 mL). The layers were separated and the organic extract washed with saturated sodium chloride (600 mL), dried (Na2SO4) and concentrated. Purification by preparative HPLC (Waters Prep 500, 9:1 hexane: ethyl acetate as eluant) afforded 6-hydroxy-3,4-dihydrobenzopyran-5 -carboxaldehyde (22.46 g, 80.8%), m.p. 93-95.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1.Cl.C(N=C=N)C.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 40.1 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.3 mmol), 1-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (87 mg, 0.45 mmol), 4-dimethylaminopyridine (55 mg, 0.45 mmol), methane sulfonamide (86 mg, 0.9 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (57 mg, 40%) as a light yellow solid: LC/MS m/e calcd for C24H31N3O5S (M+H)+: 474.6, observed: 474.0.
Reaction SMILES: [N:1]1[C:10]2[O:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:17])C>C(O)(=O)C>[N+:1]1([O-:17])[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:6]2
Reactant: CC(=O)OO
Reactant: c1ccc2c(c1)Oc1cccnc1O2
Solvent: CC(=O)O
Product: [O-][n+]1cccc2c1Oc1ccccc1O2
Temperature: 70 °C

Procedure:
A solution of 32 g of pyrido[2,3-B][1,4]benzodioxin in 100 ml of glacial acetic acid is treated with 36 g of 40% peracetic acid in acetic acid in four equal portions. After the fourth portion is added, the mixture is heated at 70° C. for 10 minutes. Another 4 g of 40% peracetic acid in acetic acid is added and the temperature is maintained at 70° C. for 10 minutes and then heated to reflux for 10 minutes. The mixture is concentrated at reduced pressure, 100 ml of isopropanol is added and the mixture is concentrated again. The resulting oil is dissolved in 700 ml of dichloromethane and the organic layer is washed with excess cold 25% sodium hydroxide solution. The organic layer is dried and evaporated to yield the pyrido[2,3-B][1,4]-benzodioxin 1-oxide, mp 223°-226° C. after recrystallization from acetonitrile.
Reaction SMILES: C(O[C:6](=O)[CH2:7][CH2:8][N:9]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=O)(C)(C)C.[CH2:28](Br)[CH:29]=C>C1(C)C=CC=CC=1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:9]1[CH2:10][CH2:11][C:12](=[O:14])[CH:7]([CH2:6][CH:28]=[CH2:29])[CH2:8]1
Reactant: CC(C)(C)OC(=O)CCN(CCC(=O)OC(C)(C)C)Cc1ccccc1Cl
Reactant: C=CCBr
Solvent: Cc1ccccc1
Product: C=CCC1CN(Cc2ccccc2Cl)CCC1=O
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
16.60 g (0.145 mol) of K-tert-butylate was introduced and warmed to 75° to 80° C. Then 50 g (0.125 mol) of di-tert-butyl-N-[(2-chlorophenyl)methyl]-3,3'-iminodipropionate in 100 ml of toluene was added within 10 minutes. After 20 minutes, the toluene was practically completely evaporated at 75° C. and 220 mbars. Then 400 ml of tert-butanol was added to 40° C. 17.94 g (0.145 mol) of allylbromide was added to the resulting suspension at 40° C. in 10 minutes. It was allowed to stir for 45 minutes more at 40° C. The reaction mixture was then completely concentrated by evaporation and then the solid residue was dissolved in 500 ml each of H2O plus 300 ml of ether. The aqueous phase was again extracted twice with 100 ml each of ether. The combined ether phases was washed with 50 ml of saturated Na2SO4 and then concentrated by evaporation. Then 500 ml of 0.5 n HCl was added to the resulting oil and refluxed for 30 to 45 minutes (CO2 development). The reaction mixture was cooled to room temperature and mixed again with 20 ml of HCl conc. It was extracted three times with 100 ml of ether and the ether phase was dried with MgSO4 and evaporated. The acidic water phase was made basic with NaOH and extracted three times with 200 ml of ether. The ether phases were combined and dried with MGSO4 and evaporated. A yellowish oil resulted. The yield was 28.66 g (87 percent). Data concerning the compound was:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:5]1)([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pt]=O>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:5][N:4]2[CH:1]([CH3:2])[CH3:3])=[CH:8][CH:9]=1
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc(N)cc21
Yield: 99.7 %

Procedure:
Method E Placc 4-(1-isopropyl-6-nitro-1H-indol-3-yl)-benzonitrile (4, R1=i-Pr, R3=4-benzonitrile) 250 mg, 0.82 mmol) in a 50 mL flask and add a suspension of platinum (II) oxide (16 mg) in tetrahydrofuran (9 mL). Place the reaction under 1 atmosphere of hydrogen and stir until the starting material is consumed. Filter through a celite pad and wash the pad with ethyl acetate (50 mL). Concentrate the combined filtrates to give 225.0 mg of the title compound (99%). LRMS (API ES+)=276.0 (M+H).
Reaction SMILES: C(Cl)(Cl)Cl.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][CH:26]([C:31]([F:34])([F:33])[F:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[CH2:17][CH2:16]2)C1C=CC=CC=1.I[Si](C)(C)C>CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][C@@H:26]([C:31]([F:32])([F:33])[F:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[CH2:17][CH2:16]2
Reactant: CCCCC(OC(=O)C1=Cc2ccc(OCc3ccccc3)cc2CC1)C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCC[C@@H](OC(=O)C1=Cc2ccc(O)cc2CC1)C(F)(F)F
Yield: 61 %

Procedure:
To 10 ml of a chloroform solution of 0.23 g (0.5 mmol) of the (R) 1-trifluoromethylpentyl 6-benzyloxy-3,4-dihydro-2-naphthalenecarboxylate obtained in the third step was added 0.1 ml (0.7 mmol) of iodotrimethylsilane in a nitrogen atmosphere with stirring, and the mixture was reacted at room temperature for two and a half hours with stirring. Then, 10 ml of methanol was added, and the mixture was rapidly concentrated at room temperature under reduced pressure. The concentrate was separated by column chromatography, to obtain 0.11 g of (R)1-trifluoromethylpentyl 6-hydroxy-3,4-dihydro-2-naphthalenecarboxylate as a white solid (yield: 61%). The 1H-NMR data of this compound are described below.