Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH:7]=[CH:8][N+:9]([O-])=O)=[CH:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[O:3][C:4]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C=C[N+](=O)[O-])o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CCN)o1
Temperature: 0 °C
Yield: 107.1 %

Procedure:
A solution of 2.0 g of 2-methyl-5-(2-nitrovinyl)furan prepared in the step 1 in 50 mL of dry THF was slowly dropped into a solution of 1.0 g of ice-cooled lithium aluminum hydride in 50 mL of dry THF. The reaction solution was gradually heated followed by heating to reflux for 4 hours. The reaction solution was cooled, ice was gradually added thereto to decompose an excess of lithium aluminum hydride and the reaction solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 1.75 g of the objective compound as yellow liquid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([CH3:26])=[CH:24][S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1](Cl)(=O)C.[Na+].[Cl-].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[CH2:19][CH:18]([CH2:20][C:21]([OH:23])=[O:22])[O:17][N:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].Cl>CO>[CH3:1][O:22][C:21](=[O:23])[CH2:20][CH:18]1[O:17][N:16]=[C:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[CH2:19]1
Reactant: CC(=O)Cl
Reactant: O=C(O)CC1CC(c2ccc(Cl)c(Cl)c2)=NO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1CC(c2ccc(Cl)c(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (5 eq) was added to MeOH (50 vol) externally cooled with a mixture saturated aqueous NaCl solution and ice. After 10 minutes the solution was warmed to room temperature. After a further 90 minutes, [3-(3,4-dichloro-phenyl)-4,5-dihydro-isoxazol-5-yl]-acetic acid (1.0 eq) in MeOH (25 vol) was added to the hydrogen chloride methanolic solution and stirred for 16 hours. The solvent was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluent: [3:7] EtOAc:heptane) to afford [3-(3,4-dichloro-phenyl)-4,5-dihydro-isoxazol-5-yl]-acetic acid methyl ester.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.Cl>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 0 °C

Procedure:
Procedure-B: 2-(4-cyclopropanesulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (obtained in step III) was dissolved in DCM. To this solution was added DMF and cooled to 0° C., followed by the addition of oxalyl chloride under stirring. To this mixture, a solution of 2-aminothiazole and pyridine in DCM was added drop wise at 0° C. and was stirred further for 4 h. at room temperature. The reaction mixture was poured into 1N aqueous HCl under stirring, organic layer was again washed with 1N HCl, followed by 5% brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[N:7]([CH2:17][C@@H:18]([OH:49])[C@@H:19]([NH:29][C:30](=[O:48])[C:31]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][S:38]2(=[O:44])=[O:43])[CH:34]=[C:33]([C:45](=[O:47])[CH3:46])[CH:32]=1)[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:50])[N:7]([CH2:17][C@@H:18]([OH:49])[C@@H:19]([NH:29][C:30](=[O:48])[C:31]1[CH:32]=[C:33]([CH:45]([OH:47])[CH3:46])[CH:34]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][S:38]2(=[O:43])=[O:44])[CH:36]=1)[CH2:20][C:21]1[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)=O)cc(N3CCCCS3(=O)=O)c2)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)O)cc(N3CCCCS3(=O)=O)c2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(2R,3S)-3-[3-Acetyl-5-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzoylamino]-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(3-methoxy-benzyl)-carbamic acid tert-butyl ester (16 mg, 0.022 mmol) was dissolved in MeOH (0.2 mL) and sodium borohydride (1.13 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The organic layer was separated and concentrated to give the title compound which was used in the next step without further purification: HPLC retention time: 2.073 min (method A). MS (ESI) (M+H)+ 718.30.
Reaction SMILES: [BrH:1].[NH:2](C(OCC1C=CC=CC=1)=O)[C@H:3]([C:8]([NH:10][C@H:11]([C:17]([N:19]1[CH2:28][CH2:27][CH2:26][C@H:20]1[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[O:18])[CH2:12][CH2:13][C:14](=[O:16])[NH2:15])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]>C(O)(=O)C>[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:17]([N:19]1[CH2:28][CH2:27][CH2:26][C@H:20]1[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[O:18])[CH2:12][CH2:13][C:14](=[O:16])[NH2:15])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[BrH:1]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
70 ml of a 4N solution of hydrogen bromide in glacial acetic acid are added to a solution containing 7.6 g (14.6 mmoles) of Z-Leu-Gln-Pro-NHEt in 50 ml of glacial acetic acid, then the mixture is left to stand at room temperature for 90 minutes. The mixture is slowly poured into 800 ml of ice-cold ether while stirring. After 30 minutes, the stirring is stopped and the settled precipitate is filtered and dried in a desiccator over phosphorus pentoxide to give 7.9 g of the aimed product, m.p.: 147° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([CH:25]=[CH2:26])[O:19]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:14][C@H:9]1[O:10][C@@H:11]([CH3:13])[CH2:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2](/[CH:26]=[CH:25]/[B:20]3[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:27])([CH3:17])[O:19]3)=[CH:3][CH:4]=2)[CH2:8]1
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)O1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2)C[C@H](C)O1
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromobenzyl)-cis-2,6-dimethylmorpholine (20 g, 71 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (13 mL, 77 mmol, 1.1 eq.) in toluene (250 mL) was added triethylamine (19.7 mL, 142 mmol) and Pd(PtBu3)2 (368 mg, 0.71 mmol) and the solution was heated to 80° C. for 2 h under argon. After cooling to rt, the reaction was quenched with sat. NaHCO3 (50 mL), water (50 mL), extracted with EtOAc (3×100 mL) and dried over MgSO4. After evaporation of the solvents, the residue was purified by Biotage column system (EtOAc/hex gradient: 0-100%) to give the title compound as a white solid (16 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0 Hz, 2H), 7.40 (d, J=18.4 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 6.16 (d, J=18.4 Hz, 1H), 3.75-3.65 (m, 2H), 3.47 (s, 2H), 2.70 (d, J=10.8 Hz, 2H), 1.75 (t, J=10.2 Hz, 2H), 1.32 (s, 12H), 1.14 (d, J=6.4 Hz, 6H); MS ESI 358.2 [M+H]+, calcd for [C21H32BNO3+H]+ 358.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][C:12]([O:15]CC1C=CC=CC=1)=[CH:11][CH:10]=3.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3
Reactant: [H][H]
Reactant: Cc1ccccc1-c1nc2c3cc(OCc4ccccc4)ccc3ccn2c1N
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1-c1nc2c3cc(O)ccc3ccn2c1N
Yield: 83.9 %

Procedure:
To a solution of 5 g of 3-amino-9-benzyloxy-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 40) in 100 ml of ethanol was added 0.5 g of palladium on activated carbon (Pd 10%). After introduction of hydrogen, the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. Resultant residue was purified by column chromatography on silica gel and recrystallized from water/methanol to give 3.2 g of the title compound as pale yellow needles.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:55](O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.O1CCCC1>[CH2:55]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:34])([F:35])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=S(=O)(Oc1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1ccc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Combine trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (247 mg, 0.48 mmol), triphenylphosphine (190 mg, 0.725 mmol), benzyl alcohol (0.075 mL, 0.725 mmol) and tetrahydrofuran (5 mL) in a flask placed in an ice bath. Add diisopropyl azodicarboxylate (0.14 mL, 0.725-mmol), stir for 1 hour, warm to ambient temperature and stir for 30 minutes. Dilute with ethyl acetate and wash with 50% saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry with magnesium sulfate and remove solvent under vacuum. Chromatograph on silica gel with dichloromethane/methanol mixtures to give 213 mg of the title compound (73%).
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13]>CO.O>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[CH2:3][CH:2]=[O:1])[C:8]#[N:9]
Reactant: COc1cc(C#N)ccc1CC(O)CO
Solvent: O
Solvent: CO
Product: COc1cc(C#N)ccc1CC=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,3-dihydroxypropyl)-3-methoxybenzonitrile (500 mg, 2.6 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0° C. by ice bath, then NaIO4 (830 mg, 3.9 mmol) was added and the mixture was stirred at 0° C. for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 3-methoxy-4-(2-oxoethyl)benzonitrile. MS m/z 176 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][C:21](=O)[CH3:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][C:21](=[N:25][OH:26])[CH3:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12)=NO
Temperature: 60 °C

Procedure:
The product from Example 24 (0.50 g, 0.0015 mol), hydroxylamine hydrochloride (0.21 g, 0.0031 mol) and 4 Å molecular sieves were suspended in pyridine (10 ml) and heated at 60° C. for 14 h. A further amount of hydroxylamine hydrochloride (0.42 g, 0.0062 mol) was added and the reaction mixture heated under reflux for a further 24 h. The reaction mixture was diluted with ethyl acetate (30 ml) and filtered through hiflo. The mixture was washed with 1N hydrochloric acid (100 ml), the acid layer was back extracted with ethyl acetate (2×20 ml) and the combined organic layers were washed consecutively with water (20 ml), saturated sodium hydrogen carbonate solution (20 ml) and brine (20 ml), then dried (MgSO4), filtered, and concentrated in vacuo to give a white solid. This was recrystallised from ethanol/water to give a white crystalline solid; yield=278 mg. Mp=196°-198° C. Found: C, 62.93; H, 4.37; N, 8.10. C18H15ClN2O3 requires C, 63.07; H, 4.41; N, 8.17. δ (360 MHz, DMSO-d6), 1.60 (3H, s, CH3), 4.06 (2H, s, OCH2), 7.28 (1H, dd, J=8.6 and 2.1 Hz, 6-H), 7.32-7.48 (6H, m, aromatics), 7.78 (1H, d, J=8.7 Hz, 5-H), 10.88 (1H, s, NOH), 11.92 (1H, s, br, NH). MS (CI) m/z=343 [MH]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:10]=1.[OH-].[Na+].C(OCC)(=O)C>C(#N)C>[Br:1][C:14]1[N:9]=[CH:10][C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
2.70 g (15.19 mmol) of N-bromosuccinimide (NBS) are added portionwise to a solution of 4 g (15.19 mmol) of 1,1-dimethylethyl 4-(3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.1, in 50 ml of acetonitrile, cooled to about 0° C. Stirring is continued at 0° C. for 15 minutes and then at room temperature for 2 hours. 100 ml of aqueous sodium hydroxide solution (1M) and 100 ml of ethyl acetate are added to the reaction medium. The aqueous phase is separated out and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. 5.16 g of product are thus obtained in the form of an orange-yellow solid, and are used without further purification in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([NH2:27])=[C:22]([Cl:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:36]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:36])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([NH2:27])=[C:22]([Cl:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1cc(Cl)c(N)c(Cl)c1)CC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-(4-amino-3,5-dichlorophenylamino)-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 21.3 %

Procedure:
A mixture of 4-chloro-3-nitro-phenol (5.00 g, 28.81 mmol), phenylboronic acid (7.03 g, 57.62 mmol), copper(II) acetate (5.23 g, 28.81 mmol) and 4 Å molecular sieves (0.5 g) in dichloromethane (200 mL) and triethylamine (20.08 mL, 144.04 mmol) was placed in a round bottomed flask. The resulting suspension was stirred under a dry ambient atmosphere at room temperature for 4 days. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The resulting residue was re-dissolved in EtOAc, adhered to silica gel and flash chromatographed (2% EtOAc/hexane) to give 1-chloro-2-nitro-4-phenoxy-benzene as a yellow oil (1.53 g, 22.0% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC>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.O1CCCC1>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2)(=[O:19])[CH3:18]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2c(c1)CCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CCCO2

Procedure:
In accordance with this scheme a 6-bromochroman compound of Formula 2 (see Reaction Scheme 1) is reacted with by tributyl(1-ethoxyvinyl)tin in the presence dichlorobis(triphenylphosphine)palladium(II) under an inert gas (argon) atmosphere in an aprotic neutral solvent, such as tetrahydrofuran (THF), to provide a 6-acetylchroman derivative of Formula 25. The 6-acetylchroman derivative of Formula 25 is then reacted with iodine and silver(I)trifluoromethanesulfonate (AgOTf) to give a 6-acetyl-8-iodochroman derivative of Formula 26. The compound of Formula 26 is reacted with with trimethylsilyl acetylene in triethyl amine under argon atmosphere in the presence of copper(I)iodide and dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2) to give the 6-acetyl-8-trimethylsilanyl-ethynyl-chroman derivative of Formula 27. The latter reaction is analogous to the conversion of the 8-iodo-substituted chroman compounds of Formula 4 to the 8-trimethylsilanyl-ethynyl-chroman derivatives of Formula 5, as shown in Reaction Scheme 1.
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:19])([O:16]CC)[O:13]CC)=O)(C)(C)C.Br[Si](C)(C)C>ClCCl>[NH2:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:13])([OH:16])[OH:19]
Reactant: CCOP(=O)(CC[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)NC(=O)OC(C)(C)C)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: C[C@@](N)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)CCP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of diethyl (3R)-3-t-butoxycarbonylamino-3-methyl-5-[5-(5-phenylpentanoyl)furan-2-yl]pentylphosphonate (108.2 mg, 0.19 mmol) obtained in Example (29d) in dichloromethane (1.9 ml) was added bromotrimethylsilane (0.255 ml, 1.93 mmol), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After stirring, the reaction mixture was evaporated in vacuo, and the residue was diluted with aqueous ethanol, and then the resulting mixture was adjusted to pH 4 with aqueous ammonia and acetic acid. The crystals precipitated were collected by filtration, washed successively with water and ethanol and dried to afford the title compound (51.4 mg, yield: 66%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12](=[CH2:18])[C:13]([O:15]CC)=[O:14])=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH2:25]([SH:27])[CH3:26]>C(OCC)(=O)C>[CH2:25]([S:27][CH2:18][CH:12]([CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)[C:13]([OH:15])=[O:14])[CH3:26]
Reactant: C=C(Cc1ccnc2ccccc12)C(=O)OCC
Reactant: CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCSCC(Cc1ccnc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
597 mg of ethyl 2-(4-quinolylmethyl)acrylate was dissolved in 3 ml of ethylmercaptan. Then, 50 mg of potassium tert-butoxide was added thereto, and the mixture was stirred at room temperature for two hours. Then, the reaction solution was diluted with 60 ml of ethyl acetate and washed with 40 ml of water and then with 40 ml of a saturated sodium chloride aqueous solution. The organic layer was separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual syrup was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/2) and dried to obtain 640 mg (yield: 85%) of the desired product as syrup.
Reaction SMILES: Cl[CH2:2][C:3]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:24]Cl)=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:24][C:9]1[C:10]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:11][C:12]2[C:13]3[C:5](=[CH:4][C:3]([CH3:2])=[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:14]=3)[CH2:6][C:7]=2[CH:8]=1
Reactant: CC(C)(C)c1cc2c(cc1CCl)Cc1cc(CCl)c(C(C)(C)C)cc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(C)(C)C)-c1cc(C(C)(C)C)c(C)cc1C2
Yield: 85 %

Procedure:
To a solution of 2,7-dichloromethyl-3,6-di-t-butylfluorene (0.75 g, 2.0 mmol) in THF (15 ml) was added a small portion of LiAlH4 (220 mg, 5.8 mmol) under stirring and the mixture was refluxed for 4 hours. The reaction was quenched with water and NaOH and extracted with ether. The ether solution was evaporated under vacuum to give a white solid of 2,7-di-methyl-3,6-di-tert-butyl-fluorene with a yield of 85%.