Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To the crude product (700 mg) of t-butyl 2-bromoethylcarbamate obtained in Step 1 were added 4-fluorophenol (875 mg), potassium carbonate (1.08 g) and DMF (7 ml), and the mixture was stirred overnight at 90° C. The solvent was evaporated, and the mixture was diluted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give t-butyl 2-(4-fluorophenoxy)ethylcarbamate (390 mg).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 67.4 %

Procedure:
To a suspension of methyl 4-(phenylmethoxy)benzenepropanoate (0.60 g, 2.2 mmol) in methanol (20 mL) was added 2N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 15 hrs. 2N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.38 g, yield 67%).
Reaction SMILES: [BH4-].[Na+].Cl.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C:12]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH2:14][CH:13]=1>>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C:12]1[CH2:17][CH2:16][CH:15]([C@H:18]2[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][CH2:23]2)[CH2:14][CH:13]=1
Reactant: O=C1CCC(C2CC=C(c3cccc(F)c3F)CC2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
First, 100 ml of a mixed solvent (methanol/tetrahydrofuran=1/7) and 1.5 g of sodium borohydride were placed in a 300 ml flask. Then, a solution in which 5.65 g of 4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanone was dissolved in 80 ml of a mixed solvent (methanol/tetrahydrofuran=1/7) was added dropwise to the mixture at -25° C. The mixture was allowed to warm to room temperature and stirred for 6 hours. Thereafter, diluted hydrochloric acid was added to the reaction mixture, and an organic layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=3/1) to obtain 4.6 g of trans-4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanol (Y: 80.7%). The compound thus obtained had a purity of 99.3% by GC.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH:16]=[CH:17]/[CH2:18][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.C(Cl)(Cl)Cl>CC#N>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:16]([F:31])[CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(C)C/C=C/[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C=C[C@@H](F)[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R,3E)-2-benzyl-5-(trimethylsilyl)pent-3-enoyl]-1,3-oxazolidin-2-one (0.88 mmol, 370 mg) in CH3CN (8 mL) was added [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (referred to hereafter as Selectfluor) (0.88 mmol, 310 mg). The reaction was allowed to stir at RT for 48 hr. The solvent was removed in vacuo. The crude product was purified by column chromatography to yield a mixture of diastereoisomers de=10% (250 mg, 95%). 1H NMR (400 MHz, CDCl3): δ=6.98-7.3 (m, 10H), 6.0 (m, 1H), 5.5 (dm, J=17, 1H), 5.42 (d, J=10.6, 1H), 5.1 (ddd, J=7.1, 8.1, 47.2, 1H), 4.85 (m, 1H), 4.64 (m, 1H), 3.98-4.12 (m, 2H), 2.84-3.0 (m, 3H), 2.2 (m, 1H); 13C NMR (100 MHz, CDCl3): δ=172.5, 152.9, 137.2, 135.1, 133.7, 133.6, 129.5, 129.3, 128.9, 128.5, 127.2, 126.8, 120.6, 120.5, 94.4 (d, J=175), 65.6, 55.1, 48.1 (d, J=21), 37.3 34.8 (d, J=6); 19F {1H} NMR (376.5 MHz, CDCl3): δ=−175.7; IR (CHCl3): v 3444, 2957, 1645, 1367, 1235, 1205 cm−1; [α]D20=−18.4° (c, 0.5 CHCl3); HMRS required for C22H23NO3F 368.1662 ([M+H+]) found 368.1669.
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC.CC(C)([O-])C.[K+].C([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=O.O>C1(C)C=CC=CC=1.O1CCCC1>[N:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][CH:32]=1
Reactant: O=Cc1ccc2ccccc2n1
Agent: CC(C)(C)[O-]
Agent: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc2ncccc2c1
Reaction time: 0.25 h

Procedure:
4.90 g (12.7 mmol) of propyltriphenylphosphonium bromide are suspended in 15 ml of anhydrous toluene at 0° C., in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet, and then 1.71 g (15.2 mmol) of potassium tert-butoxide (tBuOK) are added. After stirring for 15 minutes, a solution at 0° C. containing 1 g (6.36 mol) of 2-formylquinoline in 10 ml of anhydrous tetrahydrofuran is added. The reaction mixture is brought to the reflux temperature of toluene for 90 minutes, and the solution is then slowly brought back to ambient temperature and hydrolyzed with 20 ml of water.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13]>ClCCl.[O-2].[Mn+2]>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCOc1cc(CO)ccc1I
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCCOc1cc(C=O)ccc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
The (4-iodo-3-propoxyphenyl)methanol is dissolved in 30 mL of dichloromethane and 3.9 g (45 mmol) of manganese oxide are added. The reaction medium is stirred for 12 hours at room temperature. After filtering off the solid through Celite, the filtrate is evaporated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 1.5 g (57% yield for the three steps a-c) of 4-iodo-3-propoxybenzaldehyde are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:23][O:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:29][CH:30]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.0629 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (29.6 mg, 0.126 mmol), palladium acetate (1.4 mg, 0.00630 mmol), S-Phos (5.2 mg, 0.0126 mmol) and potassium phosphate (26.7 mg, 0.126 mmol), dimethylformamide (1 ml) was added, followed by being degassed under ultrasonic irradiation. This was stirred at 100° C. for 3 hours, followed by extraction with ethyl acetate with the addition of water, and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, concentration was carried out under reduced pressure, followed by elution with 2M ammonia methanol solution through SCX resin and then concentration.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[O:8][C:7]([O:19]CC)([O:16][CH2:17][CH3:18])[C@H:6]1[CH3:22])(=[O:3])[CH3:2].O.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][CH:6]([CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9](=[O:8])[CH3:15])[C:7]([O:16][CH2:17][CH3:18])=[O:19]
Reactant: CCOC1(OCC)OC(C)=C(C(=O)OC)[C@@H](NC(C)=O)[C@@H]1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(NC(C)=O)C(C(C)=O)C(=O)OC
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a solution of methyl trans-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate (12.2 g) (Example 6) in 200 ml tetrahydrofuran was added 3.0 ml water and 1.0 ml 1N HCl. The mixture was stirred at 20°-25° C. for 16 hours, then neutralised by adding 1.0 g anhydrous potassium carbonate. The mixture was filtered and the filtrate evaporated at reduced pressure to give 11.4 g of crude product which was crystallised from toluene/hexane (50:50) giving ethyl 2-methyl-3-acetylamino-4-methoxycarbonyl-5-oxohexanoate (6.8 g), m.p. 93°-6° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:15]>CCO>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]2[C:14](=[O:15])[C:13]3[C:12](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=[C:6]2[C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([CH3:10])[CH:4]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: Cc1cc(C=O)ccc1O
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1O
Yield: 57.6 %

Procedure:
Anhydrous CuCl2 (0.306 g, 2.20 mmol) and 4-hydroxy-3-methylbenzaldehyde (0.155 g, 1.10 mmol) were added to a solution of 2-amino-N-(4-chlorophenyl)benzamide (0.280 g, 1.10 mmol) in anhydrous EtOH (10 mL). The mixture was heated at reflux temperature for 4 hours and concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 50% EtOAc in heptane, afforded 3-(4-chlorophenyl)-2-(4-hydroxy-3-methylphenyl)quinazolin-4(3H)-one (0.230 g, 57%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:40]=[CH:39][C:12]([O:13][CH2:14][C:15]3([CH3:38])[CH2:24][CH:23](O)[C:22]4[C:17](=[C:18]([CH3:37])[C:19]([CH3:36])=[C:20]([O:27][CH2:28][C:29]([O:31][CH2:32]COC)=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:11][CH:10]=2)[S:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3([CH3:38])[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([CH3:37])[C:19]([CH3:36])=[C:20]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:39][CH:40]=2)[S:3]1
Reactant: COCCOC(=O)COc1c(C)c(C)c2c(c1C)C(O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: COC(=O)COc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 970 mg of 2-methoxyethyl α-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]4-hydroxy-2,5,7,8-tetramethylchroman-6-yloxy}acetate (prepared as described in Example 37), 50 mg of p-toluenesulfonic acid, 10 ml of benzene and 1 ml of dioxane was heated under reflux in a nitrogen stream for 60 minutes. The reaction mixture was then washed with a 5% w/v aqueous solution of sodium bicarbonate and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with a 7:3 by volume mixture of benzene and ethyl acetate), to give the title compound.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.C1(C)C=CC=CC=1>[C:19]1([O:18][C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C1Nc2cccnc2N(C(=O)Oc2ccccc2)c2ccccc21

Procedure:
From 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and phenyl chlorocarbonate in a mixture of dioxan and toluene, 5,11-dihydro-11-phenyloxycarbonyl-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.[CH:35](OC)(OC)OC.CC(O)=O.C=O>CO.CCOC(C)=O.C1COCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][N:14]3[CH3:35])[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Reactant: COC(OC)OC
Agent: C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(13 mg, 0.027 mmol) was taken up in MeOH (0.5 mL) and THF (0.5 mL) and trimethyl orthoformate (0.225 mL, 2.036 mmol), AcOH (6.22 μl, 0.109 mmol), and formaldehyde (2.492 μl, 0.027 mmol) were added. The reaction was stirred at 25° C. for 5 min, then NaCNBH4 (0.271 mL, 0.271 mmol) was added and the reaction stirred at 25° C. 1 hr. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, then brine. The organic layer was dried over Na2SO4, and concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 50-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-methylhexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=1)[CH2:7][CH2:6]2.[H][H].[ClH:25]>C(O)C.O.[Pd]>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=1)[CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)N(c1ccc([N+](=O)[O-])cn1)CC2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)N(c1ccc(N)cn1)CC2
Yield: 70.8 %

Procedure:
5,6-Dimethoxy-1-(5-nitro-(2-pyridyl))-indoline was hyrogenated overnight with Pd (5%) on carbon in ethanol/water (8:2) in a shaking “duck”. When the uptake of hydrogen had come to an end, 10% hydrochloric acid was added, the catalyst was filtered off and the remainder was concentrated to dryness. The residue was recrystallized with ethanol and active carbon. The product 6-(5,6-dimethoxyindolin-1-yl)-3-pyridylamine hydrochloride was obtained in a yield of 70.8% (melting point: 168-171° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH2:17]([OH:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:30][C:7]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: OCCCCCCCCCCCCO
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OCCCCCCCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,12-dodecanediol under conditions shown in Table 19, ethyl N-{2-(12-hydroxydodecyloxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 9.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CI.[CH2:16](N(CC)CC)C>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][CH3:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)N1CCc2cc(S)ccc21
Solvent: ClCCl
Solvent: CI
Product: CSc1ccc2c(c1)CCN2C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
A mixture of 1-acetyl-5-mercaptoindoline (D3) (0.98 g, 5.07 mmol), methyl iodide (0.35 ml, 5.6 mmol) and triethylamine (0.78 ml, 5.6 mmol) in dichloromethane (25 ml) was stirred for 18 h at room temperature. The mixture was evaporated, and the residue was redissolved in dichloromethane and washed with dilute hydrochloric acid. The organic solution was dried and evaporated to give the title compound (0.98 g, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C1COCC1.[CH2:51](Br)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCN1[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccccc2)CCN1[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reaction time: 1 h

Procedure:
In 5 mL of THF, 145 mg (0.35 mmol) of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl)-pyrrolidin-2-one obtained in Example 47-1 was dissolved, and 2.84 mL (1.02 mmol) of 0.36 N LDA/THF solution was added at −78° C., followed by stirring the mixture for 1 hour. Thereafter, 0.10 mL (0.87 mmol) of benzyl bromide was added thereto and the resulting mixture was stirred for 3 hours. To this reaction solution, aqueous saturated sodium hydrogen carbonate solution was added and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl)-3-benzyl-pyrrolidin-2-one as a crude product.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[BH4-].[Na+].Cl>O1CCCC1>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(CC(C#N)C#N)no1
Reaction time: 8 h
Yield: 53.8 %

Procedure:
9.91 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 100 ml of tetrahydrofuran, and 3.78 g of sodium borohydride was then added under ice-cooling. The mixture was stirred for 8 hours under ice-cooling. The reaction mixture was added to 0.5 N hydrochloric acid over 30 minutes and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.38 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methyl}malononitrile.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CN(C)C=O.CS([Cl:20])(=O)=O.[OH-].[Na+]>O>[Cl:20][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccnc2[nH]ccc12
Temperature: 73 °C
Yield: 135.4 %

Procedure:
To a 50° C. pink solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (2.47 g, 0.0184 mol) in N,N-dimethylformamide (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052 mol). The pink color changed to orange. The mixture was heated to 73° C. for 2 h, and cooled to 40° C. Then 35 mL of water was added and the resulting suspension was cooled to 0° C. NaOH was added to adjust the pH of the mixture to ˜7. The mixture was filtered and washed with water (×3) to give 3.8 g of wet pale orange solid that was dried at 40° C. overnight to give 2.35 g (82.2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.BrC1C=CC=C2C=1C(C#N)=[CH:15][NH:16]2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]#[N:16]
Reactant: N#Cc1c[nH]c2cccc(Br)c12
Reactant: Brc1ccc2[nH]ccc2c1
Product: N#Cc1c[nH]c2ccc(Br)cc12
Yield: 66 %

Procedure:
5-Bromo-1H-indole-3-carbonitrile LXII (3.72 g, 66% yield) was prepared from 5-bromo-indole using the procedure described for 4-bromo-1H-indole-3-carbonitrile LVII (see Example 14).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:1](=[O:2])([O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Cl
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In a planar-section pot with flow-spoilers, a blower/stirrer and reflux condenser, 0.75 mol/h of phosgene was continuously bubbled into 141 g (1.50 mol) of phenol in the presence of 14.1 g (10 wt. % with reference to phenol) of a powdered aluminium oxide 507-C-I (neutral) from CAMAG. After about 2 h reaction time, the phenol conversion was 41%, wherein 66 g of diphenyl carbonate were formed. The selectivity to give carbonate was >99%.