Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8]/[C:9](/[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:35][CH2:34][CH2:33][C@@H:26]2[C:27]([NH:29][CH:30]2[CH2:32][CH2:31]2)=[O:28])=[CH:21][CH:20]=1)=[N:10]/C(OC(C)(C)C)=O)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[CH:30]1([NH:29][C:27]([C@H:26]2[CH2:33][CH2:34][CH2:35][N:25]2[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:9]([NH2:10])=[NH:8])=[CH:24][CH:23]=2)=[O:28])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To 1-[4-({(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]-N-cyclopropyl-D-prolinamide (Method 62; 2.0 g) was added DCM (60 ml) and TFA (20 ml). The reaction stirred for 4 hours before removal of the solvent in vacuo. To the gum was added DCM (75 ml) and macroporous polystyrene carbonate resin (0.49 g of capacity 3.0 m.equ per g) solid supported reagent (20 g), the reaction was slowly stirred overnight. The reaction was filtered and the solvent removed in vacuo to yield very little product. A white solid was present in the filter cup, this was dissolved in MeOH, the resin was also added to the MeOH, the system was stirred for 10 minutes before being filtered, the solvent was removed in vacuo to yield the title compound as a white solid (0.90 g, 75%). NMR (299.954 MHz, CDCl3) δ 7.26 (s, 3H), 6.85 (d, 2H), 6.49 (d, 2H), 3.93 (d, 1H), 3.62-3.60 (m, 1H), 3.17 (q, 1H), 2.70-2.62 (m, 1H), 2.32-2.14 (m, 2H), 2.00-1.92 (m, 2H), 0.76-0.63 (m, 2H), 0.42 (q, 2H); m/z 287.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)=[N:5][CH2:4][C:3]1=[O:28]>CO.C(Cl)Cl.[Pd]>[NH2:25][C:21]1[CH:20]=[C:19]([C:6]2[C:7]3[CH:12]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3](=[O:28])[CH2:4][N:5]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CN1C(=O)CN=C(c2cccc([N+](=O)[O-])c2)c2cc(-c3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN1C(=O)CN=C(c2cccc(N)c2)c2cc(-c3ccccc3)ccc21
Yield: 16 %

Procedure:
1-Methyl-5-(3-nitro-phenyl)-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one Example 65 (40 mg, 0.11 mmole)was dissolved in Methanol/CH2Cl2 then Pd/C (10 mg) was added and the flask was stirred over hydrogene atmosphere. The solution was filtered over celite, and the solvent was evaporated. The crude material was chromatographied: eluant: AcOEt/Hexane: 1/1. The title compound (6 mg) was obtained as a beige solid, (yield=16%).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]2[CH2:7][O:8][C:9]3[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]([N:22]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:18][CH:19]([CH3:21])[CH3:20])[CH:12]=[CH:13][C:14]=3[C:2]=12.NN>C(O)C>[CH:1]1[CH:6]=[N:5][CH:4]=[C:3]2[CH2:7][O:8][C:9]3[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]([NH2:22])[CH2:18][CH:19]([CH3:20])[CH3:21])[CH:12]=[CH:13][C:14]=3[C:2]=12
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OCc1cnccc1-2)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OCc1cnccc1-2
Temperature: 45 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To the solution of (S)-2-(1-((5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (1.47 g, 3.43 mmol) in ethanol (8 mL) under a nitrogen atmosphere was added hydrazine (0.754 mL, 24.02 mmol) at rt and the reaction mixture was then stirred at 45° C. in an oil bath for 3 h. A white precipitate formed during the course of the reaction. The reaction mixture was quenched by addition of water (15 mL) and the product was extracted with ethyl acetate (3×25 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC on a reverse phase C-18 column using 10 mM ammonium acetate buffer and acetonitrile gradient. The fractions were concentrated under reduced pressure and lyophilized to yield (S)-1-((5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (0.4 g, 0.970 mmol, 39% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=5.6 Hz, 1H), 8.37 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.70 (d, J=5.2 Hz, 1H), 6.83 (dd, J=8.4, 2.4, 1H), 6.70 (d, J=2.4 Hz, 1H), 5.20 (s, 2H), 4.28 (dd, J=11.2, 3.6, 1H), 4.10 (dd, J=10.4, 6.4, 1H), 3.66 (m, 1H), 1.82 (m, 1H), 1.69-1.63 (m, 2H), 1.04 (m, 6H); LCMS (ESI) m/e 299.2 [(M+H)+, calcd for C18H22N2O2 299.38]; LC/MS retention time (Method E): tR=1.78 min. HPLC retention time (method A): tR=7.97 min; CHIRAL HPLC retention time (method C): tR=12.87 min; optical rotation: [α]20D (MeOH)=+7.1°.
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[CH:5]=[C:6]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:8]1([CH2:10][CH2:9]1)[C:7]2([C:23]([F:30])([F:29])[C:24](OCC)=[O:25])[NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18].O>C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[CH:5]=[C:6]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:8]1([CH2:10][CH2:9]1)[C:7]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:23]([F:29])([F:30])[CH2:24][OH:25]
Reactant: CCOC(=O)C(F)(F)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2OCC12CC2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2
Reaction time: 0.25 h

Procedure:
Under ice cooling, to a solution of LiBH4 (458 mg, 21.0 mmol) in THF (30 mL) was added a solution of ethyl {6-bromo-4-[(tert-butylsulfinyl)amino]-4H-spiro[chromene-3,1′-cyclopropan]-4-yl}(difluoro)acetate (5.05 g, 10.5 mmol) in THF (20 mL), and the mixture was stirred for 15 minutes at same temperature and stirred for 2 hours at room temperature. After adding H2O and brine, the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to obtain crude N-[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H-spiro[chromene-3,1′-cyclopropan]-4-yl]-2-methylpropane-2-sulfinamide. The desired compound (4.6 g) was applied to the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH2:12](O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O>[C:1]1([C:7](=[CH2:12])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: N#CCc1ccccc1
Agent: C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Product: C=C(C#N)c1ccccc1

Procedure:
Phenylacetonitrile (117 g, 1.0 mol), 37% formaldehyde solution 85 g, 1.0 mole of formaldehyde), ethanol (100 ml), and 40% benzyltrimethylammonium hydroxide (Triton B) (2 ml) were mixed in a 500 ml 3-necked round-bottomed glass flask equipped with a magnetic stirrer, water-cooled condenser and thermometer. A static atmosphere of argon was maintained throughout the course of the reaction. The reaction mixture was mixed and heated to reflux temperature whereupon the heat of reaction was sufficient to maintain the reaction without external heating. After ten minutes the mixture had formed two layers. It was cooled and the top layer containing mostly alcohol and water was separated. The lower viscous yellow layer was dissolved in acetone and charged to a distillation flask together with 0.1 g hydroquinone. Distillation under reduced pressure yielded 30 g of a water-white distillate boiling at 95°-100°/1.0 mm Hg (23 percent of theory). 1H NMR: (CDCl3, TMS), δ7.0 (S, 5H), 6.1, 5.85 (s, s, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].C[Si]([C:19]#[CH:20])(C)C.C([O-])([O-])=O.[K+].[K+]>C(N(CC)CC)C.CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:19]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])#[CH:20]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H) -one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium (II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of trimethylsilyl acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through Celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(2-trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([NH2:17])=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]#[N:17])[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C(N)=O)cc2C)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C#N)cc2C)cc1
Reaction time: 0.5 h

Procedure:
To a mechanically stirred solution of 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxamide (Step 1, 200 mg, 0.872 mmol) and N,N-diisopropylethylamine (760 μL, 4.36 mmol) in dichloromethane (10 mL) was added dropwise trifluoromethanesulfonic acid anhydride (266 μL, 1.57 mmol) at 0° C. After stirring for 30 minutes at this temperature, all volatiles were removed in vacuo. Then, in a first purification step, the crude product was subjected to preparative HPLC, followed by a second purification using MPLC (silica, dichloromethane) to afford the title compound in pure form (140 mg, 76%): 1H NMR (400 MHz, CDCl3) δ 7.13 (d, 2H), 7.02 (d, 2H), 6.43 (s, 1H), 5.27 (s, 2H), 2.33 (s, 3H), 2.21 (s, 3H); ES-MS m/z 211 (M)+; HPLC RT (Method J) 4.54 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH3:20])[CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:8]([CH3:10])[CH3:9])=[C:14]([CH2:19][CH3:20])[CH:13]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OC(C)C
Temperature: 60 °C
Yield: 74 %

Procedure:
Potassium carbonate (3.1 g, 22.4 mmol) followed by 2-iodopropane (0.75 mL, 7.5 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.5 g, 7.5 mmol) in DMF (10 mL). The mixture was heated at 60° C. for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (hexanes) to give the desired product (1.35 g, 75%). 1H NMR (400 MHz, CDCl3): δ 1.16 (t, J=7.6 Hz, 3 H), 1.32 (d, J=6.1 Hz, 6 H), 2.58 (q, J=7.6 Hz, 2 H), 4.49 (m, 1 H), 6.70 (d, J=8.6 Hz, 1 H), 7.23 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[F:1])[CH2:10][N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
2-Fluoro-5-formylbenzonitrile (25 g, 167.6 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (450 mL) at RT. To this solution was added tert-butyl piperazine-1-carboxylate (31.2 g, 167.6 mmol, 1 equiv.) followed by the portion-wise addition of sodium triacetoxyborohydride (49.7 g, 234.6 mmol, 1.4 equiv.). The reaction vessel was placed under an atmosphere of nitrogen and allowed to stir at room temperature for 1 hour. Saturated NaHCO3 was added and the resultant mixture stirred for 10 minutes. The mixture was concentrated under reduced pressure, diluted with EtOAc (700 mL), and extracted into IN KHSO4 (3×150 mL). The aqueous layer was basified to pH 10 using 50% NaOH solution, saturated with NaCl, extracted into DCM (2×100 mL) and EtOAc (1×200 mL), and dried over Na2SO4. Concentration in vacuo resulted in the isolation of 10.2 g of tert-butyl 4-(3-cyano-4-fluorobenzyl)piperazine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:14])[C:6]2=[O:13].[BH4-].[Na+].Cl.Br[C:19]1C=CC(OC)=C2C=1CC(C)C2O.[OH-].[K+].CI>C1COCC1.O.CS(C)=O.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:14])[CH:6]2[O:13][CH3:19]
Reactant: COc1ccc(Br)c2c1C(O)C(C)C2
Reactant: COc1ccc(Br)c2c1C(=O)C(C)C2
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Br)c2c1C(OC)C(C)C2
Reaction time: 4 h

Procedure:
To a mixture of 104 g (0.407 mmol) of 4-bromo-7-methoxy-2-methylindan-1-one and 15.0 g (0.397 mmol) of NaBH4 in a mixture of 410 ml of THF 205 ml of methanol was added dropwise with vigorous stirring for 4 h at +5° C. This mixture was stirred overnight at room temperature and then added to 1 liter of cold water. The resulting mixture was carefully acidified by 2 M HCl to pH 5.0, and the formed indan-1-ol was extracted with 500 ml of dichloromethane. The aqueous layer was additionally extracted with 2×200 ml of dichloromethane. The combined organic extract was evaporated to dryness. To the resulting yellowish liquid of the crude 4-bromo-7-methoxy-2-methylindan-1-ol 800 ml of DMSO, 92.0 g (1.64 mol, 4.0 eq) of KOH, and 116 g (0.817 mol, 2.0 eq) of MeI were added. This mixture was stirred for 3 h at ambient temperature and then added to 3 L of cold water. The crude product was extracted with dichloromethane (500 ml, then 3×250 ml). The combined organic extract was washed 5 times by 1 liter of water and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 μm; eluent: hexanes-dichloromethane=2:1, then 1:2 and, finally, 1:5, vol.) followed by rectification in vacuum, 149-154° C./8 mm Hg. Yield 96.0 g (87%) of a ca. 1 to 2 mixture of two diastereomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@@H:31]([CH2:33][C:34](=[O:52])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:32][C:21]=2[CH:20]=1>>[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@H:31]([CH2:33][C:34]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[C:8](=[O:17])[NH:9][C:10]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][N:11]=5)[CH2:5][CH2:6]3)=[O:52])[CH2:32][C:21]=2[CH:20]=1
Reactant: O=c1[nH]c2ncccc2cc1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccnc4[nH]c3=O)CC2)C1=O
Yield: 64 %

Procedure:
3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one (57 mg, 0.19 mmol) and [4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (60 mg, 0.16 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 64% yield. High resolution MS m/e (M+H)+=575.2538.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[CH2:21](O)[CH2:22][CH3:23].S(=O)(=O)(O)O>CCOCC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][C:3]1=2
Reactant: CCCO
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
A mixture of 7.0 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, Example 2, 175 ml of n-propanol, and 4.6 ml of concentrated sulfuric acid is refluxed for 17 hours. The reaction mixture is permitted to cool and the solvent removed leaving an oil. The oil is dissolved in ether and washed successively with water, a 5% sodium hydroxide solution and water and dried and the ether removed to give a yellow oil which crystallizes upon standing. The solid is dried on a porous plate resulting in an off-white solid, mp 30°-32° C, of n-propyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate.
Reaction SMILES: [N-]=[C:2]=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)O[C:15](=O)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:15]1([C:14]2([CH:2]=[O:3])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CC1(c2ccccc2)CCCCC1
Reaction time: 2 h
Yield: 150.3 %

Procedure:
To compound 2 (5.0 g, 26.3 mmol) in CH2Cl2 (50 mL) was added 13.4 g (31.6 mmol) of Dess-Martin periodinane. After 2 h, sodium thiosulfate (58 g) followed by sat. NaHCO3 (200 mL) was added. After stirring for 1 h, the reaction mixture was diluted with EtOAc then washed with H2O, brine and dried over anhydrous sodium sulfate. Purification by flash chromatography (3:1, hexane-EtOAc) gave 1-phenyl-cyclohexanecarbaldehyde (4.47 g, 90%) as a colorless oil. Mass Spec [M+H]+=189.1.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)([OH:3])=[O:2].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CN(C1C=CC=CN=1)C>ClCCl>[CH2:30]([O:2][C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCCCCO
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reaction time: 48 h

Procedure:
A mixture of 4-carboxy-2-nitroaniline (0.52g), heptadecanol (0.7 g) and dimethylaminopyridine (20 mg) in dichloromethane (20 ml) was prepared and dicyclohexyldicarbodiimide (0.62 g) was added. The mixture was stirred for 48 hours and filtered. After separating between chloroform and 3% caustic soda solution the organic phase was washed with water, dried with magnesium sulphate and the solvent removed to leave a yellow solid. The solid was purified by chromatography to give a yellow solid which was recrystallised from 50:50 chloroform-hexane (yield: 0.85 g, m.p. 103°-105° C).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8]2)[CH2:6][CH2:7]1
Reactant: Fc1ccccc1
Reactant: CN1CCC2(CC1)CNc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC2(CC1)CN(c1ccccc1)c1ccccc12
Reaction time: 45 h

Procedure:
A mixture of 2.1 g of 1'-methylspiro[indoline-3,4'-piperidine] (Example 1b), 3 g of 50% sodium hydride and 12 ml of fluorobenzene in 18 ml of dimethyl sulfoxide is stirred at 65°-70° C. for 45 hours. The well stirred mixture is poured into water and extracted thrice with ether. The combined ether extracts are dried briefly before forming, the hydrochloride salt. The salt is collected, basified and then extracted into ether, giving a yellowish oil which is crystallized from hexane, producing off-white crystals, mp 90°-92° C. of 1'-methyl-1-phenylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH3:26])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].BrCC1C=C[C:34]2C3SC(C(N(C4C=CC=CC=4Cl)C)=O)=CC=3C[CH2:37][O:36][C:35]=2C=1.N1CCOCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:34][CH2:35][O:36][CH2:37][CH2:26]4)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Solvent: C1COCCN1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(CN3CCOCC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure in Example 153 for the synthesis of 243, 8-(bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with morpholine to give 261. MS: (ESI+) 469.0
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:12][CH2:13][CH3:14])=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:11][C:10]1[O:9][N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[C:6]=1[CH2:4][OH:3]
Reactant: CCCc1noc(C)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1noc(C)c1CO
Yield: 80.1 %

Procedure:
To a stirred solution of 5-methyl-3-propyl-isoxazole-4-carboxylic acid ethyl ester (13.8 g, 70 mmol) in THF (140 mL) under argon and at 0° C. was added lithium aluminium hydride (3.05 g, 80 mmol) in five portions. After 90 min the reaction mixture was quenched dropwise with Seignette salt solution. The reaction mixture was filtered and the filtrate extracted with ethyl acetate. The combined organic extracts were washed with Seignette salt solution then dried over sodium sulfate, filtered, concentrated and purified by chromatography (silica, 0 to 60% ethyl acetate in heptane) to give the title compound (8.7 g, 80%) as a yellow liquid. MS: m/e=232.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[CH:11]=[C:10]([CH3:24])[N:9]=1)=[O:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[C:12]1[CH:11]=[C:10]([CH3:24])[N:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][OH:3])[CH:13]=1
Reactant: CCOC(=O)C(=O)Nc1cc(N2CCc3ccccc3C2)cc(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(N2CCc3ccccc3C2)cc(NC(=O)CO)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-pyridin-2-yl]-oxalamic acid ethyl ester (example 33) (0.43 g, 1.3 mmol) in THF (20 ml) was cooled in an ice bath and lithium aluminum hydride (0.12 g, 3.2 mmol) was added in. The mixture was stirred at rt for 2 hr, quenched with saturated aqueous Seignette-salt solution and filtered. The organic phase was dried (Na2SO4) and concentrated. After chromatograpy (SiO2 with CH2Cl/CH3OH/NH4OH=200/10/1) the title compound was obtained as a colorless oil (0.18 g, 47%). Mp. 160-162° C. (AcOEt), MS: m/e=296(M−H−).