Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].II.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:13][CH3:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)CCCc1ccc(Cl)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCCCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
At 0° C., a solution of of 4-(4-chlorophenyl)-N-methylbutyramide (3.80 g, 18.0 mmol) in tetrahydrofuran (60 ml) was added to a suspension of sodium borohydride (1.60 g, 43.1 mmol) in THF (60 ml). The mixture was stirred for 20 min at 0° C. A solution of iodine (4.6 g, 18.0 mmol) in THF (100 ml) was added dropwise. After the addition was finished, the reaction mixture was warmed to 70° C. It was stirred for 16 hours at this temperature. It was cooled to 0° C. Methanol (100 ml) was added dropwise. The solvents were removed in vacuo. The residue was dissolved in a 20% aqueous solution of sodium hydroxide (160 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×70 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using DCM/methanol/25% aqueous ammonia as eluent, to give 820 mg of N-[4-(4-chlorophenyl)butyl]-N-methylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([N:15]3CCCC(O)C3)=[O:14])[N:12]=2)=[C:4]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.N1CCCC(O)[CH2:27]1.[Cl-].[NH4+]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:27])=[C:11]([C:13]([NH2:15])=[O:14])[N:12]=2)=[C:4]([NH:22][CH:23]([CH3:24])[CH3:25])[CH:3]=1
Reactant: OC1CCCNC1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1sc(-c2cnc(Cl)cc2NC(C)C)nc1C(N)=O

Procedure:
Followed the same procedure as mentioned in the synthesis of compound no. 24a, instead of piperidin-3-ol, ammonium chloride was used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]1=[O:24].[H-].[Na+].I[CH3:28]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([N:16]([CH3:28])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]1=[O:24]
Reactant: CI
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCCC[C@H](N(C)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
THF (0.8 mL) was added to a reaction vessel containing (S)-tert-butyl 1-(2-methoxyphenyl)-2-oxoazepan-3-ylcarbamate (53 mg, 0.16 mmol). NaH (60% dispersion in oil, 25.4 mg, 0.634 mmol) was then added to the reaction mixture followed by iodomethane (180 mg, 1.27 mmol). The turbid mixture was left to stir at rt for 2 hr. The reaction was quenched by addition of water. The mixture was concentrated to remove some of the THF. The mixture was then partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give (S)-tert-butyl 1-(2-methoxyphenyl)-2-oxoazepan-3-yl(methyl)carbamate (52 mg, 0.15 mmol, 94% yield) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1>C(Cl)(Cl)Cl.CO.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1)=[O:1]
Reactant: CCOC(=O)Nc1nc(CO)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)Nc1nc(C=O)cs1
Reaction time: 2 h
Yield: 106.4 %

Procedure:
To a mixed solution of ethyl 4-(hydroxymethyl)-1,3-thiazol-2-ylcarbamate (446 mg) in chloroform (30 ml) and methanol (3 ml) was added portionwise manganese (IV) oxide chemicals treated (1.92 g) at room temperature. After the mixture was stirred at the same temperature for 2 hours, then treated manganese (IV) oxide chemicals (250 mg) was added again to the solution, and it was stirred at 50° C. for 3 hours. Manganese (IV) oxide was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless powder (470 mg, 106.4%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([Cl:14])[CH:6]=1)=[N+:2]=[N-:3].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][N:16]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])=[O:10])=[C:7]([Cl:14])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(C(=O)O)c(Cl)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Yield: 97 %

Procedure:
A solution of 4-(azidomethyl)-2-chlorobenzoic acid (6.82 g, 32.2 mmol), N-hydroxysuccinimide (5.19 g, 45.1 mmol) and dicyclohexylcarbodiimide (9.31 g, 45.1 mmol) in tetrahydrofuran (250 mL) was stirred overnight at room temperature. The dicyclohexylurea (7.70 g, 76%) was filtered off and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (40-60% ethyl acetate/hexanes) to give 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (9.64 g, 97%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:5][CH:6]=[C:7]([CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)=[O:9])#[N:2].OS([O-])=O.[Na+].[CH2:34](N)[CH2:35][NH2:36].[NH4+]>CCOC(C)=O>[NH:2]1[CH2:34][CH2:35][N:36]=[C:1]1[C:3]1[C:4]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:5][CH:6]=[C:7]([CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=1)=[O:9]
Reactant: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Reactant: NCCN
Agent: O=S([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(C2=NCCN2)c1
Temperature: 100 °C

Procedure:
A stirred mixture of (R)-5-cyano-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 70.2, 1 g, 2.55 mmol), NaHSO3 (0.953 g, 15.3 mmol) and ethylenediamine (7.66 g, 1.27 mmol) was treated dropwise with 40% aq. ammonium silfide (4.34 mL, 25.5 mmol) and heated at 100° C. for 18 h. The cooled mixture was treated with EtOAc, washed with sat. aq. NaHCO3 and brine, was dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/(5% aq. NH3 in MeOH) from 0 to 40% (5% aq. NH3 in MeOH)) to afford the product as a pale-yellow solid. HPLC (Condition 4) tR=3.89 min, UPLC-MS (Condition 8) tR=0.72 min, m/z=436.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.98 (m, 3H) 3.40-3.75 (m, 8H) 4.30 (br. s, 1H) 4.91 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.78-7.91 (m, 2H) 8.06 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]2[CH2:9][C:6]([CH3:10])([CH2:7][CH:8]=1)[CH2:5][CH2:4]2.C(OO)(=[O:13])C.C([O-])(=O)C.[Na+]>>[CH3:1][C:2]12[O:13][CH:8]1[CH2:7][C:6]1([CH3:10])[CH2:9][CH:3]2[CH2:4][CH2:5]1
Reactant: CC1=CCC2(C)CCC1C2
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC12CCC(C1)C1(C)OC1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
2,5-Dimethyl-bicyclo[3.2.1]oct-2-ene (800 g, 5.88 mol, obtained as above in EXAMPLE I) was fed into a solution of peracetic acid (CH3CO3H, 32%, 1.466 Kg, 6.18 mol) and sodium acetate (CH3CO2Na, 72 g, 0.882 mol), and cooled to 0° C. The reaction mixture was aged for 6 hours, and subsequently quenched with water and toluene. The reaction mixture was shaken and split. The organic layer was first washed with a solution of sodium carbonate (Na2CO3), and then with a solution of sodium sulfite (Na2SO3). Fractional distillation of the organic layer provided 2,6-dimethyl-3-oxa-tricyclo[4.2.1.0*2,4*]nonane (734 g) having a boiling point of 31° C. at a pressure of 18 mmHg
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH2:22][CH3:23])[C:12]2[C:11](=[O:24])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:25])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32].CO>ClCCl>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH2:22][CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:24][CH2:31][CH3:32])[NH:6][C:5]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: CCc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cc[nH]c(=O)c21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1CC)C(C(C)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
275 mg (0.82 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-ethylbenzonitrile are suspended under an argon atmosphere in dichloromethane (10 ml), 313 mg (1.65 mmol) of triethyloxonium tetrafluoroborate are added, and the mixture is stirred at RT for 12 h. The reaction mixture is then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 152 mg (50% of theory) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[N:25]1(C(OC(C)(C)C)=O)[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][NH:32][CH2:33][C@@H:26]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:16])[N:32]3[CH2:31][C@H:27]4[C@H:26]([NH:25][CH2:30][CH2:29][CH2:28]4)[CH2:33]3)[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1C[C@@H]2CCCN[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D) (0.331 g, 1 mmol) and (4aS,7aS)-tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (Example 50B) (0.226 g, 1 mmol) in methylene chloride (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.38 g, 1 mmol) and diisopropylethylamine (0.45 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel chromatography eluting with ethyl acetate to yield the t-butoxycarbonyl-protected title compound. That material was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2 mL) for 1 hour at room temperature. The reaction mixture was concentrated and partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic layer was separated, dried over MgSO4 and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.35 (m, 4H), 7.00 (m, 4H), 4.25 (dd, 1H), 3.96 (t, J=16.78 Hz, 1H), 3.47 (m, 7H), 3.00 (m, 1H), 2.78 (m, 2H), 2.63 (m, 1H), 2.27 (m, 1H), 1.72 (m, 2H) 1.45 (m, 2H); MS (ESI+) m/z 440 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][C:33]=1[OH:34]>ClCCl.O>[OH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:32]=1[NH:31][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: Nc1c(O)cccc1O
Reactant: COc1ccc(CC(=O)O)cc1OC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC(=O)Nc2c(O)cccc2O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A suspension of 3-cyclopentyloxy-4-methoxyphenylacetic acid (2.49 g) and 1,1'-carbonyldiimidazole (2.31 g) in dichloromethane (10 ml) was stirred at room temperature, under argon, for 2 hours. The resulting solution was added to a stirred suspension of 2-aminoresorcinol (1.62 g) in dichloromethane (15 ml) and the mixture stirred at room temperature, under argon, overnight. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (100 ml), 1N HCl (100 ml) and brine (100 ml), dried over CaSO4 and evaporated in-vacuo to yield the title compound (2.122 g, 60%) as a beige solid. δH (250MHz;d6DMSO) 1.53-1.95 (SH,m,4×CH2), 3.65 (2H, s,CH2), 3.70 (3H,s,OMe), 4.75 (1H,m, CH), 6.3 (1H,s,ArH), 6.35 (1H,s,ArH), 6.90 (4H,m,ArH), 9.40 (2H,s,ArOH), 9.6 (1H,s,CONH).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].[CH3:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([S:2]([C:5]2[CH:6]=[C:7]([CH2:8][OH:10])[CH:11]=[CH:12][CH:13]=2)(=[O:3])=[O:4])[CH2:17][CH2:16]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC1CCNCC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(S(=O)(=O)c2cccc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11 g (50 mmol) of 3-chlorosulphonylbenzoic acid in suspension in dichloromethane (300 ml) is treated with 12.4 g (125 mmol) of 4-methylpiperidine and the reaction mixture is maintained under stirring at ambient temperature overnight. The resulting solution is washed successively with a 10% aqueous solution of citric acid and a saturated solution of sodium chloride, followed by drying (Na2SO4) and concentrating under reduced pressure in order to produce a colourless viscous residue. The latter is taken up in methanol and, whilst maintaining the temperature between 0° C. and 10° C., is titrated by trimethylsilyldiazomethane until a characteristic yellow coloration persists. The excess reagent is destroyed with a few drops of formic acid, and the reaction medium is concentrated under reduced pressure. The traces of acid and methanol are eliminated by two azeotropic evaporations under reduced pressure with toluene. The residue, taken up in tetrahydrofuran (300 ml), is treated with lithium borohydride (2N in THF, 30 ml). The reaction medium is taken to reflux for 2 hours then cooled down and hydrolyzed with a saturated solution of ammonium chloride. The resulting mixture is extracted with ethyl acetate then the organic phase is washed with a saturated solution of sodium chloride, followed by drying (Na2SO4) and concentrating under reduced pressure. The residue is purified on a silica column (eluent: 5% acetone in dichloromethane) in order to produce the expected benzyl alcohol in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][N:11]([CH:17]([CH3:21])[C:18](O)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][N:11]([CH:17]([CH3:21])[C:18]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCOc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CCOc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
89 mg (purity 86%, 0.22 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 47 mg (0.24 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 32 mg (purity 89%, 25% of theory)
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11]1
Reactant: CC/C=C/C(=O)OC
Reactant: C1COCCN1
Product: CCC(CC(=O)OC)N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 171 g of methyl 2-trans-pentenoate and 130.5 g of morpholine was heated for 46 hours at 100° C. After distillation of the reaction mixture over a Vigreux column, 179 g (59% of theory) of methyl 3-morpholinovalerate of boiling point 85° C./0.4 mbar, nD20 =1.4610, were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]=2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(C2=CCNCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Dissolve tert-butyl 4-(3-nitro-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.81 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (3 mL), stir at room temperature overnight. Adjust pH=8 with saturated NaHCO3 solution, extract with ethyl acetate, wash the organic extract with water and brine sequentially, dry over anhydrous sodium sulfate. Concentrate under reduced pressure to provide yellow oil (220 mg, 100%) which is used directly in next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25][CH:26]([CH3:28])[CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CNCC(C)C
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1)CC(C)C
Yield: 41.9 %

Procedure:
1.3 g (3.6 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1.6 ml (8.9 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.69 g (42%) of 7-chloro-3-(5-diisobutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 158°-160°, which was converted into the hydrochloride of m.p. 125°-128°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1.[BH4-].[Na+]>C1COCC1.CO.Cl>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([OH:11])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 7-chloro-6-(4-ethoxybenzyl)-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzofuran-3(2H)-one (285 mg, 0.345 mmole) in THF/MeOH (9 mL/3 mL) was added NaBH4 (39.2 mg, 1.04 mmole) at 0° C. The resulting solution was stirred at 0° C. for 1 hr, diluted with 1N—HCl and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (260 mg, 91%) as a yellow gum.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.[CH2:22]([Li])CCC.CI>CCOCC>[CH3:17][Si:16]([CH3:19])([CH3:18])[C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:5](=[CH:4][C:3]([Si:2]([CH3:21])([CH3:20])[CH3:1])=[CH:15][CH:14]=3)[CH:6]([CH3:22])[C:7]=2[CH:8]=1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)c1ccc2c(c1)Cc1cc([Si](C)(C)C)ccc1-2
Solvent: CI
Solvent: CCOCC
Product: CC1c2cc([Si](C)(C)C)ccc2-c2ccc([Si](C)(C)C)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of 1.0 g of 2,7-bis(trimethylsilyl)fluorene in 15 mL of dry ether was added dropwise 2.8 mL of 1.3 M n-butyllithium at 0° C. The mixture was stirred at room temperature for 3 hours, cooled to 0° C., and treated with a solution of 0.25 mL of methyl iodide in 5 mL of dry ether over a period of 5 minutes. The mixture was stirred at room temperature for 8 hours and washed with 2% Na2S2O3 (10 mL) and water (2×10 mL). The pooled aqueous layer was extracted with ether (2×15 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated under reduced pressure to give 1.03 g (98.7%) of the crude 2,7-bis(trimethylsilyl)-9-methylfluorene as a yellow oil which was chromatographed on silica gel (230-400 mesh, 2×40-cm packed column) with an eluant consisting of Skelly B--dichloromethane (6:1) to give 0.78 g (74.7%) of the crude hydrocarbon as a colorless oil. Crystallization from 95% ethanol gave 0.69 g (66.1%) of the pure 2,7-bis(trimethyl-silyl)-9-methylfluorene as white needles, m.p. 107°-108.5° C.; 1H NMR (CDC13): δ 0.34 (s, 18H, SiMe3), 1.58 (d, 3H, CH3), 3.96 (q, 1H, CH), 7.40-7.90 (m, 6H, aryl).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].C(=O)(O)[O-].[Na+].[CH2:12]([S:16](Cl)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15].C(=O)=O>O.CO>[CH2:12]([S:16]([NH:1][NH:2][C:3]([NH:5][NH:6][S:16]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:18])=[O:17])=[O:4])(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NNC(=O)NN
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCS(=O)(=O)NNC(=O)NNS(=O)(=O)CCCC

Procedure:
A mixture of 11.25 g (0.125 mole) carbohydrazide, 25 g sodium bicarbonate, 200 ml methanol and 37 g (0.25 mole) 1-butanesulfonyl chloride was heated to 60° C until evolution of CO2 ceased. The mix was cooled and water was added to precipitate the product. The initial precipitate weighed 12 g (dry). This melted with decomposition at 195°-197° C.