Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH:20]=[CH2:21]>CO>[CH2:19]([N:22]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:18])[CH:11]=[C:12]1[CH:15]([F:16])[F:17])[CH:20]=[CH2:21]
Reactant: C=CCN
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Solvent: CO
Product: C=CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 5-benzyloxy-2-difluoromethyl-pyran-4-one (4.00 g, 15.8 mmol), allylamine (3.60 mL, 47.5 mmol) in methanol (40 mL) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, and the residual solid was dissolved in 10 mL of ethyl acetate, and again concentrated in vacuo. The solid was suspended in a mixture of ethyl acetate and ether, then collected by suction filtration and thoroughly washed with ether. The off-white solid was dried to constant weight in a vacuum oven at 40° C. to afford the title product (3.38 g, 73% yield). HPLC purity (peak area percent) is 98.9% at λ=278 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.35-7.43 (m, 5H, ArH), 7.16 (s, 1H), 6.79 (s, 1H), 6.48 (t, J=53.1 Hz, 1H, CF2H), 5.80-5.86 (m, 1H), 5.29 (d, J=10.4 Hz, 1H), 5.22 (s, 2H, OCH2), 5.10 (d, J=17.1 Hz, 1H), 4.58 (d, J=5.2 Hz, 2H); MS-ESI (m/z): 291.9 [M+1]+, 91.0.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[C:11]#[N:12].[OH-:20].[Na+].C1(C)C(C)=CC=CC=1>C(O)(=O)C.S(=O)(=O)(O)O.O>[N+:17]([C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:12][C:11](=[O:20])[C:10]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2Sc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
2-(2-Aminophenylthio)-5-nitrobenzonitrile (8.5 g, 25 mmol) was dissolved in a mixture of glacial acetic acid (80 ml), concentrated sulphuric acid (100 ml) and water (80 ml) and then heated under reflux for 6 hours. The cooled mixture was added to ice water (500 ml) and brought to pH 4 by addition of 10N aqueous sodium hydroxide. Extraction with dichloromethane followed by filtration, drying (sodium sulphate), and evaporation of the organic layer afforded a residue which was put into xylene (500 ml) and refluxed for 15 hours with azeotropic removal of water. On cooling a brown powder deposited which was filtered off and purified by chromatography on silica gel eluting with 1:1 v/v ethyl acetate-hexane. Recrystallisation from ethanol gave the product as a greyish powder (2.80 g, m/s M- =272).
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].II.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22].[Cl-].[NH4+]>C(OCC)C.C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Cc1ccsc1Br
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccsc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 21 °C
Yield: 88.5 %

Procedure:
Magnesium turnings (6.8 g, 0.27 mmol) are introduced into diethyl ether (30 ml), and, while stirring, a solution of 2-bromo-3-methyl-thiophene (50 g, 0.282 mol) in diethyl ether (100 ml) is added dropwise. The reaction can be initiated if necessary by adding iodine crystals. During the addition, the reaction mixture should boil gently. After the addition, the mixture was stirred at room temperature for 1 hour. A suspension of 5-chloroisatin (19 g, 0.105 mol) in THF (200 ml) was added to the Grignard solution while cooling slightly (temperature 18-24° C.) and the mixture was stirred at room temperature for 30 min. The reaction mixture was stirred into ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred with diethyl ether. The resulting precipitate was filtered off, washed with diethyl ether and dried. 26 g of the desired intermediate were obtained.
Reaction SMILES: CNC.[CH:4]([NH:7][C:8]([C:10]1([CH3:23])[C:15]2=[CH:16][CH:17]=[CH:18][N:14]2[C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=2[O:11]1)=O)([CH3:6])[CH3:5].O1C2C=CC=C[C:28]=2[N:27]([C:34](N)=O)[CH:26]=C1.Cl>>[CH3:26][N:27]([CH2:34][C:18]1[N:14]2[C:15]([C:10]([CH2:8][NH:7][CH:4]([CH3:6])[CH3:5])([CH3:23])[O:11][C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=32)=[CH:16][CH:17]=1)[CH3:28]
Reactant: CC(C)NC(=O)C1(C)Oc2ccccc2-n2cccc21
Reactant: NC(=O)N1C=COc2ccccc21
Agent: CNC
Agent: Cl
Product: CC(C)NCC1(C)Oc2ccccc2-n2c(CN(C)C)ccc21

Procedure:
Alternatively, the procedure of this Example is followed to prepare compounds of formula 3 in which R2 is CH2NR4R5 in which R4 and R5 are as defined herein and A is COOR6 or CONR4R5 in which R4, R5 or R6 are as defined herein. For example, by using dimethylamine (40% aqueous solution) as the base and N-isopropyl-4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-carboxamide, described in Example 15, 1-[(dimethylamino)methyl]-N-isopropyl-4-methyl-4H-pyrrolo-2,1-c][1,4]benzoxazine-4-carboxamide, nmr (CDCl3) δ 1.02 and 1.16 (2 xd, J = 7Hz, 6H), 1.75 (s, 3H), 2.70 (d, J = 4Hz, 6H), is obtained. [The corresponding hydrochloric acid addition salt of the latter compound has m.p. 125° - 127° C). Reduction of the latter compound according to the procedure of Example 42 yields 1-[(dimethylamino)-methyl]-4-[(isopropylamino)methyl]-4-methyl-4H-pyrrolo[2,1-c][1,4]-benzoxazine.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Mg]I>C(OCC)C.C1(C)C=CC=CC=1>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])[C:7]1=[O:8])[CH3:23]
Reactant: Clc1ccccc1[Mg]I
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (4 g, 9.09 mmol) in a mixture of diethyl ether (60 mL) and toluene (20 mL) was added dropwise a freshly prepared 0.67 N 2-chlorophenylmagnesium iodide in ether (15 mL, 10.1 mmol) over 20 min at room temperature. The mixture was stirred for 20 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were washed with sat. aqueous NaHCO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 100:1 to 50:1 chloroform/methanol to give the title compound (2.81 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][NH:21][CH3:22])[CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])O.[Na+]>O1CCCC1.ClCCl.CO>[CH3:40][O:39][C:37](=[O:38])[N:21]([CH2:20][C:16]1[CH:15]=[C:14]([C:13](=[O:23])[NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)[CH:19]=[CH:18][N:17]=1)[CH3:22]
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N(C)Cc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.4 %

Procedure:
A solution of N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (180 mg, 0.44 mmol) in tetrahydrofurane(15 ml) is subsequently treated with pyridine(52 μl, 0.65 mmol) and methyl chloroformate (43 μl, 0.57 mmol)and stirred at ambient temperature for 15 h. Additional pyridine (25 μl, 0.31 mmol) and methylchloroformate (20 μl, 0.26 mmol) are added and the mixture stirred for another hour. Saturated sodium hydrogen carbonate (15 ml) is added and the mixture extracted four times with ethyl acetate. The combined organic ohases are dried with magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2, eluent: dichloromethane/methanol 19:1) afforded the title compound as yellow crystals (115 mg, 56% yield). MS: m/e=472 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Reactant: C1COCCN1
Solvent: O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)cc1
Temperature: 110 °C

Procedure:
Using an analogous procedure to that described in Example 3, a mixture of N-[3-(4diethylaminomethylbenzamido)-4-methylphenyl]-2-chloropyridine-4-carboxamide (0.5 g) and morpholine (5 ml) was stirred and heated to 110° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 40° C. There was thus obtained the title compound (0.021 g); NMR Spectrum: (DMSOd6) 1.0 (t, 6H), 2.2 (s, 3H), 2.44-2.49 (m, 4H), 3.42-3.57 (m. 4H), 3.6 (s, 2H), 3.65-3.63 (m, 4H), 7.08 (d, 1H), 7.2-7.25 (m, 2H), 7.45 (d, 2H), 7.58 (d, 1H), 7.79 (s, 1H), 7.92 (d, 2H), 8.26 (d, 1H), 9.83 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H− 502.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH:3]=[CH:2]1.C(=O)=O.C(N(CC)CC)C.C12(Cl)CC3CC(CC(C3)C1)C2.[Li+].[Cl-].[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][C:31]1=[O:39]>C(O)CO.CN(C)C1C=CN=CC=1.C1COCC1>[CH:1]1([C:4]([N:32]2[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:30][C:31]2=[O:39])=[O:6])[CH:3]=[CH:2]1
Reactant: O=C(O)C1C=C1
Reactant: O=c1[nH]c2ccccc2o1
Agent: CN(C)c1ccncc1
Agent: ClC12CC3CC(CC(C3)C1)C2
Agent: O=C=O
Solvent: C1CCOC1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: O=C(C1C=C1)n1c(=O)oc2ccccc21
Reaction time: 1 h

Procedure:
A flame-dried 100 mL round bottomed flask containing 6 (84 mg, 1.0 mmol) and 20 mL of THF was chilled by a cold bath at −30° C. (dry ice/30% ethanol in ethylene glycol). The mixture was allowed to stir under nitrogen atmosphere. Distilled triethylamine (0.36 g, 0.50 mL, 3.5 mmol) and 1-adamantyl chloride (238 mg, 1.2 mmol) were added sequentially, and stirring at −30° C. was continued for one hour. LiCl (0.21 g, 5.0 mmol) was added. After five minutes, 2-benzoxazolinone (203 mg, 1.50 mmol), and 4-dimethylamino pyridine (13 mg, 0.10 mmol) were added. The whole reaction mixture was allowed to stir overnight at room temperature. The solvents were removed under reduced pressure, and the residue was partitioned between 20 mL of CH2Cl2, and 20 mL water. The aqueous layer was extracted twice with 20 mL portions of CH2Cl2, and the combined organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on silica gel. The eluent was 1:3:6 CH2Cl2:ethyl acetate:hexane. The yield of 27 was 161 mg (0.80 mmol, 80%). Compound 27 is a white solid.
Reaction SMILES: P([N:17]=[N+:18]=[N-:19])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.N12CCCN=C1CCCCC2.[Br:31][C:32]1[C:33]([O:40][CH3:41])=[C:34]([CH2:38]O)[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1>[N:17]([CH2:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([Br:31])[C:33]=1[O:40][CH3:41])=[N+:18]=[N-:19]
Reactant: COc1c(Br)cccc1CO
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1c(Br)cccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.00 g of diphenyl phosphorazidate and 4.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to 4.0 g of 3-bromo-2-methoxy-phenyl-methanol 6 in 100 mL of toluene at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate/THF. The pooled organic extracts were washed with brine and dried over magnesium sulfate. The mixture was filtered. The solvents were removed under vacuum. The residue was purified by chromatography on silica gel to give 1-azidomethyl-3-bromo-2-methoxy-benzene 7.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])/[CH:4]=[C:5](\[CH3:11])/[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CCOC(C)=O.O=[Pt]=O>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C(C)=C/C(OC)OC
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)CC(OC)OC
Yield: 66 %

Procedure:
To a stirred solution of (E)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (1.32 g, 7.01 mmol) in EtOAc (30 mL) was added PtO2 (51 mg, 0.22 mmol). The slurry was hydrogenated over night. Filtration trough celite, concentration and purification using silica gel (CH2Cl2-Et2O 1:0 to 0:1) afforded ethyl 4,4-dimethoxy-2-methylbutanoate (0.88 g, 66%).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C-:13]#[N:14].[K+]>ClCCl>[CH2:1]([C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: OCc1ccccc1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#CCc1ccccc1
Temperature: 52.5 °C
Yield: 195.4 %

Procedure:
To a solution of 40.00 g (180 mmoles) of benzyl alcohol in. 530 ml of dichloromethane was added within 5 min 32.7 ml (450 mmoles) of thionyl chloride. The solution was evaporated in vacuo to dryness, which was repeated after toluene addition: 46.30 g (106.9%) of crude benzyl chloride, which was dissolved in 230 ml of dimethylformamide and treated with 23.50 g (360 mmoles) of potassium cyanide. The mixture was heated for 4 hours to 50-55° C. The salt was filtered off and the filtrate evaporated in vacuo to dryness, which was repeated after the addition of water, the residue was taken up in ether and extracted with 1N NaOL. The ether phase is evaporated to dryness to yield 41.20 g (99.0%) of crude benzyl cyanide.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:4][C:5]([C:11]2([OH:38])[C@H:16]([O:17][Si](C)(C)C)[C@@H:15]([O:22][Si](C)(C)C)[C@H:14]([O:27][Si](C)(C)C)[C@@H:13]([CH2:32][O:33][Si](C)(C)C)[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[CH3:48]S(O)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:4][C:5]([C:11]2([O:38][CH3:48])[C@H:16]([OH:17])[C@@H:15]([OH:22])[C@H:14]([OH:27])[C@@H:13]([CH2:32][OH:33])[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc(Cc2cc(C3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)c3c(c2Br)CCC3)cc1
Reactant: CS(=O)(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Br)CCC3)cc1
Temperature: -40 °C

Procedure:
To a solution of crude alcohol 14 (2.03 g) in anhydrous THF (11.9 mL) were added CH3SO3H (0.6 N in MeOH, 7.0 mL, 4.18 mmol) at −78° C. under nitrogen atmosphere. The mixture was slowly warmed up to −40° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 15, which was used without further purification (0.94 g, 1.85 mmol, 80%). [M-OMe]+ 477.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17].[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:7]=2[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN1C(=O)C2CCCN2C(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 2 h

Procedure:
To 10-methyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine-5,11(10H, 11aH)-dione (5.7 g, 24.7 mmol) in concentrated sulfuric acid (60 ml) at 0° C. was added potassium nitrate (2.62 g, 25.9 mmol). After stirring for 2 h the mixture was dumped onto ice (500 g) and extracted with ethyl acetate (5×75 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to a solid which was recrystallized from ethyl acetate-hexane (5.2 g, 77%), m.p. 160-162° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.C(OC([NH:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1)=O)(C)(C)C.CO>O>[NH2:35][C:36]1([C:39]([N:2]2[CH2:3][CH:4]([C:6]3[CH:27]=[CH:26][C:9]4[C:10]5[N:14]([CH:13]=[C:12]([C:18]6[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=6)[N:11]=5)[CH2:15][CH2:16][O:17][C:8]=4[CH:7]=3)[CH2:5]2)=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)C4(N)CC4)C3)cc1OCC2

Procedure:
Following the procedure for 127, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid. The crude product was subjected to reverse phase HPLC (Gemini C18 column, gradient 20 to 95% MeOH in H2O+0.1% HCO2H) to give 193 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.36 (1 H, d, J=8.28 Hz), 8.09 (1 H, s), 7.88-7.86 (2 H, m), 7.14 (1 H, dd, J=8.35, 1.82 Hz), 7.01 (1 H, d, J=1.78 Hz), 5.88-5.80 (1 H, m), 4.50-4.44 (4 H, m), 3.83-3.71 (2 H, m), 1.44 (6H, d, J=6.60 Hz), 1.05 (2 H, d, J=4.13 Hz), 0.67 (2 H, d, J=4.01 Hz). 2 Exchangeable protons not seen. 4 protons obscured by water peak. LCMS: RT=6.73 min, M+H+=434
Reaction SMILES: Cl.[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]COC(C)=O.O>CN(C=O)C>[C:14]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]2[CH2:12][CH:11]([O:13][CH3:22])[CH2:10]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(C)=O
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(diphenylmethyl)-3-azetidinol hydrochloride (5.0 g) in DMF (25 ml), was added sodium hydride under ice-bath cooling. After 10 minute stirring at the same temperature, the mixture was allowed to warm to 25° C. and then stirred for 15 hours. EtOAc (500 ml) and water (200 ml) were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; 200 ml, toluene:EtOAc=15:1-8:1) to give 1-(diphenylmethyl)-3-methoxyazetidine (3.41 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH3:11][N:12]([CH2:14][CH2:15]Cl)[CH3:13].Cl>CS(C)=O.O>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:15][CH2:14][N:12]([CH3:13])[CH3:11])[C:2](=[O:1])[CH:7]=1
Reactant: Oc1cc(Br)ccn1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of 2-hydroxy-4-bromopyridine (0.10 g, 0.57 mmol) in DMSO (1.0 mL) was added KOH (0.13 g, 2.29 mmol) and the resulting reaction mixture was stirred for 10 min at room temperature followed by addition of N,N-dimethylaminoethylchloride.HCl (0.098 g, 0.68 mmol). The reaction mixture was then stirred at 40° C. for 1 h. After the completion of reaction (TLC monitoring), water was added to the reaction and extracted with EtOAc (3×25 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was triturated with ether to obtain the desired product (0.10 g, 72%). MS: 245.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[BH4-].[Na+].B(F)(F)F.Cl>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([CH2:6][NH2:7])=[CH:8][CH:9]=1
Reactant: Cc1nc(Cl)ccc1C#N
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(Cl)ccc1CN
Reaction time: 3 h

Procedure:
To a solution of 6-Chloro-2-methyl-nicotinonitrile (6 g) in THF (120 ml) at 25° C. was added NaBH4 (3 g) followed by the dropwise addition of BF3 etherate (6 ml). The reaction mixture was stirred for 3 h. MeOH (100 ml) and 2N HCl (100 ml) was added and refluxed for 1 h. The organic solvent was removed in vacuum and conc. NaOH (40 ml) was added followed by extraction with diethyl ether. The organic layer was separated, dried and concentrated in vacuum followed by filtration over silica gel (EtOAc/MeOH 80:20). The title compound was crystallized from MeOH/HCl (5.5 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (45 mg, 18%)
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(OCC)C.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 4-bromomethylbenzenesulfonyl chloride (0.81 g) in anhydrous diethyl ether (5.0 mL) at −10° C. was treated with a solution of morpholine (0.26 mL) and triethylamine (0.46 mL) in anhydrous diethyl ether (5.0 mL). The resulting mixture was warmed to room temperature over 1 hour and then stirred at this temperature for 17 hours. The mixture was diluted with water, extracted with dichloromethane and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) to afford title compound, 0.53 g.