Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.CN([CH2:8][N:9]([CH3:11])[CH3:10])C.[Cl:12][C:13]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.[OH-].[Na+]>ClCCl>[CH3:11][N:9]([CH2:8][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:13]=2[Cl:12])[NH:17][CH:16]=1)[CH3:10]
Reactant: Clc1c(OCc2ccccc2)ccc2[nH]ccc12
Reactant: CN(C)CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CN(C)Cc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Reaction time: 0.08 h
Yield: 50.6 %

Procedure:
Acetyl chloride (6.42 g, 81.7 mmol) was added dropwise to a stirred solution of bis-dimethylamino-methane (BDAM) (8.34 g, 81.7 mmol) in dry dichloromethane (100 ml), while cooling in an ice bath. After 5 minutes, a solution of 4-chloro-5-benzyloxyindole (15.6 g, 60.7 mmol) in dichloromethane (100 ml) was added, dropwise, followed by addition of 10% aqueous sodium hydroxide (300 ml) after a further 10 minutes. The mixture was extracted with dichloromethane, and the extracts dried (Na2SO4) and stripped to a crude solid which was purified by chromatography (SiO2 ; CHCl3 /MeOH/NH4OH) and recrystallised from ethanol to give 3- dimethylaminomethyl-4-chloro-5-benzyloxyindole (9.66 g), m.p. 137°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:36](O)[CH:37]([CH3:39])[CH3:38].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:36][CH:37]([CH3:39])[CH3:38])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added isobutanol (0.03 mL, 0.33 mmol), and NaH (0.0132 g, 0.33 mmol). The resulting solution was stirred under nitrogen for 1 hour. The reaction was poured into H2O and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The crude solid was purified using flash chromatography (SiO2, 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.1088 g 76%). mp 166–169° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.84 (m, 1H), 3.29 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.51–7.63 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 433 (M+H)+, 450 (M+NH4)+. Anal. calc. for C21H21ClN2O4S: C, 57.07; H, 5.01; N, 6.33. Found: C, 57.06; H, 4.78; N, 6.13.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][C:18]1[N:19]=[C:20]([NH:23][CH2:24][CH2:25][NH2:26])[S:21][CH:22]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:9][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([NH:26][CH2:25][CH2:24][NH:23][C:20]1[S:21][CH:22]=[C:18]([CH3:17])[N:19]=1)=[O:7]
Reactant: CC(F)(F)/C=C/C(=O)O
Reactant: Cc1csc(NCCN)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NCCNC(=O)/C=C/C(C)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in DCM (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N′-(4-methylthiazol-2-yl)ethane-1,2-diamine hydrochloride (24 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) dissolved in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 11 mg of a solid (0.04 mmol, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]#[C:7][C:8]1([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)=[O:5])[CH3:2].[H][H].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1([OH:19])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C#CC1(O)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CCOC(=O)CCC1(O)CN(C(=O)OC(C)(C)C)C1
Yield: 54.4 %

Procedure:
To palladium on carbon (10%, 75 mg) under a nitrogen atmosphere was added a solution of tert-butyl 3-(2-(ethoxycarbonyl)ethynyl)-3-hydroxyazetidine-1-carboxylate (0.20 g, 0.74 mmol) in ethanol (10 ml). The suspension was subjected to hydrogen (Parr hydrogenation apparatus) at 45 Psi for 3 hr. The reaction was filtered and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 50% ethyl acetate/hexanes to give the title compound as a colorless oil 0.11 g, 50%. 1H NMR (CDCl3, 400 MHz) 1.28 (3H, t), 1.43 (9H, s), 2.15 (2H, t), 2.50 (2H, t), 3.32 (1H, s), 3.83 (4H, dd), 4.18 (2H, q).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22].O>C1C=CC=CC=1>[NH2:22]/[C:9](/[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:10]\[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]
Reactant: [NH4+]
Reactant: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccccc1
Product: C=CCOC(=O)/C=C(\N)Cc1ccc(F)cc1
Yield: 100.4 %

Procedure:
Allyl 4-(4-fluorophenyl)-3-oxobutanoate (47 g, 198.95 mmol) and ammonium acetate (46.00 g, 596.85 mmol) were refluxed in benzene (250 mL) for 2 h with azeotropic removal of H2O and then cooled and concentrated. The residue was redissolved in Et2O and the organics washed with 1N HCl (2×), H2O, brine, and then dried (Na2SO4), filtered and concentrated to give 47 g (100% yield) of the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.17 (dd, J=8.4, 5.2 Hz, 2H), 6.99 (t, J=8.6 Hz, 2H), 5.28 (dd, J=17.2, 1.6 Hz, 1H), 5.18 (dd, J=10.3, 1.0 Hz, 1H), 4.61 (s, 1H), 4.55 (d, J=5.6 Hz, 2H), 3.41 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.[C:30]([C:32]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:36]2[N:46]=[C:47]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:48]=[C:35]2[N:34]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=2)[C:33]=1[CH3:70])#[N:31]>CN(C=O)C>[CH2:52]([O:51][C:50](=[O:59])[N:49]([C:47]1[N:48]=[C:35]2[N:34]([C:60]3[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:67])[F:68])[CH:61]=3)[C:33]([CH3:70])=[C:32]([C:30]#[N:31])[C@@H:37]([C:38]3[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=3)[N:36]2[N:46]=1)[CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reactant: BrCC1CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC3CC3)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 μmol, 2.1 eq.), 18-crown-6 (30 mg, 113 μmol, 2.1 eq.) and 1-(bromomethyl)cyclopropane (15.3 mg, 113 μmol, 2.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (22 mg, 66% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][S:10]([CH3:12])=[O:11].Cl.[N:15]([O-])=O.[Na+]>O>[CH3:12][S:10]([C:9]1[C:8](=[O:13])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][N:15]=1)=[O:11]
Reactant: O=N[O-]
Reactant: CS(=O)CC(=O)c1ccccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)c1n[nH]c2ccccc2c1=O
Temperature: 20 °C

Procedure:
A solution of 5.0 g (0.025 mole) of 2'-amino-2-(methylsulfinyl)-acetophenone, 30 ml (0.03 mole) of cold (15°C) 1N hydrochloric acid and 100 ml of cold water cooled to 5°C. A solution of 2.07 g (0.03 mole) of sodium nitrite in 10 ml of water was added over a period of 3 minutes with stirring, keeping the temperature at 5°C. A deep red color developed as yellow solid separated. The mixture was allowed to warm up to 20°C. After 15 minutes at 20° the product was filtered, washed with water, 2-propanol and then ether. Wt 5.0 g (64%) mp. 266°-269°. Recrystallization from N,N-dimethylformamide gave pure, white crystals melting at 274°-276°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([N:33](C)[C:34](=O)OC(C)(C)C)[C:10](=[O:32])[NH:11][C:12]2[CH:13]=[C:14]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]4=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]([CH:20]=2)=[C:15]34)=[CH:4][CH:3]=1.[ClH:42].C(N(CC)CC)C>O1CCOCC1>[ClH:42].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][CH3:34])[C:10]([NH:11][C:12]2[CH:13]=[C:14]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]4=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]([CH:20]=2)=[C:15]34)=[O:32])=[CH:4][CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 48 %

Procedure:
Preparation of example 167 from the title compound of Example 151 (47 mg, 0.085 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, included freebasing with triethylamine and subsequent silica gel chromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purified freebase in CH2Cl2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of the volatile components, the title compound (20 mg, 0.041 mmol) was obtained as an orange/yellow powder in 48% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:23]2[CH:22]=[C:21]([CH3:20])[CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccnc(CN)c1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccnc(CNc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(4-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:31])[C@H:12]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH:42][C:11](=[O:31])[C@H:12]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CSCC[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A solution of 26.6 parts N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester and 12.0 parts L-methionine benzyl ester in 200 parts methylene chloride is stirred overnight at room temperature. The solvent is then removed by evaporation under reduced pressure. The crude dipeptide is then subjected to low-pressure column chromatography on silica gel to afford N-t-butoxycarbonyl-L-tryptophyl-L-methionine benzyl ester.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[S:22](=[O:31])(=[O:30])[N:21]=1.CCOCC.[K+].[Br-]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[S:22](=[O:30])(=[O:31])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc2c(c1)C(Cl)=NS2(=O)=O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)C(NCCCOc1cccc(CN3CCCCC3)c1)=NS2(=O)=O
Reaction time: 0.25 h

Procedure:
To a refluxing solution of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (1.33 g, 5.36 mmoles) in dried chloroform (50 ml) under dry nitrogen is added over 45 minutes a solution of 3-chloro-5-methyl-1,2-benzisothiazole 1,1-dioxide (1.21 g, 5.64 mmoles) in dried chloroform (25 ml) while maintaining reflux. After the addition is complete refluxing is continued for 15 minutes and the clear brown solution is allowed to come to room temperature. Evaporation in vacuo gives a tan solid which cannot be crystallized. Column chromatography on silica gel using methylene chloride/methanol/ammonium hydroxide 95/5/0.5 as eluent gives the free methanol base as a brown foam, 1.22 g. Trituration with ether gives an off-white colored solid, 0.73 g, m.p. 120°-124° C. Recrystallization from ethyl acetate/pentane and finally ethyl acetate gives the pure product, 0.169 tan solid, m.p. 120°-4° C. IR (KBr) 3300, 2938, 1622, 1530 cm-1 ; NMR (in DMSO) 6.8-8.0 (7 H,m), 4.05 (2H,t), 3.76 (2H,t), 1.37 (6H,s), 1.4 (6H,s), 2.0-2.4 (6H,m), 2.5 (3H,s), 3.4 (2H,s), 3.6 (2H,t), 4.1 (2H,t), 6.7-8.0 (7H,m), 9.3 (1H,n).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14]
Reactant: ClCc1ccccc1Cl
Reactant: NCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCCN(Cc1ccccc1Cl)c1ccccn1
Reaction time: 8 h
Yield: 25.1 %

Procedure:
Sodium hydride (1.32 g) was disolved in DMSO (25 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(3-aminopropylamino)pyridine (7.5 g) added at room temperature. 2-Chlorobenzyl chloride (8.86 g) in DMSO (15 ml) was added dropwise maintaining the temperature at 20°-25° C. After standing overnight water (200 ml) was added and the mixture extracted with ether. The ether extracts were washed with 2N hydrochloric acid and after partitioning into ether and chloroform at pH 3.5 and 14, an oil was obtained which was further purified by HPLC (silica gel, dichloromethane then 2% ammoniacal methanol/dichloromethane) to give 2-[N-(3-aminopropyl)-N-(2-chlorobenzyl) amino]pyridine (3.44 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH2:14][CH3:15])[C:6]=2[CH:16]=1.[CH2:18](I)CC>>[Br:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH:14]([CH3:18])[CH3:15])[C:6]=2[CH:16]=1
Reactant: CCCI
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(Br)cc21
Product: Cc1cc2c(cc1Br)N(C(C)C)C(=O)C(C)(C)O2

Procedure:
This was prepared using a procedure similar to that described to make Compound 1C, except using l-propyl iodide in Step C. MS (electrospray): mass calculated for C14H18BrNO2, 311.05; m/z found 312 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=O)=[O:4].[O:10]=[C:11]1[C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]=2[O:14][C:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:12]1)[NH:22][C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20]C3=O>ClCCl>[CH3:31][O:30][C:28]([C:21]1[CH:20]=[C:6]([NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[C:18]2[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]3[O:14][C:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:12][C:11](=[O:10])[C:16]=3[CH:17]=2)[N:22]=1)=[O:29]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Solvent: ClCCl
Product: CCCc1c2nc(C(=O)OC)cc(NC(=O)C(Cl)(Cl)Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trichloroacetyl isocyanate (1.18 ml, 10 mmol) was added to a solution of ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano [3,2-g]quinoline-2-carboxylate (3.85 g, 10 mmol) in dichloromethane (20 ml) at room temperature. The solution was then agitated gently for 24 hours at room temperature and then the solvent removed by distillation in vacuo. Trituration of the resulting solid with ether gave the sub-title compound as yellow cubes, 4.25 g (80%), mp 167°-169° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)(=[O:34])[CH3:33]
Reactant: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Product: CC(=O)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21

Procedure:
A solution of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 103, 0.504 g), dimethylaminopyridine (0.03 g) and acetic anhydride (12 ml) is stirred at 100° for 1 hr. After cooling, excess acetic anhydride is removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. Chromatography on silica gel (320 ml) eluting with methanol/dichloromethane (2/98) gives a poor separation of the product from the imine byproduct. The imine impurily is successfully removed by taking up the mixture in dichloromethane and allowing the imine to precipitate out. The filtrate is collected, concentrated and the product crystallized from dichloromethane and hexane to give the title compound, mp 208.5°-210.0°; MS m/z at 339; IR (mineral oil) 1671, 1503, 1254, 879 and 1204 cm-1 ; NMR (CDCl3) 1.28, 2.38, 2.13, 2.29, 7.16, 7.41 and 8.13 δ.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ccnc(Cl)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.9 %

Procedure:
To a solution of 2,4-dichloro-3-nitropyridine (12.0 g, 62.2 mmol) in DMF (78 mL) was added NEt3 (10.4 mL, 74.6 mmol) and p-methoxybenzylamine (8.12 ml, 62.18 mmol) at 0° C. After stirring for 10 h at rt, DMF was removed at reduced pressure. The residue was triturated with EtOAc, filtered, washed with EtOAc and hexane, and dried to afford 2-chloro-N-(4-methoxybenzyl)-3-nitropyridin-4-amine (9.29 g, 51%). Additional product (8.0 g, 44%) was obtained by column chromatography (SiO2, eluent) from the filtrates.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[CH:17][C:16]=2[O:29][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>ClC(Cl)C.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]([C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:29])[CH2:13][CH2:14]1)[C:44](=[O:47])[CH2:45][CH3:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
cis-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl] amine (0.084 g) was dissolved in dichloroethane (7 ml), and triethylamine (0.045 ml) and 4-dimethylaminopyridine (catalytic) added. Propionyl chloride (0.028 ml) was then added, and the mixture stirred at room temperature for 60 hr. The reaction mixture was partitioned between dichloromethane (10 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic extracts washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved with stirring in dichloroethane (16 ml) and heated with a mixture of water (10 ml), methanol (5 ml) and trifluoroacetic acid (10 ml) at 80° C. for 17 hr. Toluene (25 ml) was then added and the mixture concentrated in vacuo. Methanol (25 ml) was then added and the mixture again concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded the title compound (0.021 g, 37%) as a colourless solid. Rf 0.20 (ethyl acetate/petroleum ether, 1:1, v/v); m/s(ES+) 354.17 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:32])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-nitrophenyl isocyanate (0.33 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 24 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield an orange oil, which was crystallized from 95% ethanol to yield the title compound as an off-white solid (0.20 g, 30% yield), mp=168–170° C.; MS (−) ESI m/z=343 (M−H)−; [α]D25=+29.4° (c=1, DMSO).