Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[C:14]2[N:15]=[N:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10]1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1C2N=CC=C(OC(N(C)C)=[N+](C)C)C=2N=N1.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29]([N:10]1[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[N:15][C:14]=2[CH:9]1[CH3:8])=[O:30])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CC1NCCc2ccnnc21
Agent: CN(C)C(Oc1ccnc2[nH]nnc12)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2nnccc2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 73.9 mg (0.281 mmol) of 8-methyl-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, trifluoroacetate salt (Intermediate 34), 93.6 mg (0.281 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3) and 0.150 mL (0.843 mmol) of N,N-diisopropylethylamine in 2.5 ml of DMF were added O-(7-azabenzotriazol-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (HATU; 128 mg, 0.337 mmol), 1-hydroxy-7-azabenzotriazole (HOAt; 45.9 mg, 0.337 mmol). The reaction was stirred at room temperature for 18 h. Then the reaction mixture was partitioned between ethyl acetate and 0.5M aqueous sodium bicarbonate solution. The aqueous phase was extracted with three portions of ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The mixture was purified by preparative TLC (100% ethyl acetate), then by chiral HPLC (ChiralCell OJ column, 14% ethanol/hexanes) to afford the title compound as a solid. The slower eluting isomer was used in Step B below. LC/MS: 409 (M+1-56).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](=[O:16])(Cl)[S:11][CH:12]([CH3:14])[CH3:13].[Br:17][C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1>C(OCC)(=O)C>[Br:17][C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:10](=[O:16])[S:11][CH:12]([CH3:14])[CH3:13])[CH2:31][CH2:32]3)[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1
Reactant: CC(C)SC(=O)Cl
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)SC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Hunig's base [7087-68-5] (0.4 mL, 2.4 mmol), then S-isopropyl carbonochloridothioate [13889-93-5] (0.2 mL, 1.6 mmol) were added to a stirred, ambient temperature solution of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine (450.0 mg, 1.6 mmol) in ethyl acetate (30 mL). Then rapidly formed suspension was stirred overnight, under N2 blanket, then washed with brine, dried (MgSO4), evaporated, and crystallized from ethyl acetate/heptane to afford 482.9 mg of white powder, mp. 186-187° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 2.51 (dt, J=3.60, 1.86 Hz, 1H) 3.49-3.59 (m, 1H) 3.59-3.71 (m, 7H) 7.58 (d, J=9.85 Hz, 1H) 8.09-8.13 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 23.22, 35.48, 44.71, 101.63, 110.84, 113.71, 114.69, 116.58, 119.46, 123.56, 126.04, 134.22, 155.61, 157.77, 158.15, 158.53, 158.90, 166.18. LRMS (ESI) m/z 384.0/386.0 [(M+H)]+, calc'd for C14H15BrN6OS: 384.30.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[C:14]([F:21])[CH:13]=2)[CH2:7]1)(=S)[CH3:2].F[P-](F)(F)(F)(F)F.N1([O:38]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C[CH2:47][N:48]([CH:52](C)C)C(C)C.Cl.CNC>CN(C=O)C>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:48]([CH3:52])[CH3:47])=[O:20])=[C:14]([F:21])[CH:13]=2)[CH2:7]1)(=[O:38])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(=S)NC[C@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)N(C)C)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-(S)-thioacetamidomethyl-3-(4′-carboxy-3′-fluorophenyl)oxazolidine-2-one (0.33 g, 1.06 mmol; prepared as described in Example 13), O-(7-azabenzotriazol-1-yl)-N, N, N′, N′,-tetramethyluronium hexafluorophosphate (0.428 g, 1.1 mmole) and N,N′-diisopropylethylamine (0.38 ml, 2.1 mmol) in DMF (1.5 ml) was stirred at r.t. for 20 min. Dimethylamine hydrochloride (96 mg, 1.2 mmole) was added, and the mixture stirred at r.t. overnight. Solvent was removed under vacuum, and the product purified by by silica gel PTLC (eluent: 10% MeOH in ethyl acetate). White crystals (117 mg, 33%). HPLC Rt=4.2. MS (m/z): [M+H]+=340.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(Cl)(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1.N1C=CN=C1.[Si:47](Cl)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>N1C=CC=CC=1.O>[Si:47]([O:10][C@@H:9]1[C@@H:11]([CH2:12][OH:13])[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8]1)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 5-fluoro-2′-deoxyuridine (FDUR) (4.92 g, 20 mmol) in pyridine (100 mL) was added DMTrCl (10.16 g, 30 mmol) portion-wise at 0° C. and the solution was stirred at 0° C. for 2 h. Water (5 mL) was added and the mixture was evaporated to dryness and the residue was co-evaporated with toluene (2×20 mL). The residue was dissolved in EtOAc (200 mL) and the solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was dissolved in CH2Cl2 (100 ml). To the solution were added imidazole (4.08 g, 60 mmol) then t-butyldimethylsilylchloride (TBSCl, 4.52 g, 30 mmol) and the mixture was stirred at room temperature for overnight. Water (50 mL) was added and the mixture was evaporated to dryness. The residue was dissolved in EtOAc (300 mL) and the solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was co-evaporated with toluene twice then dissolved in CH2Cl2 (200 mL). To the solution was added trifluoroacid (TFA, 3 mL) and the solution was stirred at room temperature for 3 h. Water (5 mL) was added and the mixture was stirred for 30 min then methanol (10 mL) added. After 10 min, the solution was neutralized with 30% ammonium hydroxide. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography to give product as solid (5.6 g. 78%). 1H-NMR (CDCl3): δ 8.88 (br s, 1H), 7.96 (d, J=6.4 Hz, 1H), 6.23 (m, 1H), 4.78 (m, 1H), 3.95 (m, 1H), 3.79 (m, 1H), 2.28 (m, 2H), 0.88 (s, 9H), 0.00, 0.09 (ss, 6H). LC-MS (ESI): 361 [M+1]+.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH3:17])=[CH:9][CH:8]=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C1CCCCC1.C(OCC)C>[CH3:22][O:21][C:19]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH3:17])=[CH:9][CH:8]=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: CCn1ccc2ccc(Br)cc21
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C

Procedure:
Sec-butyllithium (9.4 ml of a 1.3M solution in cyclohexane) was added to a stirred solution of 6-bromo-1-ethylindole [the compound of step (a), 2.5 g]in diethylether (20 ml) at −78° C. under a nitrogen atmosphere. After 30 minutes this solution was transferred by cannula to a stirred solution of methyl chloroformate (1.29 ml, 16.74 mmol) in diethyl ether (8 ml) at −78° C. under a nitrogen atmosphere. After 1 hour the cooling bath was removed and the mixture was allowed to warm to room temperature. After a further 1 hour the mixture was poured into brine and extracted with ethyl acetate. The organic layers were dried (MgSO4 ) and concentrated in vacuo to give a yellow oil. Flash column chromatography (elution with 90% hexane, 10% ethyl acetate) gave 1.76 g of the subtitle compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:7]([C:13]#[N:14])[C:8](=[NH:12])[O:9]2)=[CH:4][C:3]=1[Cl:21].CC1C(Cl)=CC(C(C2C=CC=CC=2)=O)=C(O)C=1.C(#N)CC#N.N1CCCCC1>C(O)C>[NH2:12][C:8]1[O:9][C:10]2[C:5]([CH:6]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=1[C:13]#[N:14])=[CH:4][C:3]([Cl:21])=[C:2]([CH3:1])[CH:11]=2
Reactant: Cc1cc2oc(=N)c(C#N)c(-c3ccccc3)c2cc1Cl
Agent: Cc1cc(O)c(C(=O)c2ccccc2)cc1Cl
Solvent: CCO
Solvent: C1CCNCC1
Solvent: N#CCC#N
Product: Cc1cc2c(cc1Cl)C(c1ccccc1)C(C#N)=C(N)O2
Yield: 17 %

Procedure:
7-Methyl-6-chloro-3-cyano-2-imino-4-phenyl-2H-chromene. To a mixture of 4-methyl-5-chloro-2-hydroxybenzophenone (500 mg, 2 mmol) and malononitrile (132 mg, 2 mmol) in ethanol (15 mL) was added piperidine (0.1 mL, 1.0 mmol). The mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 100 mg (17%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([C:4]([OH:6])=[O:5])[NH2:3].[CH3:8][Si]([Cl:12])(C)C>CO>[ClH:12].[CH3:8][O:5][C:4](=[O:6])[C:2]([CH3:7])([CH3:1])[NH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(N)C(=O)O
Solvent: CO
Product: COC(=O)C(C)(C)N
Product: Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred [solution of 2,2-dimethylglycine (10.0 g, 0.097 mol) in methanol (200 ml) was added trimethylsilyl chloride (37 ml, 0.29 mol). After stirring at room temperature for 14 h. The mixture was evaporated to dryness to give crude 2,2-dimethylglycine methyl ester hydrochloride as a white solid which was used directly in the next step.
Reaction SMILES: C[O:2][C:3]1(C(O)=O)[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH2:4]1.[C:18]([OH:21])(=[O:20])C.Br(O)(=O)=O>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:18]([OH:21])=[O:20])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COC1(C(=O)O)C=CC(c2ccccc2)=CC1
Reactant: CC(=O)O
Agent: [O-][Br+2]([O-])O
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(O)cc1

Procedure:
A mixture of 25 of 4-methoxybiphenyl-4-carboxylic acid, 1 1 of acetic acid and 200 ml of 48% bromic acid was refluxed for 12-14 hours and then throwninto 2.5 l of water. After cooling, the resultant crystal was collected to obtain 4'-hydroxybiphenylcarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([N:17]1[CH2:18][CH2:19][CH:14]([O:13][CH3:12])[CH2:15][CH2:16]1)=[O:6]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: COC1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc(I)ccc2F)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 8.5 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (5.99 g, 15.79 mmol) was added portionwise to 2-fluoro-5-iodobenzoic acid (3.000 g, 11.28 mmol), 4-methoxypiperidine (1.364 g, 11.84 mmol) and triethylamine (3.93 mL, 28.19 mmol) in DMF (40 mL). The resulting solution was stirred at room temperature for 7 hours. The reaction mixture was poured into water (350 mL), extracted with Et2O (2×200 mL), the combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered and evaporated to afford a dark orange gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (0.348 g, 67% yield); 1H NMR (400.132 MHz, CDCl3) δ1.57-1.99 (4H, m), 3.18 (1H, m), 3.39 (3H, s), 3.50 (2H, m), 3.63 (1H, m), 3.98 (1H, m), 6.89 (1H, t), 7.69 (2H, m); m/z (LC-MS, ESI+), RT=2.05 (M+H 364.0).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH2:7]([Br:9])[CH3:8]>C(#N)C>[Br-:9].[NH2:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH3:8])[N:3]=1
Reactant: Nn1ccnn1
Reactant: CCBr
Solvent: CC#N
Product: CCn1cc[n+](N)n1
Product: [Br-]
Temperature: 25 °C
Yield: 520.7 %

Procedure:
In a 100 ml glass reactor, equipped with a magnetic stirrer was placed 2.00 g (3.8 mmoles) of 1-amino-1,2,3-triazole (1) and dissolved in 40 ml of acetonitrile. To the reaction mixture was added 12.05 g (110.5 mmoles) of ethyl bromide and the reactor was sealed. The reaction mixture was stirred vigorously at 45° C. until all 1-amino-1,2,3-triazole was consumed. As the reaction progressed, white crystals of 1-amino-3-ethyl-1,2,3-triazolium bromide (2b) precipitated. The reaction mixture was cooled down to room temperature. The product salt was filtered and washed with several aliquots (50 ml total) of diethyl ether. The mother liquor was concentrated by distillation under reduced pressure, resulting in a second crop of crystals that were filtered, washed with diethyl ether, combined with the first crop and dried under high vacuum, resulting in a good yield of 3.82 g (83%) of 1-amino-3-ethyl-1,2,3-triazoliumbromide (2b), mp 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br>>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Cl)c1O
Agent: Br
Product: O=Cc1ccc(O)c(O)c1Cl

Procedure:
2-Chloro-3-hydroxy-4-methoxybenzaldehyde is treated with hydrogen bromide to give 2-chloro-3,4-dihydroxybenzaldehyde which is converted to the methylenedioxy derivative with dibromoethane as described above. The product is condensed with nitromethane and the resulting nitroethylene reduced to give the phenethylamine. This compound is condensed with p-methoxystyrene oxide to give the α-hydroxyphenethylamine intermediate which is treated with an excess of trifluoroacetic acid at room temperature for 18 hours to give 6-chloro-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. This compound is split using boron trichloride as described above to give 6-chloro-7,8-dihydroxy-1-p-methoxyphenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [NH2:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[Na].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[C:19]([NH:21][C@@H:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH3:23])=[O:20]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][O:4][CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[C:19]([NH:21][C@@H:22]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH3:23])=[O:20]
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: CC(N)(CO)Cc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-2-methyl-3-phenylpropan-1-ol I (28 mg, 0.17 mmol) in 0.5 nL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.17 mL, 0.17 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate III 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (25 mg, 0.06 mmol) in 0.5 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h and purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 8.87 (d, J=8 Hz, 1H), 7.86-7.80 (m, 2H), 7.66 (s, 1H), 7.45-7.40 (m, 2H), 7.36-7.24 (m, 3H), 7.22-7.16 (m, 2H), 7.10-7.02 (m, 2H), 5.30-5.20 (m, 1H), 4.73-4.64 (m, 2H), 3.44 (A of AB, d, J=10 Hz, 1H), 3.39 (B of AB, d, J=10 Hz, 1H), 3.35 (s, 3H), 3.09 (A of AB, d, J=13.2 Hz, 1H), 2.94 (s, 3H), 2.87 (B of AB, d, J=13.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.25 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][NH:30]2)[CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:27]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CN1CCN(C[C@@H]2CCCN2)CC1
Product: CN1CCN(C[C@@H]2CCCN2CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-(+)-2-[(4-methyl-1-piperazinyl) methyl]pyrrolidine to give colorless crystals, mp. 182°-185° C. (D) (from ethyl acetate/methanol 99:1 v/v); [α]D20 =-11.2° (ethanol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:2]1=2.[Cl-:11].[C:12]([C:15]1[CH:20]=[CH:19][N+](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])[NH2:13]>CO>[Cl-:11].[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]3[CH:19]=[CH:20][C:15]([C:12](=[O:14])[NH2:13])=[CH:16][CH:17]=3)[C:2]1=2
Reactant: Nc1cccc2c1OCC2
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1cc[n+](-c2cccc3c2OCC3)cc1

Procedure:
A mixture of 2,3-dihydrobenzo[b]furan-7-ylamine (6.8 g prepared in a similar manner to that described in Tetrahedron Letters 1982,23,147), 4-carbamoyl-1-(2,4-dinitrophenyl)pyridinium chloride (14.7 g prepared in a similar manner to that described in Example 2) and methanol (400 ml) was stirred under reflux for 5 hours then allowed to stand at ambient temperature and heated for 16 hours. The solvent was removed in vacuo, and the residue was triturated with hot acetone, cooled and filtered to give 1-(2,3-dihydrobenzo[b]furan-7-yl)-4-carbamoylpyridinium chloride as a yellow solid (11.5 g), m.p. 289°-290° C.
Reaction SMILES: CC([C:5]1([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:14](=[O:16])[O-:15])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)(C)C.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[CH2:9][CH2:10][CH:5]([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:27]([O:26][CH3:25])=[O:28])[CH:30]=3)=[CH:20][CH:19]=2)[C:14]([O:15][C:8]([CH3:11])([CH3:9])[CH3:7])=[O:16])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(N(Cc2ccc(Br)cc2)C(=O)[O-])(C(C)(C)C)CC1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1cccc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCC(C)(C)CC3)cc2)c1

Procedure:
A flask equipped with a septum-sealed reflux condenser was charged with 1,1-dimethylethyl[(4-bromophenyl)methyl](4,4-dimethylcyclohexyl)carbamate (0.988 g; 2.49 mmol; Example V-11), {3-[(methyloxy)carbonyl]phenyl}boronic acid (0.493 g; 2.74 mmol), Pd(OAc)2 (0.0028 g; 0.012 mmol) and 2-(2′,6′-dimethoxybiphenyl)di-cyclohexylphosphine (S-Phos; 0.010 g; 0.025 mmol) was evacuated and back-filled with N2 several times. PhMe/EtOH (4:1 v/v, 7.5 mL), and 2M Na2CO3 were added via syringe through the condenser's septum and the mixture was heated under reflux for 2 h (until consumption of the aryl bromide was observed). Upon cooling, the mixture was poured into EtOAc/water, the whole was filtered through a 0.45 μm PTFE membrane filter and the layers were separated. The aqueous layer was extracted with EtOAc, combined organics were washed (brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum/syrup. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (s, 6H), 1.07-1.79 (m, 18H), 3.89 (s, 3H), 4.42 (br. s., 2H), 7.36 (d, J=8.03 Hz, 2H), 7.62 (t, J=7.85 Hz, 1H), 7.67 (d, J=8.03 Hz, 2H), 7.95 (t, J=6.96 Hz, 2H), 8.18 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>>[O:23]1[CH2:28][CH2:27][CH:26]([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[C:8]([O:13][C:14]4[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=4)=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH2:25][CH2:24]1
Reactant: O=C1CCOCC1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCOCC2)nc1
Yield: 45.2 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)nicotinamide (intermediate 20, 238 mg, 0.800 mmol), tetrahydro-4H-pyran-4-one (160 mg, 1.60 mmol), and NaBH3CN (100 mg, 1.60 mmol) gives the title compound (138 mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.16 (d, 1H), 7.23-7.16 (m, 2H), 6.94-6.90 (m, 2H), 5.86 (br. s, 2H), 4.00 (d, 2H), 3.40 (t, 2H), 3.15-2.78 (m, 3H), 2.65-2.41 (m, 2H), 1.97-1.46 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([Pb+3])=[C:32]([CH2:37][CH3:38])[CH:31]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])=[C:32]([CH2:37][CH3:38])[CH:31]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 80 °C
Yield: 60.2 %

Procedure:
2,2,6,6-Tetramethylpyran-3,5-dione (8 g, 0.047 mol) and 4-dimethylaminopyridine (24 g, 0.196 mol) are added to a mixture of chloroform (160 ml) and toluene (40 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethyl-phenyllead triacetate (29.4 g, 0.051 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×100 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione as a white solid (10 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[OH-].[K+].O>CN(C)C=O>[N+:8]([C:7]1[C:2]2[NH:1][CH2:14][CH2:13][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: BrCCBr
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1NCCO2
Temperature: 200 °C
Reaction time: 48 h
Yield: 14.3 %

Procedure:
To a solution of 2-amino-3-nitrophenol (15.0 g, 97 mmol) and 1,2-dibromoethane (29.1 g, 155 mmol) in dimethylformamide (80 mL) was added KOH (10.9 g, 194 mmol) at 180° C. After stirring at 200° C. for 2 days, the mixture was poured to 150 g water. The mixture was concentrated under reduced pressure. The crude product was purified using column chromatography to give the title compound (2.50 g) as a red solid. MS (ESI): m/z 181 [M+H]+