Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:30](=[O:32])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: CNC
Product: CN(C)C(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 73 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with dimethylamine to give the title compound as a white solid (183 mg, 73%); NMR Spectrum 2.97 (s, 3H), 3.04 (s, 3H), 5.17 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.22 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.76-7.69 (m, 3H), 7.91 (m, 1H), 8.15 (s, 1H), 8.53 (m, 2H), 8.57 (s, 1H), 11.21 (br s, 1H); Mass spectrum MH+ 454.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][CH2:27][CH2:26][NH2:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (dd, J=7.83, 1.01 Hz, 1 H), 7.81 (d, J=7.07 Hz, 1 H), 7.64-7.54 (m, 2 H), 7.47-7.35 (m, 2 H), 7.26 (dd, J=8.59, 1.77 Hz, 1 H), 5.98 (s, 1 H), 5.12 (s, 2 H), 3.56 (t, J=4.93 Hz, 2 H), 3.39 (t, J=6.82 Hz, 2 H), 2.82 (t, J=6.95 Hz, 2 H), 2.39 (s, 3 H), 1.89 (t, J=6.95 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14](C)[C:15](=O)OCC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:26])[N:3]=1>CO>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:26])[N:3]=1
Reactant: Cc1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)nc(C)n1
Solvent: CO
Product: CNC1CCN(c2cc(C)nc(C)n2)CC1
Reaction time: 4 h
Yield: 95 %

Procedure:
Benzyl 1-(2,6-dimethylpyrimidin-4-yl)piperidin-4-yl(methyl)carbamate (3.6 g, 10.169 mmol, 1.0 eq.) was dissolved in MeOH (40 ml) and degassed for 15 min with N2. Pd(OH)2 (800 mg) was then added, and hydrogenation was carried out for 4 hours at room temperature under balloon pressure. After monitoring by TLC, the reaction mixture was filtered over Celite and washed with methanol (100 ml). The filtrate was concentrated under reduced pressure and the crude product was used in the next stage without being purified further. Yield: 95% (2.12 g, 9.636 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC(C)(C)C)c(Cl)c3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(Cl)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of tert-butyl (2-chloro-4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetate (0.96 g, 1.86 mmol) in DCM (10 ml) was treated with TFA (10.0 ml, 130 mmol) and the mixture stirred at RT for 50 min. The volatiles were removed and the residue purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 0-100% water:acetonitrile+0.05% formic acid. to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([O:24][CH3:25])=[C:22]3[C:17]([C:18](=[O:32])[C:19]([C:29]([OH:31])=[O:30])=[CH:20][N:21]3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][C:15]=2[F:33])[CH2:9]1)=O)(C)(C)C.[ClH:34]>C(O)(=O)C>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([O:24][CH3:25])=[C:22]3[C:17]([C:18](=[O:32])[C:19]([C:29]([OH:31])=[O:30])=[CH:20][N:21]3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][C:15]=2[F:33])[CH2:9]1
Reactant: COc1c(OC2CCN(C(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(OC2CCNC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
The whole amount of the 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid obtained above was dissolved in a mixture which consisted of 1.25 ml of concentrated hydrochloric acid and 5 ml of acetic acid. The resultant solution was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue thus obtained was recrystallized from ethanol, whereby 120 mg of the title compound was obtained as colorless needle crystals.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (2.7 g) in anhydrous tetrahydrofuran (35 mL) at 0° C. was treated with a mixture of tert-butanol (0.1 mL) and 3-oxopentanoic acid methyl ester (3.2 g). After stirring at room temperature for 15 minutes a solution of 1-chloromethyl-4-methanesulfonylbenzene (5.0 g) in tetrahydrofuran (15 mL) was added and the resulting mixture heated at 70° C. for 16 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases 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 toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:4:1 by volume) to afford title compound as a waxy white solid, 3.0 g.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24].I.[NH2:27][C:28]1[C:29]([C:36]([NH:38][C:39](=[NH:42])SC)=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1>C(O)C>[NH2:27][C:28]1[C:29]([C:36]([N:38]=[C:39]([NH2:42])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1
Reactant: NCCCCCCCCCCCC(N)=O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)CCCCCCCCCCCNC(N)=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
Diisopropylethylamine (0.24 mL, 1.38 mmol) was added to a suspension of 12-amino-dodecanoic acid amide hydrochloride (8) (0.068 g, 0.27 mmol) in absolute ethanol (5 mL). The resulting solution was stirred at 70° C. (oil bath) for 5 min, after which time 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (115 mg, 0.30 mmol) was added in one portion. The reaction mixture was then stirred at this temperature for 3 hours then cooled to room temperature. After removal of the solvent by rotary evaporation the resulting residue was dissolved in small volume of methanol, and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution concentrated in vacuo to a yellow residue. This residue was stirred in a minimal volume of methanol and the resulting solid was collected by suction filtration and washed with a small amount of methanol to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-dodecanoic acid amide 9 (0.065 g, 56%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) 1.23 (m, 14H), 1.49 (m, 4H), 2.01 (t, 2H), 3.11 (m, 2H), 6.65 (m, 4H), 7.21 (br, 1H), 9.06 (br, 1H). m/z (ESI) 427 [C18H31ClN8O2+H]+. mp 192-194° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[NH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[I:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[I:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:12]2[CH:13]([CH3:16])[CH2:14][CH2:15][C:10]([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:4]=3)=[N:11]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC1CCC(c2ccc(Cl)c(C(F)(F)F)c2)=NN1
Solvent: ClCCl
Product: CC1CCC(c2ccc(Cl)c(C(F)(F)F)c2)=NN1S(=O)(=O)c1ccc(I)cc1
Temperature: 105 °C
Yield: 14.8 %

Procedure:
3-(3-trifluoromethyl-4-chlorophenyl)-6-methyl-1,4,5,6-tetrahydropyridazine (700 mg) was combined with 4-iodobenzenesulfonyl chloride (558 mg) and heated to 105° C. for 3 h. Dichloromethane was added and the solution washed with water, 10% HCl, sat'd NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and solvent removed at reduced pressure to give a residue which was recrystallized from acetone/hexane to give 148 mg of the title compound with mp 157°-158° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH:10]=2)O1.C([O-])([O-])=O.[K+].[K+].[NH2:23][C:24]1[CH:25]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[C:28](Br)[CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH3:15][N:12]1[CH2:13][CH2:14][C:9]([C:28]2[CH:27]=[C:26]([C:31]([F:32])([F:34])[F:33])[CH:25]=[C:24]([NH2:23])[CH:29]=2)=[CH:10][CH2:11]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 80 °C

Procedure:
To a mixture of 4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane (1.0 g, 4.4 mmol), PdCl2pddf (0.16 g, 0.2 mmol) and K2CO3 (1.8 g, 13.2 mmol) and 3-amino-5-bromobenzotrifluoride (0.8 g, 3.3 mmol) in DMF (25 mL) was heated at 80° C. for 16 h. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, and concentrated. The residue was purified by SiO2 chromatography to give the title intermediate. MS (ES+): 257 (M+H)+. Calc'd C13H15F3N2—256.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:23]([OH:24])=[C:22]([CH3:25])[C:21]([CH3:26])=[C:20]([CH:27]=[O:28])[C:19]=2[CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:18]2[C:23]([OH:24])=[C:22]([CH3:25])[C:21]([CH3:26])=[C:20]([CH:27]=[O:28])[C:19]=2[CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C)c(C=O)c(C)c([C@H](CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.6 %

Procedure:
To a solution of methyl (R)-7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoate (0.55 g, 1.4 mmol) in tetrahydrofuran (6 ml) was added, under argon atmosphere, 1N sodium hydroxide (2.9 ml). The mixture was stirred for 14 hours at room temperature, to which was added 1N hydrochloric acid (2.9 ml), followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from acetonitrile to give (R)-7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (0.49 g). Physico-chemical properties and spectral data of this product were shown in [Table 4]. Likewise, Compounds 26, 28, 30 and 31 were prepared.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:13])[N:9]1[CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:32]>CC#N>[C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:32])(=[O:13])[N:9]1[CH:14]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2S(=O)OCC2(C)C(=O)OC(C)(C)C)cc1
Solvent: CC#N
Product: COc1ccc(C(c2ccc(OC)cc2)N2C(C)(C(=O)OC(C)(C)C)COS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A solution of the diastereomeric sulfamidites 13a (97 mg, 0.22 mmol) in 4 mL of CH3CN was cooled in an ice bath and treated successively with 1.1 eq of NaIO4 (51 mg), a catalytic amount of RuO2H2O (˜1 mg) and 2.4 mL of H2O. After 5 minutes of stirring the ice bath was removed, and the reaction was continued for 20 minutes. The reaction mixture was diluted in 10 mL of EtOAc and washed with 10 mL of saturated NaHCO3 solution. The aqueous layer was extracted with 2×10 mL of EtOAc, and the combined organic layers were washed with 10 mL brine followed by usual work up. The crude product was purified by silica gel column chromatography (30% EtOAc in hexane) to provide the cyclic sulfamidate 14a as a light yellow solid (90 mg, 89%): mp 143.5-145 EC (EtOAc.hexane); 1H NMR (CDCl3) δ 1.29 (3H, s), 1.51 (9H, s), 3.77 (3H, s), 3.80 (3H, s), 4.16 (1H, d, J=8.8), 4.73 (1H, d, J=8.8), 5.98 (1H, s), 6.82-6.89 (4H, m), 7.38-7.44 (4H). Anal. (C23H29NO7S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:31])[C:7](=[O:30])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23](C(O)=O)[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.CC[N:34](CC)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:31])[C:7](=[O:30])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:34])[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCc3ccnc(C(=O)O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: CCN1c2ncc(CCc3ccnc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 16.3 %

Procedure:
To a solution of 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-[2-(2-carboxypyrid-4-yl)ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (92 mg, 0.21 mmol) and Et3N (0.03 mL, 0.22 mmol) in t-butanol (20 mL) was added diphenylphosphoryl azide (0.046 g, 0.21 mmol). The reaction mixture was heated at reflux under argon for 16 hours. Solvents were removed by rotary evaporation, and the residue was dissolved in ethyl acetate, washed with saturated aq. sodium bicarbonate, dried (magnesium sulfate), and concentrated. The residue was treated with 2N hydrochloric acid in ethanol at 25°-50° C. for 30 hours. The reaction mixture was concentrated, basified with 6N sodium hydroxide, and extracted with ethyl acetate. Purification by flash chromatography (elution with methanol-dichloromethane) and recrystallization (diethyl ether-petroleum ether) afforded 14 mg (16%) of the title compound, m.p. 95° C. (dec).
Reaction SMILES: Cl[C:2]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:10]=3[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:8][CH2:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[H-].[Na+].[CH3:27][SH:28]>CN(C)C=O.O>[Cl:17][C:15]1[CH:14]=[CH:13][C:11]2[C:12]3[C:2]([S:28][CH3:27])=[N:3][C:4]([CH3:24])=[N:5][C:6]=3[CH2:7][N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]=2[CH:16]=1
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(C)nc2c1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In one portion 1.0 g (2.8 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine was added to a solution of 150 mg (3.1 mmol) of 50% mineral oil dispersion of sodium hydride and an excess of methyl mercaptan (>3.1 mmol) in 25 mL of dimethylformamide. The mixture was stirred at room temperature for 30 min and diluted with water. The resulting precipitate was collected by filtration to give a yellow solid. Recrystallization from a mixture of ether and methylene chloride gave pale yellow prisms, mp 181°-183°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][CH:16]=1
Reactant: CSc1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2nc(C)nc3ccccc23)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol), 4-methylthio-aniline (139.2 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.20 mmol) in 4 mL of solvent (THF:water=1:1) was stirred at 60-70° C. for 3 h. The reaction mixture was diluted with 30 mL of ethyl acetate. It was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was rinsed with ethyl acetate and dried, yielding 273 mg of title compound (97.2%). 1H NMR (CDCl3): 7.86-7.82 (m, 2H), 7.79-7.73 (m, 3H)), 7.50-7.45 (m, 2H), 7.34-7.26 (m, 2H), 2.7 (s, 3H), 2.51 (s, 3H),
Reaction SMILES: Br[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14][CH:15]=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[C:19]([CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14][CH:15]=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:20]
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CC#N)O2
Yield: 84.6 %

Procedure:
A solution of N-(2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl)formamide (20 g) and sodium cyanide (17 g) in dimethyl sulfoxide (100 mL) was stirred under argon gas at 100° C. for 13 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/diisopropyl ether to provide 14 g of the title compound. Yield 86%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2F)CC1
Reaction time: 0.33 h

Procedure:
tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)piperidine-1-carboxylate (200 mg, 0.35 mmol) was dissolved in methanol (5 mL). Hydrochloric acid (gas) was bubbled through for 20 seconds, then removed. The reaction was allowed to stir for 20 min and the solvent evaporated. The resulting solid was dissolved in dichloromethane (2 mL) and treated with formaldehyde (37 wt. % solution in water, 1.5 mL) at 0° C. After 20 min the reaction was treated with sodium triacetoxyborohydride (297 mg, 1.4 mmol). The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 142 mg (85%). Mass Spec: 478.07 (MH)+. LC tr=1.885 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).
Reaction SMILES: [CH:1]([O:6][CH3:7])(OC)OC.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH2:12][C:11](=[O:22])[NH:10]1>C(OC(=O)C)(=O)C.CN(C)C=O>[CH3:7][O:6]/[CH:1]=[C:12]1/[C:11](=[O:22])[NH:10][C:9](=[O:8])[C:18]2[C:13]/1=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2
Reactant: O=C1Cc2cc(C(=O)O)ccc2C(=O)N1
Reactant: COC(OC)OC
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(C(=O)O)cc21
Temperature: 125 °C

Procedure:
Trimethyl orthoformate (0.114 mL, 1.04 mmol) is added to a solution of 1,3-Dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid (102.5 mg, 0.5 mmol) in acetic anhydride (0.8 mL) and N,N-dimethylformamide (0.2 mL). After it is heated at 125° C. for 30 min, it is cooled and filtered to collected 75 mg (60%) of the title compound as a yellow solid. MS (ESI) m/z 246.1 (M−1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[ClH:14].[C:15]1([NH:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=O)[CH3:28])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+].Cl>CO.O.C(O)C>[OH2:7].[ClH:14].[OH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[NH:10][CH:9]=[C:8]2[CH2:11][CH2:12][NH:13][CH:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:22]([NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:30]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(=O)CCCCC(=O)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Solvent: CO
Product: CC(CCCCC(=O)Nc1ccccc1)NCCc1c[nH]c2ccc(O)cc12
Reaction time: 96 h
Yield: 176.4 %

Procedure:
Serotonin hydrochloride (1.000 g) and N-phenyl-6-oxo-heptanamide (1.289 g) were stirred in methanol (47 mL) under a nitrogen atmosphere and treated with sodium cyanoborohydride (0.444 g), excluding light from the reaction. After 4 d at ca. 23° C., a solution of sodium bicarbonate (1.00 g) in water (25 mL) was added. One hour later, the reaction was diluted with water (75 mL) and extracted with 1:4 2-propanol:dichloromethane (3×75 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to a foaming oil which was chromatographed using 5:20:80 triethylamine:ethanol:ethyl acetate, isolating the component with an Rf of 0.3. The resulting oil was twice reconcentrated in vacuo from ethanol (100 mL) and then redissolved in ethanol (100 mL). This solution was treated with 1:9 concentrated hydrochloric acid: ethanol (6 mL), concentrated in vacuo reconcentrated from ethanol (100 mL) to an oil, and the oil placed under vacuum to yield the title compound as a solid (1.80 g).