Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]2[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2nc(N3CC(NC(=O)OC(C)(C)C)C3)sc2c1
Yield: 74.9 %

Procedure:
The same operation as in Example (221a) was performed using 3-tert-butoxycarbonylaminoazetidine (199 mg, 1.15 mmol), ethyl 2-bromo-1,3-benzothiazole-6-carboxylate obtained in Example (225a) (300 mg, 1.05 mmol) and diisopropylethylamine (0.37 mL, 2.10 mmol), to obtain 297 mg of the title compound as a milk white solid (75%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][N:19]1[C:23]2[CH:24]=[C:25]([CH3:30])[C:26]([CH3:29])=[C:27]([NH2:28])[C:22]=2[N:21]=[CH:20]1>>[CH3:18][N:19]1[C:23]2[CH:24]=[C:25]([CH3:30])[C:26]([CH3:29])=[C:27]([NH:28][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)[C:22]=2[N:21]=[CH:20]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1cc2c(ncn2C)c(N)c1C
Product: Cc1cc2c(ncn2C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1C

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 1,5,6-trimethyl-4-aminobenzimidazole (50 mg, 0.288 mmol) similar to Example 185 and was isolated as a solid (5 mg, 6%). 1H NMR (CDCl3): 9.36 (ddd, J=7.8, 3.0, 1,2 Hz, 1H), 9.68 (s, 1H), 9.01 (ddd, J=5.7, 2.7, 1.2 Hz, 1H), 8.87 (s, 1H), 8.46 (dd, J=8.4, 6.0 Hz, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 6.93 (s, 1H), 2.62 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:30]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[O:30])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cccc3c2NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 8-[4-(4-acetamidophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH2:42][CH2:43][C:44]([OH:46])=[O:45]>>[CH3:22][O:21][N:16]1[C:15]([CH3:23])([CH3:24])[CH2:14][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][C:34]([CH3:36])([CH3:37])[N:33]([O:38][CH3:39])[C:32]([CH3:40])([CH3:41])[CH2:31]3)[N:3]=[C:2]([NH:42][CH2:43][C:44]([OH:46])=[O:45])[N:7]=2)[CH2:18][C:17]1([CH3:20])[CH3:19]
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCC(=O)O
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(NCC(=O)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and glycine according to the procedure of Example 15.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH2:22]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a suspension of morphine (10.0 g, 35.1 mmol) in THF (200 ml), was added benzyl bromide (5.5 ml, 98%, 45.3 mmol) and sodium hydroxide (1.48 g, 37.0 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction temperature rose gradually to rt during the process. THF in the reaction mixture was removed on a rotary evaporator. The residue was dissolved in CH2Cl2 (150 ml) and water (50 ml). The organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo to obtain a crude product (13 g), which was dissolved in CH2Cl2 and loaded onto a silica gel column (3×30 cm). The column was first eluted with 3% methanol in CH2Cl2, followed by 5% methanol in CH2Cl2. Pure fractions were combined to obtain 3-benzylmorphine (7.9 g, 60% yield). IR (KBr)(v, cm-1): 3540 (m, sharp, --OH), 3020 (m, sharp), 2900 (s, sharp), 1600 (m, sharp); NMR (δH)(CDCl3): 7.50-7.20 (5, m, --C6H5), 6.70 (1, d, J, 8.1, 2-H), 6.51 (1, dd, J, 8.1 & 0.9, 1-H), 5.65 (1, dm, J, 9.9, 7-H), 5.26 (1, dt, J, 9.9 & 2.5, 8-H), 5.12 (2, AB, OCH2Ph), 4.85 (1, dd, J, 6.6 & 1.2, 5-H), 4.22-4.05 (1, m, 6-H), 3.32 (1, dd, J, 6.2 & 3.3, 9-H), 3.02 (1, d, J, 18.6, 10-Hβ), 2.75-2.65 (1, m, 14-H), 2.75-2.65 (1, b, --OH), 2.58 (1, dm, J, 12.0, 16-He), 2.5-2.3 (1, m, 16-Ha), 2.42 (3, s, N--CH3), 2.27 (1, dd, J, 18.6 & 6.6, 10-Hα), 2.05 (1, td, J, 12.1 & 5.3, 15-Ha), 1.85 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[O:14]1[CH:18]2[O:19][CH2:20][CH2:21][CH:17]2[CH:16]([O:22][C:23](=[O:41])[NH:24][CH:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]([OH:33])[CH2:27][NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:14]1[CH:18]2[O:19][CH2:20][CH2:21][CH:17]2[CH:16]([O:22][C:23](=[O:41])[NH:24][CH:25]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:26]([OH:33])[CH2:27][N:28]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:15]1
Reactant: O=S(=O)(Cl)c1ccc2occc2c1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzofuran-5-sulfonyl chloride 148 mg (0.68 mmol) was dissolved in 5 mL of methylene chloride. (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 (244 mg, 0.62 mmol) was added followed by 0.63 mL 10% NaHCO3 solution (0.75 mmol). The reaction was stirred at room temperature for 16 hours. The organic phase was separated and loaded onto silica gel in methylene chloride. The excess of benzofuran-5-sulfonyl chloride was washed out by several portions of methylene chloride. The final product was obtained by eluting with 3/1 ethyl acetate/methylene chloride. Concentration in vacuo afforded 350 mg (98.5% yield) of the final product with HPLC purity of >97% (220 nm). The product can be recrystallized from ethyl acetate/hexanes to get colorless crystals m.p. 122-124° C. MS 573 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>C(O)(=O)C>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]3[CH:31]=[CH:35][CH:34]=[CH:33]3)=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Yield: 95.1 %

Procedure:
A solution of ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.74 g, 2 mmol), 2,5-dimethoxytetrahydrofuran (0.40 g, 3 mmol) in acetic acid was heated to 90° C. for 3 h. The reaction was cooled and concentrated. The residue was then purified by flash silica gel chromatography (hexanes/ethyl acetate 5/1) to afforded 0.8 g (95%) of ethyl 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylate as an off-white solid: 1H NMR (CDCl3) δ 0.97 (t, J=7.1 Hz, 3 H), 4.11 (q, J=7.1 Hz, 2 H), 5.84 (s, 2 H), 6.30 (t, J=2.1 Hz, 2 H), 7.01 (t, J=2.1 Hz, 2 H), 7.10-7.50 (m, 13 H); MS (ESI) m/z 421 (MH+); HRMS calcd for C28H25N2O2: 421.1917; found (ESI+): 421.1903; Anal. calcd for C28H24N2O2: C, 79.98; H, 5.75; N, 6.66. Found: C, 80.03; H, 5.67; N, 6.49.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Br:15]N1C(=O)CCC1=O.O>C1COCC1>[Br:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl-2-indole carboxylate (1.89 g) and N-bromosuccinimide (1.77 g) in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was poured into water (150 mL) and filtered. The filtrant was washed with THF, dried under vacuum at 60° C., and recrystallized from ethyl acetate/hexanes.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[O:38]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:37]([OH:38])[CH2:36][CH2:35][CH2:34][CH2:33][Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=CCCCCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)CCCCCl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.32 mL (2.2 mmol) of diisopropylamine in 10 mL of THF at 0° C. was treated with 0.92 mL (2.3 mmol) of 2.5 M n-butyllithium in sol'n in hexanes. The resulting solution was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 0.51 g (1.8 mmol) of (1-tert-butoxycarbonylpiperidin-4-yl)acetic acid, ethyl ester (from Piperidine 35, Step A) in 2 mL of THF was added. After stirring for 30 minutes, a solution of 0.26 g (2.1 mmol) 5-chloropentanal in 2 mL of THF was added (J. Org. Chem. 1981, 46, 2007). The reaction was stirred for 1.75 hours at −78° C. and 3.5 hours at 0° C. After quenching the reaction with saturated NH4Cl, volatiles were removed under reduced pressure. The residue was partitioned between 100 mL of Et2O and 100 mL of H2O. After separating phases, the organic layer was washed with 100 mL of 0.5 N HCl and 100 mL of 1 N NaHCO3, dried over MgSO4 and concentrated. The residue was purified with a 40M Biotage column using 3:1 v/v of hexanes/EtOAc as the eluant to afford impure title compound: RF: 0.27 (7:3 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.24–2.08 (m, 23H), 2.38 (t, J=6.2, 1H), 2.63–2.71 (m, 2H), 3.53–3.56 (m, 2H), 3.92 (m, 1H), 4.09–4.19 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C@:23]12[CH2:30][C@H:27]([NH:28][CH2:29]1)[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][C@:23]4([CH3:22])[CH2:30][C@H:27]3[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)C[C@@H]2C[C@@](C)(CN2)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@@H]2C[C@@](C)(CN2C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane hydrochloride (380228-03-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=420.2 [MH+].
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40]>O1CCOCC1>[NH2:40][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:14][O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@H:27]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Solvent: C1COCCO1
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CO
Temperature: -78 °C

Procedure:
The compound from Step A (150 mg, 0.23 mmol) was dissolved in the minimum amount of 1,4-dioxane (10 mL) and placed in a stainless steel bomb. The bomb was cooled to −78° C. and liquid ammonia was added. The bomb was sealed and heated at 90° C. for 24 h. The ammonia was allowed to evaporate and the residue concentrated to a white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:22][NH2:23])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 72 h

Procedure:
To a solution of 2 parts of 7-chloro-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine in 70 parts by volume of ethanol is added 5 parts by volume of 80% hydrazine hydrate and the mixture is allowed to stand at room temperature for 3 days. After evaporation of the solvent, a small amount of water is added to the residue, whereby 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine is obtained as crystals. Recrystallization from a mixture of methylene chloride and benzene gives crystals. Melting point; 175° C (browning), 205° C to 207° C (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Solvent: ClCCl
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C

Procedure:
To a mixture of 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2 (50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) and the mixture was allowed to slowly warm to RT (ca. 1 h). The mixture was diluted with CH2Cl2 and washed with saturated NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography using CH2Cl2:MeOH 100.0 to 90:10 to afford 7-methoxy-4-(phenylsulfinyl)quinoline as a off-white solid. MS found: M+H+=284.0.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][N:24]=CC=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[NH:34][N:24]=[CH:25][CH:26]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2cc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: OB(O)c1ccncc1
Product: Cc1cc2cc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-5-yl)naphthalen-2-yl)acetic acid (56) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of 1H-pyrazol-5-ylboronic acid for pyridin-4-ylboronic acid in step 5. The title compound (0.004 g) was isolated as an amorphous white powder. LCMS-ESI− (m/z): [2M−H]− calcd for C52H49Cl2N4O6: 895.30; found: 895.45. 1H-NMR: 400 MHz, (CD3CN) δ: 8.23 (br s, 1H); 7.93 (d, J=9.6 Hz, 1H); 7.79 (s, 1H); 7.68 (s, 1H); 7.61-7.53 (m, 3H); 7.40-7.35 (m, 1H); 7.30 (d, J=9.6 Hz, 1H); 6.78 (s, 1H); 5.22 (s, 1H); 2.57 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH2:7])(=[O:6])=[O:5])[CH3:3].[H-].[Na+].[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:7][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:25]=1
Reactant: CC(C)S(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a suspension of propane-2-sulfonic acid amide (168 mg, 1.37 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (52 mg, 1.3 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.27 mmol) and 1,1′-carbonyldiimidazole (89 mg, 0.55 mmol) in N,N-dimethylformamide (1 mL) was stirred at 70° C. for 1 h. Then the above suspension of propane-2-sulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded Propane-2-sulfonic acid [3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (23 mg, 18%) as a white solid: LC/MS m/e calcd for C25H33N3O4S (M+H)+: 472.62, observed: 472.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:3]=1
Reactant: CON(C)C(=O)Cc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(-c2ccccc2)c1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
The mixture of 2-(3-bromophenyl)-N-methoxy-N-methylacetamide (2.0 g, 7.7 mmol), phenylboronic acid (1.42 g, 11.6 mmol), 1-1′-bis(diphenylphosphino)derrocene palladium dichloride (500 mg, 0.77 mmol), and saturated aqueous sodium carbonate solution (1 mL) in N,N-dimethylformamide (20 mL) was heated at 80° C. under N2 overnight. The mixture was poured into water, extracted with EA, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=30:1-10:1) to afford 2-(biphenyl-3-yl)-N-methoxy-N-methylacetamide (1.8 g, yield 94.7%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([OH:18])=O)=[CH:5][N:4]=1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:28]>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([F:28])=[O:18])=[CH:5][N:4]=1
Reactant: CSc1ncc(C(=O)O)c(Nc2ccccc2)n1
Reactant: Fc1nc(F)nc(F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(C(=O)F)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution containing 2.88 g (11.02 mmol) of the product prepared in step 20.2 and 2.1 mL (15.0 mmol) of triethylamine in 55 mL of CH2Cl2 are added 1.40 mL (16.53 mmol) of cyanuric fluoride. The mixture is stirred at room temperature overnight and washed twice with 50 mL of ice-cold aqueous NaHCO3 solution. The organic phase is washed with 75 mL of ice-cold water and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 3.0 g of the expected product are obtained in the form of a yellow solid. The yield is quantitative.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:21]=[C:20]3[S:22][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:9]=1)[O:15][C:16]1[N:21]=[C:20]2[S:22][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:24][C:19]2=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)ccc3F)nc2s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2ccc(Oc3cc(N)ccc3F)nc2s1
Yield: 98 %

Procedure:
A solution of tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}-4-fluorophenyl)carbamate (1.05 g, 2.5 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with 0.1N aqueous sodium hydroxide solution (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (0.78 g, 98%) as a pale-yellow amorphous.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])SC)#[N:2].[NH2:18][CH2:19][CH2:20][NH2:21]>>[C:1]([NH:3][C:4]([NH:18][CH2:19][CH2:20][NH2:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])#[N:2]
Reactant: NCCN
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Product: Cc1[nH]cnc1CSCCN=C(NC#N)NCCN

Procedure:
Reaction of N-cyano-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-S-methylisothiourea with excess 1,2-diaminoethane at room temperature gave N-cyano-N'-(2-aminoethyl)-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, m.p. 164°-167°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine