Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>C1COCC1>[CH:26]([C:2]1[O:1][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: O=C(Nc1nccc2occc12)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7.13 g (30 mmol) N-(Furo[3,2-c]pyridin-4-yl)benzamide (Example 2A) were dissolved in 150 ml dry THF under inert gas atmosphere. At −78° C., 26.4 ml (66 mmol) n-butyllithium solution (2.5 M in hexane) were added dropwise, and the mixture was stirred for 30 min at this temperature. Then, 5.1 ml (66 mmol) dry N,N-dimethylformamide were added dropwise. After addition was completed, the mixture was slowly warmed up to rt, and 300 ml saturated aq. ammonium chloride solution were added. After extraction with 300 ml diethyl ether, the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a brown solid. This material was purified by chromatography on silica gel (eluent dichloromethane/methanol 99:1 v/v) to afford 5.2 g (65% of th.) of the title compound as a pale yellow solid [cf. J. B. M. Rewinkel et al., Bioorg. Med. Chem. Lett. 9, 2837-2842 (1999)].
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CC(C)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 55 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and [(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.66 g) as starting materials, N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained. melting point: 120-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:21][O:22][C:23]([N:25]=[C:26]=S)=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C.C1C=CC=CC=1>[CH3:21][O:22][C:23]([NH:25][C:26]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]([C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:3][C:2]=2[N:1]=1)=[O:24]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c(N)c1
Reactant: COC(=O)N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: CC#N
Product: COC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)OC)ccc2[nH]1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 2-[(3,4-diaminophenyl)carbonyl]benzoate (134 mg, 0.50 mmol) in a mixture of acetonitrile-benzene (1:1, 5 mL) methyl isothiocyanatidocarbonate (70 mg, 0.60 mmol) was added followed by the addition of DCC (153 mg, 0.75 mmol) and the reaction mixture was heated to reflux for 18 h. After cooling to room temperature the reaction mixture was concentrated. The residue was triturated with diethyl ether (2×, 10 mL) and the pale orange solid was collected by filtration to give methyl 2-[(2-{[(methoxy)carbonyl]amino}-1H-benzimidazol-5-yl)carbonyl]benzoate (125 mg, 71%). MS (EI) for C18H15N3O5: 354 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])([C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].I[CH2:38][C:39]([F:42])([F:41])[F:40].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[O:26])([C:16]2[CH:21]=[C:20]([O:22][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35]
Reactant: FC(F)(F)CI
Reactant: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(O)cc(F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(F)cc(OCC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 58 %

Procedure:
To a solution of (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 254, 15 mg, 0.03 mmol) in DMSO (0.15 mL) was added ICH2CF3 (0.02 mL) and K2CO3 (20 mg, 0.2 mmol). The reaction mixture was heated at 70° C. overnight. The reaction was cooled to rt and diluted with CH3CN, filtered and purified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 255) as white solid (10 mg, yield 58%). LCMS: RT=2.18 min [M+H] 601.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.43 (2H, m), 7.21 (1H, d, J=6.60 Hz), 7.12-7.19 (2H, m), 6.68 (2H, d, J=7.70 Hz), 6.54-6.63 (3H, m), 4.19-4.30 (2H, m), 3.73-3.84 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1>[C:4]([C:3]1[C:6]([NH:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: CNc1cccc(N)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Product: CNc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (example 156b) (0.14 g, 0.97 mmol) in 1,4-dioxane (3 mL) was added benzoyl isocyanate (0.17 g, 1.17 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The obtained precipitate was filtered and dried under vacuum to give N-(2-cyano-3-(methylamino)phenylcarbamoyl)benzamide (57 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 2.75 (d, J=4.4 Hz, 3H), 6.26 (d, J=4.8 Hz, NH), 6.43 (d, J=9.6 Hz, 1H), 7.40-7.43 (m, 2H), 7.51-7.55 (m, 2H), 7.63-7.65 (m, 1H), 8.01 (d, J=8.4 Hz, 2H), 11.23 (s, NH), 11.30 (s, NH). MS 295 (MH+).
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.[C:23]1([P:29](Cl)(Cl)=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CC(OC)(C)C>[CH:3]([C@H:2]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C@H:12]([CH:13]([CH3:15])[CH3:14])[O:16][P:29](=[O:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:1]1)([CH3:5])[CH3:4]
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CC(C)[C@H](O)c1ccccc1[C@@H](O)C(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC(C)[C@@H]1OP(=O)(c2ccccc2)O[C@@H](C(C)C)c2ccccc21
Reaction time: 1.5 h

Procedure:
A solution of (S)-1-[2-((S)-1-Hydroxy-2-methylpropyl)phenyl]-2-methyl-propan-1-ol (1.0 g, 4.9 mmol) in pyridine (1.16 g 14.7 mmol) was cooled with an ice-bath. To this mixture was then added drop wise phenyl phosphonic acid dichloride (0.96 g, 4.9 mmol). After stirring for 90 minutes the reaction was complete by 31P-NMR. To the mixture was then added TBME (ca. 20 ml) and hydrochloric acid (ca. 5 ml 4N-solution). The organic layer was separated, dried (Na2SO4), and removal of the solvent left the product as an oil. Yield 1.50 g (89%). 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 0.965 (d, J=6.5 Hz)/20.38 (CH3); 1.075 (d, J=6.5 Hz)/19.05 (CH3); 1.106 (d, J=6.5 Hz)/17.71 (CH3); 1.112 (d, J=6.7 Hz)/20.38 (CH3); 2.37 (m)/34.58 (d, J=8.3 Hz) (CHMe2); 2.49 (m)/31.28 (d, J=7.6 Hz) (CHMe2); 5.17 (dd, J=5.6 Hz, J=7.6 Hz)/83.85 (d, J=8.9 Hz) (CH(i-Pr)); 5.53 (dd, J=3.8 Hz, J=5.9 Hz)/84.36 (d, J=7.6 Hz) (CH(i-Pr)); 7.24 (m)/127.28 (Ar CH); 7.24 (m)/127.93 (Ar CH); 7.24 (m)/127.95 (Ar CH); 7.27 (m)/128.31 (Ar CH); 7.37 (m)/128.43 (d, J=15.1 Hz) (Ph meta-CH); 129.12 (d, J=193 Hz) (Ph ipso-C); 7.47 (m)/132.38 (d, J=3.0 Hz) (Ph para-CH); 7.70 (m)/131.63 (d, J=9.8 Hz) (Ph ortho-CH); 137.23 (s), 138.48 (d, J=1.0 Hz) (2 Ar ipso-C). 31P-NMR (CDCl3) δ 18.72.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].Br[CH2:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C:24]3[N:26]=[CH:27][CH:28]=[N:29][C:23]=3[N:22]([CH2:30][O:31][CH3:32])[C:21]=2[CH:33]=1)=[O:16]>C(O)C.O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C:24]3[N:26]=[CH:27][CH:28]=[N:29][C:23]=3[N:22]([CH2:30][O:31][CH3:32])[C:21]=2[CH:33]=1)=[O:16]
Reactant: COCN1c2cc(C(=O)CBr)ccc2Sc2nccnc21
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCN1c2cc(C(=O)CNc3ccccn3)ccc2Sc2nccnc21
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To 3 ml of a solution of 140 mg of 2-aminopyridine in ethanol was added 130 mg of sodium hydrogencarbonate and the resulting mixture was stirred at room temperature. Next, 2 ml of a solution of 360 mg of bromomethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketone in tetrahydrofuran was dropped thereinto and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was brought back to room temperature and silica gel was added thereto. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 200 mg of the title compound as yellow crystals.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][CH2:4][C:5]1([CH2:34][CH2:35][CH:36]([OH:39])CO)[CH2:10][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=[CH:26][CH:25]=3)=[C:15]([CH2:16][CH2:17][CH3:18])[C:7]=2[O:6]1.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.O>[O:11]=[C:9]1[C:8]2[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=[CH:26][CH:25]=3)=[C:15]([CH2:16][CH2:17][CH3:18])[C:7]=2[O:6][C:5]([CH2:4][CH2:3][CH:2]=[O:1])([CH2:34][CH2:35][CH:36]=[O:39])[CH2:10]1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(O)CO)(CCC(O)CO)CC2=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC=O)(CCC=O)CC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 90 mg (0.158 mmol) of the title product of Example 66 in 3.7 ml of t-butanol was added a solution of 135 mg (0.629 mmol) of sodium periodate in 1.0 ml of H2O. After stirring at room temperature for 2 hours, the mixture was partitioned between diethyl ether and water and the aqueous layer extracted with a fresh portion of ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was triturated with diethyl ether to give the title compound (61 mg), m.p. 107°-108° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH2:13]>>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 1.5 h

Procedure:
To 200 g of Chinese milk vetch honey was added 300 g of water followed by addition of 0.5 g of an enzyme preparation containing glucose oxidase (60 units/mg) and catalase (390 units/mg) activities and the reaction was carried out at 23° C. under aerobic conditions for 90 minutes to provide a gluconic acid-containing honey. The result of assay of gluconic acid in this reaction mixture by high performance liquid chromatography is shown in Table 10. This product has a refreshing gustatory quality possessing both a sour taste and a sweet taste.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][C:19]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)[N:25]=5)=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)=[O:13])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][C:19]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][NH:31][CH3:32])[N:25]=5)=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)=[O:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCn1nc(NC(=O)n2ccc3cc(Oc4ccnc(CN(C)C(=O)OC(C)(C)C)n4)ccc32)cc1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nc(NC(=O)n2ccc3cc(Oc4ccnc(CNC)n4)ccc32)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate (33 mg, 0.062 mmol) in DCM (2 mL) at 0° C. is added TFA (0.7 mL, 9.1 mmol). The reaction is stirred for 30 minutes at 0° C. and is then placed at room temperature for an additional 20 minutes. The reaction mixture is then concentrated in vacuo to near dryness and then diluted with DCM and water. The mixture is neutralized by the addition of saturated aqueous NaHCO3 and the resulting layers are separated. The aqueous layer is extracted two additional times with DCM. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-20% MeOH)/DCM) to give the title compound. MS (ESI) m/z 432.2 (M+1). (DMSO-d6) δ ppm 0.62-0.71 (m, 2 H)0.93-1.02 (m, 2 H) 1.37 (t, J=7.20 Hz, 3 H)1.86-1.99 (m, 1 H)2.30 (s, 3 H)3.71 (s, 2 H)4.15 (q, J=7.24 Hz, 2 H)6.16 (s, 1 H)6.71 (d, J=4.29 Hz, 1 H)6.87 (d, J=5.56 Hz, 1 H)7.12 (dd, J=9.09, 2.27 Hz, 1 H)7.46 (d, J=2.27 Hz, 1 H)8.17 (d, J=3.79 Hz, 1 H)8.31 (d, J=9.09 Hz, 1 H)8.61 (d, J=5.56 Hz, 1 H)10.64 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:27][CH2:28][CH3:29])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNCCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 91.7 %

Procedure:
3.76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]benzodiazepin-9-one were stirred at room temperature overnight with 5 g (39 mmol) of dibutylamine and 25 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 4.3 g (92%) of (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 120°-125°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:15])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Product: Clc1ncnc2cc(Br)ccc12

Procedure:
Reflux a solution of 7-bromo-3H-quinazolin-4-one (1.24 g, 0.0055 mol) in POCl3 for 3.5 h. Remove the excess POCl3 under reduced pressure and partition the residue between EtOAc and saturated aqueous NaHCO3. Dry the EtOAc layer and remove the solvent under reduced pressure to give 7-bromo-4-chloro-quinazoline as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:29]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[OH:37])[CH2:30]1>>[OH:37][C@@H:32]1[CH2:33][N:34]([CH2:6][CH2:5][C@H:4]([N:8]2[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[CH2:10][CH2:9]2)[C:3]([N:2]([CH3:1])[CH3:27])=[O:26])[CH2:35][CH2:36][C:31]21[CH2:30][CH2:29]2
Reactant: CN(C)C(=O)[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: CN(C)C(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 57 %

Procedure:
In analogy to the procedure described in example 1K, (S)—N,N-dimethyl-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyramide and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 57% yield as white foam. MS: 497.3 (MH+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][N:14]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Clc1ccn2c(Br)cnc2c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccn2c(-c3ccnc(Cl)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo-[1,2-a]-pyridine (1 eq, 6.48 mmol, 1.5 g) and 2-chloro-pyridine-4-boronic acid (1 eq, 6.48 mmol, 1.02 g) are dissolved in DME (6 ml) and water (2 ml) and Na2CO3 (2 eq, 13.0 mmol, 1.61 g) is added. PdCl2(PPh3)2 (0.06 eq, 0.389 mmol, 273 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-chloro-3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridine as an orange solid; [M+H]+=265
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH2:17][O:18][CH2:19][CH:20]=[CH2:21])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:4](=[O:22])[N:3]1[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:35])[C:5]([CH2:17][O:18][CH2:19][CH:20]=[CH2:21])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=2)[C:4](=[O:22])[N:3]1[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:24]=1
Reactant: C=CCOCC1(c2cccc(C(F)(F)F)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2cccc(C(F)(F)F)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 814 mg of 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]-4-(3-trifluoromethylphenyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in DMF (1.5 mL) is added potassium carbonate (279 mg) and methyliodide (420 μL). The mixture is stirred 5 hours at room temperature, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH:11]([NH:19][C:20]([C:22]1[S:23][C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)=[C:25]([Br:27])[CH:26]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH2:10][CH:11]([NH:19][C:20]([C:22]1[S:23][C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)=[C:25]([Br:27])[CH:26]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1nccc1-c1sc(C(=O)NC(CCN(C(=O)[O-])C(C)(C)C)Cc2ccccc2)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1sc(C(=O)NC(CCN)Cc2ccccc2)cc1Br
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[3-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-4-phenylbutyl]carbamate (130 mg, 0.24 mmol) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].[C:29](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH3:29])[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 64 h
Yield: 56.3 %

Procedure:
A mixture of (R)-N-[2-chloro-4-(4-methylphenylsulphonamido)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 356) (0.137 g), anhydrous potassium carbonate (0.043 g) and iodomethane (0.038 ml) in acetone (8 ml) was stirred for 64 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water and brine then dried. Volatile material was removed by evaporation and the residue was purified by elution through a Varian Isolute silica 10 g column with 30% ethyl acetate/hexane as eluent to give the title compound (0.079 g). NMR: 1.60 (s, 3H), 2.38 (s, 3H), 3.11 (s, 3H), 7.11 (d, 3H), 7.32 (s 1H), 7.43 (m, 4H), 7.94 (d, 1H), 9.67 (brs, 1H); MS (ESP−): 449.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:7]=1.[CH3:37][N:38]([CH3:46])[C:39]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH3:37][N:38]([CH3:46])[C:39]1[C:44]([NH:45][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)[CH:3]=2)=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: CN(C)c1ncccc1N
Reactant: COc1ccc(COc2cc(Br)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Product: CN(C)c1ncccc1Nc1cc(O)cc(-c2cccc3[nH]ccc23)c1

Procedure:
Dimethyl-(3-nitro-pyridin-2-yl)-amine was obtained as a byproduct from the reaction of 2-chloro-3-nitro-pyridine with pent-4-en-1-ol (2 eq.) and sodium hydride (3 eq.) in DMF at 100° C. overnight. To this compound (0.122 g) in a mixture of ethyl acetate/methanol (5 mL, 1:1) was added 10% Pd on carbon (24 mg). The reaction mixture was hydrogenated at 50 psi hydrogen overnight. After filtration and removal of the solvents, dimethyl-(3-amino-pyridin-2-yl)-amine (0.100 g, 100%) was obtained. 4-[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-1-triisopropylsilanyl-1H-indole and dimethyl-(3-amino-pyridin-2-yl)-amine were coupled as described for Example 82. Deprotection as described in Example 35 gave 3-(2-dimethylamino-pyridin-3-ylamino)-5-(1H-indol-4-yl)-phenol. 1H NMR (400 MHz, CD3OD): δ 7.74 (dd, J=4.8, 1.5 Hz, 1H), 7.57 (dd, J=7.9, 1.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.22 (d, J=3.3 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 7.05 (dd, J=7.3, 0.8 Hz, 1H), 6.86-6.81 (m, 2H), 6.72 (t, J=1.7 Hz, 1H), 6.62 (d, J=3.1 Hz, 1H), 6.52-6.48 (m, 1H), 2.80 (s, 6H).