Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][OH:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].[C-]#N.[Na+]>C1COCC1.[O-2].[Mn+4].[O-2]>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:17]([C:12]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:16]=2[CH:15]=[CH:14][N:13]=1)=[O:18]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: OCc1nccc2c1cnn2-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1nccc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a mixture [1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-methanol (20 mg, 0.08 mmol), 3-trifluoromethylbenzylamine (71 mg, 0.41 mmol) and sodium cyanide (4 mg, 0.08 mmol) in THF (2 mL) was added manganese (IV) oxide (107 mg, 1.23 mmol). After 30 minutes, additional manganese (IV) oxide (107 mg, 1.23 mmol) was added. After 18 hours, the reaction was filtered through a pad of diatomaceous earth and concentrated in vacuo. The mixture was purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound as a yellow solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:10]=[CH:11][C:12]3[C@H:17]([CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][N:23]([C:26]5[C:35]6[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=6)[CH:29]=[CH:28][CH:27]=5)[CH2:22][C@H:21]4[CH3:37])[O:16][CH2:15][CH2:14][C:13]=3[CH:38]=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO.O>CO>[F:36][C:32]1[CH:31]=[C:30]2[C:35](=[CH:34][CH:33]=1)[C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][C@H:17]3[C:12]4[CH:11]=[CH:10][C:9]([NH2:8])=[CH:38][C:13]=4[CH2:14][CH2:15][O:16]3)[C@H:21]([CH3:37])[CH2:22]1)=[CH:27][CH:28]=[CH:29]2
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1S)-N-(diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]-ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine (1.46 g, 2.5 mmol) in methanol (25 mL) was added sodium acetate (0.28 g, 2.65 mmol) and hydroxylamine hydrochloride (0.194 g, 2.8 mmol), and the mixture stirred at room temperature under nitrogen for 18 h. Water was added and extracted with dichloromethane. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with methanol/ethyl acetate (0:100 to 15:85), to yield (1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine. M+H=420.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[N:12]=1>O.CC(C)=O>[Cl:18][C:13]1[CH:14]=[C:15]([Cl:17])[N:16]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Clc1cc(Cl)nc(Oc2ccccc2)n1

Procedure:
Phenol (0.94 g, 10 mmol) and sodium hydroxide (0.44 g, 11 mmol) in water (20 ml) were added to 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) in acetone (20 ml) at 0° C. The mixture was stirred over night. The precipitate then filtered through celite, then the most of the acetone was removed in vacuo. The resulting aqueous solution was extracted with ethyl acetate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified in silica to provide a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].Cl[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(O)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Yield: 86.8 %

Procedure:
A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 g, 5.25 mmols), chloro-tert-butyl-dimethylsilane (0.95 g, 6.30 mmols), and imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25° C. for 3 hours. The solution was diluted with H2O and extracted with Et2O and the combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (MgSO4) before being concentrated under reduced pressure. Column chromatography (1-2% EtOAc—hexanes) afforded 1.50 g (87%) of the title compound as a colorless oil.
Reaction SMILES: C([Mg]Br)C.Br[C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)[C:13](=[O:20])[N:12]([CH2:21][C:22]([O-:24])=[O:23])[C:9]2=[CH:10][CH:11]=1.[Na+].C([Li])(C)(C)C>C1COCC1>[O:20]=[C:13]1[C:14]2([CH2:15][CH2:16][S:17][CH2:18][CH2:19]2)[C:8]2[C:9](=[CH:10][CH:11]=[CH:6][CH:7]=2)[N:12]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C([O-])CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Agent: CC[Mg]Br
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)C2(CCSCC2)c2ccccc21
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide (3 M in Et2O, 0.272 mL, 0.817 mmol) was added to a solution of sodium (5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate (194 mg, 0.545 mmol, described in Intermediate 20) in THF (5 mL) at −78° C., followed by the addition of tert-butyllithium (1.7 M in pentane, 0.801 mL, 1.36 mmol). After 1 h, the reaction was quenched with H2O and partitioned between EtOAc (20 mL) and 10% HCl (20 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials, LC-MS (UV peak area/ESI) 100%, 479.0355 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[Se](=O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:26](C)=[C:25](C)[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1.[Se]>CO.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:5]([CH:6]=[O:1])=[C:25]([CH3:26])[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Reactant: C1COCCO1
Agent: O=[Se]=O
Agent: [Se]
Solvent: O
Solvent: CO
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Temperature: 55 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a 1 L round-bottom flask equipped with a magnetic stir-bar was added dioxane (500 mL) and water (16.5 mL). The solution was heated to 55° C., and selenium dioxide (8.6 g, 77 mmole) was added. The mixture was stirred at 55° C. for one hour, over which time all the selenium dioxide had dissolved. To the solution was then added 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one. The flask was fitted with a reflux condenser and the resulting slurry heated to a bath temperature of 115° C. After 18 hours, additional selenium dioxide (4.0 g, 36 mmole) was added and stirring continued for 6 hours. The reaction mixture was dark red, with gray metallic selenium lining the sides of the flask. The reaction mixture was cooled to room temperature then filtered through a pad of celite and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo to produce a gummy red solid. Methanol (50 mL) was added, and the mixture stirred over an ice bath, during which time a flocculent yellow precipitate formed. The solid was isolated by filtration, and washed sparingly with cold methanol to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (3.90 g, 61%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.26 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): 365 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:22])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]1=[O:23])[CH3:2].[Cl:25]N1C(=O)CCC1=O>ClCCCl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:11]([Cl:25])=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:21])([F:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]1=[O:23])[CH3:2]
Reactant: CCOC(=O)Cn1ccnc(NCC(F)(F)c2ccccn2)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Product: CCOC(=O)Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 6.81 g (20.1 mmol) of [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester and 2.42 g (18.1 mmol) of N-chlorosuccinimide in 100 mL of 1,2-dichloroethane was heated to reflux. An additional 242 mg (1.81 mmol) and 75 mg (0.56 mmol) of NCS were added to the reaction mixture after 1 h and 1.5 h, respectively. After 2.5 h total, the solution was cooled to room temperature and partitioned between dichloromethane (150 mL) and sat. aq. NaHCO3 (200 mL). The layers were separated and the aqueous phase was backwashed with dichloromethane (2×200 mL). The combined organic layers were dried over MgSO4 and the solution concentrated to a volume of 10 mL. This liquid was directly loaded onto a SiO2 column and eluted with 65:35 to 55:45 hexane-EtOAc to give the title compound as a yellow solid: 1H NMR (CDCl3) δ 8.68 (d, 1H, 4.8, Hz), 7.83 (ddd,1H, 7.7, 7.7, 1.6 Hz), 7.9 (dd, 1H, 7.9 Hz), 7.40 (dd, 1H, 4.9, 7.3 Hz), 6.96 (s, 1H), 6.49 (br t, 1H, 5.9 Hz), 4.89 (s, 2H), 4.38 (td, 2H, 13.9, 6.5 Hz), 4.26 (q, 2H, 7.1 Hz), 1.30 (t, 3H, 7.1 Hz).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:25]=[CH:26][C:27]2[N:40]=[C:31]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=4[CH:38]=[CH:39][N:30]3[C:28]=2[CH:29]=1.[C:41]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:42](B(O)O)=[CH:43][CH:44]=[CH:45][CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:41]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=1[C:24]1[CH:25]=[CH:26][C:27]2[N:40]=[C:31]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=4[CH:38]=[CH:39][N:30]3[C:28]=2[CH:29]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Brc1ccc2nc3c4ccccc4ccn3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccccc2-c2ccc3nc4c5ccccc5ccn4c3c2)cc1

Procedure:
913 mg (3 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a vigorously stirred suspension of 14.8 g (50 mmol) of 9-bromobenzimidazo[2,1-a]isoquinoline, 9.9 g (55 mmol) of 1,1′-biphenyl-2-boronic acid and 25.5 g (120 mmol) of tri-potassium phosphate in a mixture of 300 ml of toluene, 100 ml of dioxane and 400 ml of water, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v), three times with 100 ml of ethanol and finally dried. The residue is recrystallised from toluene. The yield is 17 g (45 mmol, 92%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:31]([O-:33])=[O:32])=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[O:30])=[CH:17][C:16]=2[N+:31]([O-:33])=[O:32])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Yield: 97.2 %

Procedure:
A solution of the product of Example 10B (250 mg, 0.4732 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (5 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation under vacuum, and the residue taken up in ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a light orange solid (197 mg, 97%).
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].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)(C)(C)C>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3=[CH:1][CH:2]=[C:3]([OH:4])[C:5]4[O:9][C@H:8]5[C:10]([CH2:12][CH2:13][C@@H:14]2[C@:7]5([C:6]=43)[CH2:21][CH2:20]1)=[O:11]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: [Rh]
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CC(C)(C)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
Dried morphine (0.324 g), benzophenone (1.47 g), chlorotris(triphenylphosphine)rhodium (I) (Wilkinson's catalyst) (0.055 g), and tert-butanol (6 mL) were charged into a glass hydrogenation bottle. The bottle was evacuated and filled with hydrogen. The mixture was magnetically agitated at ambient temperature (24–29° C.) at 16 psi for 16 hours. Potassium tert-butylate (0.804 g) was charged into the bottle with the reaction mixture in one portion, the mixture was magnetically agitated until all solids dissolved, then heated under nitrogen at 60° C. for 4.5 hours. After aging for additional 66 hours at ambient temperature the mixture was quenched with 1.5N acetic acid (6 mL) with mixing and cooling in the water bath, diluted with methanol to 250 mL in volumetric flask and assayed by HPLC. Solution contains 1.12 mg/mL hydromorphone (86% yield), purity 94 area %.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: BrCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: BrCCCCn1ccc2ccccc21
Reaction time: 15 h

Procedure:
0.96 g (17.07 mmol) of sodium hydroxide is added in small portions to a solution, cooled by a bath of ice-cold water, of 2 g (17.07 mmol) of 1H-indole and of 1.15 ml (51.22 mmol) of 1,4-dibromobutane in 80 ml of dimethylformamide. The bath is removed and stirring is continued at ambient temperature for 15 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[N:19][N:18]=[C:17]1[CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.NN>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1c(CN2CCOCC2)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCOCC3)n1-2

Procedure:
In the manner given in Example 27, 2',5-dichloro-2-[3-(morpholinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](Cl)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the hydrochloride salt of 6-(2-chloropyrimidin-4-yloxy)-1-naphthoyl chloride (step b, 0.122 g, 0.34 mmol) in THF (3 mL) was added 3-(trifluoromethyl)benzenamine (0.047 mL, 0.38 mmol). The reaction was stirred at RT overnight. The mixture was concentrated and partitioned between EtOAc and 2N aqueous NaOH. Extraction with several portions of EtOAc was followed by washing of the organic layer with brine and drying with MgSO4. The solution was filtered and concentrated to afford the desired compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+]>C1(C)C=CC=CC=1>[CH3:14][O:15][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Clc1ccc2c(Cl)cc(Cl)nc2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c2ccc(Cl)cc2n1
Temperature: 130 °C
Yield: 89 %

Procedure:
To a solution of 2,4,7-trichloroquinoline (150 mg, 0.685 mmol) in toluene (3 mL) was added a suspension of NaOMe (136 mg, 3.4 eq.) in toluene (3 mL). The mixture was refluxed at 130° C. for 24 h. After cooling to r.t. the solid was filtered and the filtrate was evaporated. The residue was dissolved in MeOH and evaporated to afford 2-methoxy-4,7-dichloroquinoline (139 mg) as an off-white solid. To it was added 1-N-Boc piperazine (455 mg, 4.0 eq.). The mixture was heated in a sealed tube at 150° C. for 3 h, additional piperazine (6 eq.) was added and treated with n-BuOH (2 mL). The reaction mixture was heated at the same temperature overnight. Evaporation of solvent under vacuum and flash chromatography on silica gel with AcOEt in hexane affords the corresponding t-butoxy-carbonylpiperazinylquinoline (20 mg), which was treated with TFA:DCM(1:1, 0.4 mL) at rt. for 1 h. Evaporation of the solvents and dilution with DCM and evaporation affords the corresponding unsubstituted piperazine as the TFA salt, which was dissolved in DCM (15 mL), in an ice bath. NEt3 (7 eq.) and 4-fluorophenylisocyanate (9 μl, 1.5 eq.) was added. After stirring at rt. for 3 h, the mixture was diluted with DCM and washed with water, followed by the usual work up. Flash chromatography on silica gel with MeOH in DCM afforded the title compound.
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][NH:5][C:6](=[O:17])[C@@H:7]([NH:15][CH3:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:16][N:15]1[C@@H:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[O:17])[NH:5][CH2:4][C:3]1=[O:18]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC
Solvent: Cc1ccccc1
Product: CN1C(=O)CNC(=O)[C@@H]1Cc1ccccc1
Yield: 85.2 %

Procedure:
A solution of (S)-N-[2-(methylamino)-1-oxo-3-phenylpropyl)glycine methyl ester (Description 33, 1.59 g, 6.4 mmol) in toluene (15 mL) was heated at 170° C. in a sealed tube for 42 h. The mixture was cooled, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(aq.) (95:5:1), to give the title compound as a colorless solid (1.19 g, 86%). 1H NMR (360 MHz, CDCl3) δ7.31 (3H, m), 7.14 (2H, m), 5.93 (1H, br s), 4.16 (1H, m), 3.44 (1H, dd, J 17.0, 3.6 Hz), 3.27 (1H, dd, J 13.9, 3.7 Hz), 3.16 (1H, dd, J 13.9, 4.6 Hz), 3.06 (3H, s), and 2.48 (1H, d, J 17.0 Hz). mI/z (ES+) 218 (M+1).
Reaction SMILES: N[C:2]1[C:6]2=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=[C:5]2[O:4][C:3]=1C(OCC)=O.Cl.C([O-])(O)=[O:19].[Na+]>>[Cl:11][C:9]1[CH:10]=[C:5]2[O:4][CH2:3][C:2](=[O:19])[C:6]2=[N:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1oc2cc(Cl)cnc2c1N
Agent: Cl
Agent: [Na+]
Product: O=C1COc2cc(Cl)cnc21
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of ethyl 3-amino-6-chlorofuro[3,2-b]pyridine-2-carboxylate (0.81 g, 3.35 mmol) in hydrochloric acid (5.0 M in water, 50.0 mL, 3.35 mmol) was heated to reflux for 4 h and cooled to RT. The pH was adjusted to 7 with saturated NaHCO3. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel eluting with a gradient of 0% to 100% EtOAc in DCM gave 6-chlorofuro[3,2-b]pyridin-3(2H)-one (0.12 g, 0.68 mmol, 20% yield) as a yellow solid. LC/MS (ESI+) m/z=170.0 (M+H). Calculated for C7H4ClNO2 169.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:13][CH2:14][C:15]([O:17]C)=[O:16])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].CO.[OH-].[Na+]>O>[C:15]([CH2:14][O:13][C:6]1[C:5]([CH3:19])=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])([OH:17])=[O:16]
Reactant: COC(=O)COc1c(C)cc(OC)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(OCC(=O)O)c(C(=O)O)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
The synthesis was performed with reference to the known literature (Bioorganic & Medicinal Chemistry Letters, Vol. 17, p. 6354, 2007). Methyl 5-methoxy-2-(2-methoxy-2-oxoethoxy)-3-methylbenzoate (4.9 g, 18.3 mmol) was added with methanol (30 mL), and water (10 mL), and then added with sodium hydroxide (2.2 g, 55 mmol), and the mixture was stirred at 55° C. for 2 hours. The solvent was evaporated under reduced pressure, the residue was made acidic with 3 N hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the solid formed was dried to obtain 2-(carboxymethoxy)-5-methoxy-3-methylbenzoic acid (3.9 g, 89%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=O)[C:11](=O)[CH:10]([CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[CH2:1]([N:8]1[CH2:9][CH:10]([CH3:25])[C:11]2[N:31]([C:30]3[CH:32]=[CH:33][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:14][C:12]=2[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CC(CC(=O)c2ccc(Cl)cc2)C1=O
Reactant: Nc1ccc(Cl)cc1
Product: CC1CN(Cc2ccccc2)Cc2cc(-c3ccc(Cl)cc3)n(-c3ccc(Cl)cc3)c21

Procedure:
Using a procedure analogous to Example 3, 1-benzyl-3-methyl-5-(p-chlorophenacyl)-4-piperidone may be reacted with p-chloroaniline to give the title compound.