Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14][CH2:13]2.[Li+].[OH-]>CCO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14][CH2:13]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4ccsc4)cc3OC)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2ccsc2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 50 °C
Yield: 76 %

Procedure:
The ester prepared in Example 98 (83 mg 0.18 mmol) was dissolved in a mixture of EtOH (3 mL), THF (3 mL), and water (1 mL), LiOH (42.6 mg; 1.78 mmol) was added and the reaction mixture was heated at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC (CH3CN, 0.01% TFA/Water, 0.01% TFA (v/v)=2:3 to 100% CH3CN, 0.01% TFA) to give 60 mg (73%) of the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 7.62-7.61 (m, 1H), 7.52-7.47 (m, 2H), 7.29 (d, 1H), 7.23-7.20 (m, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.33-6.32 (m, 1H), 6.77-6.74 (m, 1H), 4.23-4.18 (m, 4H), 3.89 (s, 3H), 3.48-3.45 (m, 1H), 3.22-2.71 (b, 1H), 2.93-2.71 (m, 3H), 2.42-2.32 (m, 2H), 2.28-2.22 (q, 2H), 1.76-1.70 (m, 1H). LC-MS: RT=5.28 min, (M−H)437.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:15]3[C:11]([S:12][C:13]([C:19]([N:21]4[CH2:41][C@H:40]([F:42])[CH2:39][C@H:22]4[C:23]([N:25]4[CH2:32][C:29]5([CH2:31][CH2:30]5)[N:28](C(=O)C(F)(F)F)[CH2:27][CH2:26]4)=[O:24])=[O:20])=[C:14]3[CH:16]([CH3:18])[CH3:17])=[N:10][C@:9]2([C:44]2[CH:45]=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=2)[CH3:43])=[CH:4][C:3]=1[F:51].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:15]3[C:11]([S:12][C:13]([C:19]([N:21]4[CH2:41][C@H:40]([F:42])[CH2:39][C@H:22]4[C:23]([N:25]4[CH2:32][C:29]5([CH2:30][CH2:31]5)[NH:28][CH2:27][CH2:26]4)=[O:24])=[O:20])=[C:14]3[CH:16]([CH3:17])[CH3:18])=[N:10][C@:9]2([C:44]2[CH:45]=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=2)[CH3:43])=[CH:4][C:3]=1[F:51]
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CCN(C(=O)C(F)(F)F)C3(CC3)C2)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CCNC3(CC3)C2)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 40 °C
Yield: 55.1 %

Procedure:
The compound (390 mg, 0.51 mmol) obtained in Step 1 above was dissolved in 10% aqueous methanol (8 ml), potassium carbonate (400 mg, 2.89 mmol) was added and the resulting mixture was stirred under heating at 40° C. for 2 hours. The solvent was concentrated under reduced pressure and then the residue obtained was diluted with ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=15:1 (v/v)] to give the title compound (190 mg, 55%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@H:20]([OH:26])[CH2:19]2.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[O:15]=[S:7]1(=[O:16])[C:6]2[CH:17]=[CH:2][CH:3]=[CH:4][C:5]=2[C:9]2[CH:10]=[CH:11][C:12]([O:26][C@H:20]3[CH:21]4[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]4)[CH2:19]3)=[CH:13][C:8]1=2
Reactant: O=S1(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: O[C@@H]1CN2CCC1CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=S1(=O)c2ccccc2-c2ccc(O[C@@H]3CN4CCC3CC4)cc21
Temperature: 110 °C
Reaction time: 30 h
Yield: 61.7 %

Procedure:
A mixture of 3,7-dibromodibenzothiophene-5,5-dioxide (0.60 g, 1.75 mmol; see J. Med. Chem. 1978, 21, 1084), (S)-(−)-quinuclidin-3-ol (280 mg, 2.2 mmol; Acros), copper (I) iodide (33 mg, 0.17 mmol; Aldrich), 1,10-phenanthroline (63 mg, 0.35 mol; Aldrich) and powdered cesium carbonate (0.86 g, 2.64 mmol; Aldrich) in toluene (2 mL) was heated to 110° C. with vigorous stirring for 30 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate and dichloromethane, and the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH—CH2Cl2) to afford the title compound (0.37 g, 1.08 mmol; 63% yield): MS (DCI/NH3): m/z 342 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([C@@H:13]1[C:22]2[C:17](=[N:18][C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)[O:16][C:15]2[N:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:14]1=2)([CH3:12])[C:3]([NH:5][C:6]1N=N[N:9](C)[N:10]=1)=[O:4].NN1NC=[C:45]([CH:48]2[CH2:50][CH2:49]2)[S:44]1>>[CH:48]1([C:45]2[S:44][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:1])([C@@H:13]3[C:22]4[C:17](=[N:18][C:19]([C:23]5[CH:24]=[CH:25][C:26]([C:29]([N:31]6[CH2:36][CH2:35][O:34][CH2:33][CH2:32]6)=[O:30])=[CH:27][CH:28]=5)=[CH:20][CH:21]=4)[O:16][C:15]4[N:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:14]3=4)[CH3:12])=[N:10][N:9]=2)[CH2:49][CH2:50]1
Reactant: Cc1ccc2c(n1)Oc1nc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc1[C@H]2C(C)(C)C(=O)Nc1nnn(C)n1
Reactant: NN1NC=C(C2CC2)S1
Product: Cc1ccc2c(n1)Oc1nc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc1[C@H]2C(C)(C)C(=O)Nc1nnc(C2CC2)s1

Procedure:
Following conditions described for Step 9 of Example 14, the acid from Step 1 of Example 92 was coupled with 2-amino-5-cyclopropylthiadiazole to give Example 93. 1H NMR (400 MHz, chloroform-d) δ ppm 1.16-1.41 (m, 10H) 2.27-2.38 (m, 1H) 2.57 (s, 3H) 3.43-3.93 (m, 8H) 4.59 (s, 1H) 7.01 (d, J=7.78 Hz, 1H) 7.51 (t, J=8.53 Hz, 3H) 7.56-7.67 (m, 2H) 8.12 (d, 2H); MS (ES+) m/z: 597 (M+H); LC retention time: 3.08 min (analytical HPLC Method B).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:23]([Cl:25])[CH:24]=1.CO>O.C(Cl)Cl.Cl[Pd]Cl>[Cl:18][C:19]1[CH:20]=[C:21]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: CC1(C)OB(c2cc(Cl)cc(Cl)c2)OC1(C)C
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cc(Cl)cc(Cl)c2)c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
Potassium carbonate (2.416 g, 17.48 mmol), methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 2-(3,5-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.34 g, 37.88 mmol), PdCl2 (dppf) (0.633 g, 0.87 mmol), and MeOH (45.7 mL) were split in three 20 mL microwave-vials and heated to 100° C. in a single node microwave reactor for 20 min. The reaction mixture was diluted with water and DCM, the aqueous layer extracted with DCM and the combined organic layers were evaporated. Purified by automated flash chromatography using 5% EtOAc in heptane ->30% EtOAc over 15 CV at 280 nm. Methyl 2-(3,5-dichlorophenyl)isonicotinate (6.1 g, 74%) was isolated as a white powder. 1H NMR (400 MHz, cdcl3) δ 4.01 (s, 3H), 7.44 (t, 1H), 7.84 (dd, 1H), 7.96 (d, 2H), 8.23-8.28 (m, 1H), 8.85 (dd, 1H).
Reaction SMILES: [CH3:1][C:2](=O)[C:3]([CH3:6])([CH3:5])[CH3:4].Cl.[NH2:9][NH:10][C:11]([NH2:13])=[O:12].C([O-])(=O)C.[Na+]>O>[CH3:1][C:2](=[N:9][NH:10][C:11]([NH2:13])=[O:12])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: NNC(N)=O
Reactant: CC(=O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NNC(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.6 %

Procedure:
Pinacolone (10 g, 99.8 mmol) was added to a solution of semicarbazide hydrochloride (11.13 g, 99.8 mmol) and sodium acetate (16.4 g, 199 mmol) in water (60 mL). The mixture was stirred for 17 h at ambient temperature. The white precipitate was filtered and washed with water and diethyl ether. The solid was dried under vacuo at 50° C. to yield the desired product (11.09 g, 70.5 mmol, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17](=[S:26])[NH:16][N:15]=2)([CH3:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:35]=1[CH2:36]Cl>CC(C)=O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:35]=1[CH2:36][S:26][C:17]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:14]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:13])[CH3:12])=[N:15][N:16]=1
Reactant: COc1ccc(C(C)(C)c2n[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Reactant: Fc1cccc(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)c2nnc(SCc3c(F)cccc3Cl)n2-c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A mixture of 3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-1H-1,2,4-triazole-5(4H)-thione (200 mg, 0.54 mmol) and K2CO3 (111 mg, 0.80 mmol) in acetone (15 mL) was stirred for 30 min at room temperature. 2-Chloro-6-fluorobenzyl chloride (206 μL, 1.61 mmol) was added to the reaction mixture, and the resulting mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated. Purification by flash chromatography [Hex/EtOAc, 1:4 to 1:1] afforded the title product (230 mg, 0.45 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 6.95-6.91 (m, 1H), 6.84-6.80 (m, 2H), 6.68 (d, 1H), 6.54 (d, 1H), 6.50 (dd, 1H), 6.45-6.40 (m, 2H), 4.45 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 1.65 (s, 6H); MS (EI) m/z 516 (MH+).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]=[C:9]([Cl:12])[O:10][CH:11]=1)(=O)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[I-].[Na+].Cl>C(#N)C>[Cl:12][C:9]1[O:10][CH:11]=[C:7]([CH2:6][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCc1coc(Cl)n1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc(CN2CCCCC2)co1
Yield: 40 %

Procedure:
A solution of (2-chloro-1,3-oxazol-4-yl)methyl methanesulfonate i59 (7.9 g, 37.44 mmol, 1 eq), piperidine (7.41 ml, 74.89 mmol, 2 eq) and sodium iodide (0.56 g, 3.74 mmol, 0.1 eq) in acetonitrile (250 ml) is stirred at room temperature overnight. The mixture is then poured into a 0.1 N hydrochloric acid solution and extracted with diethyl ether. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 98:1.8:0.2) affords 3 g of 1-[(2-chloro-1,3-oxazol-4-yl)methyl]piperidine i60.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.CO[CH:32]1[CH2:36][CH2:35][CH:34](OC)O1>C(O)(=O)C>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]4[CH:32]=[CH:36][CH:35]=[CH:34]4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(-n2cccc2)c1
Yield: 67.8 %

Procedure:
A mixture of [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.04 g, 0.1 mmol) and 2,5-dimethoxytetrahydrofuran (0.08 g, 0.6 mmol) in 5 mL of acetic acid was heated at 80 for 1 h. Removal of solvent under reduced pressure gave a crude product that was purified by silica gel chromatography eluting with ethyl acetate/hexanes (5% to 30%) to give 30 mg (67%) of the title compound as an off-white solid. MS (ESI) m/z 443; HRMS: calcd for C27H17F3N2O, 442.1293; found (ESI, [M+H]+), 443.1373.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[CH2:13][C:14]([O:16]C)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1>[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(F)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A solution of 5′-fluoro-2′-hydroxyacetophenone (25.0 g), methyl bromoacetate (27.2 g), potassium carbonate (33.6 g) in N,N-dimethylformamide (250 mL) was stirred at room temperature for 1.5 hr. The insoluble material was filtered off, 1N hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a brown oil. Tetrahydrofuran (300 mL), ethanol (300 mL) and 1N aqueous sodium hydroxide solution (300 mL) were added to the obtained oil, and the mixture was stirred at room temperature for 30 min. The solvent was concentrated under reduced pressure, 1N hydrochloric acid (300 mL) was added, and the resulting crystals were collected by filtration. The crystals were dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (23.7 g, 69%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:29][Si:27]([CH3:30])([C:23]([CH3:26])([CH3:25])[CH3:24])[O:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2COc2ccc(O)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 10 g of 2-hydroxy-6,11-dihydrodibenz[b,e]oxepin-11-one in 50 ml of dimethylformamide are added 6.5 g of imidazole and 7 g of t-butyldimethylchlorosilane and the mixture is stirred for 1 hour. After adding 300 ml of toluene, successively washing with water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 13 g of 2-(dimethyl-t-butylsilyloxy)-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 340(M+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)([O-:7])=[O:6]>CN(C=O)C>[C:1]([O:18][C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([N+:5]([O-:7])=[O:6])([CH2:15]3)[CH2:9]1)[CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])C12CC3CC(CC(O)(C3)C1)C2
Solvent: CN(C)C=O
Product: CC(=O)OC12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-nitro-3-adamantanol obtained by the method of Example 4 and 12 mmole of triethylamine were dissolved in 10 ml of DMF. To the mixture, 11 mmole of acetyl chloride was added dropwise over 30 minutes at 40° C. The mixture was stirred for another 3 hours at 40° C. As a result, the conversion of 1-nitro-3-adamantanol was 99%, and 1-acetyloxy-3-nitroadamantane (yield 95%) was formed.
Reaction SMILES: [BrH:1].Br.[CH2:3]([N:10]1[CH2:18][CH2:17][C:16]2[CH2:15][NH:14][CH2:13][C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19]=O>C(O)=O>[BrH:1].[BrH:1].[CH2:3]([N:10]1[CH2:18][CH2:17][C:16]2[CH2:15][N:14]([CH3:19])[CH2:13][C:12]=2[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=O
Reactant: c1ccc(CN2CCC3=C(CNC3)C2)cc1
Agent: Br
Solvent: O=CO
Product: CN1CC2=C(C1)CN(Cc1ccccc1)CC2
Yield: 82 %

Procedure:
3-Benzyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene dihydrobromide (0.75 g) was refluxed in 85% formic acid (10 ml) and 37% formaline (7 ml) for 5 hours. The solvents were removed under reduced pressure and the solid was washed with isopropanol ethylether (2:1) to give 3-benzyl-8-methyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene dihydrobromide (0.64 g, yield 82%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Br[CH:13]([OH:15])[CH3:14].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:1]([NH:4][N:5]([CH2:14][CH2:13][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccccc1
Reactant: CC(O)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)NN(CCO)c1ccccc1
Yield: 34.8 %

Procedure:
To a solution of 1-acetyl-2-phenylhydrazine (2 g, 13.3 mmol) in anhydrous toluene 20 ml was added bromoethanol (1.04 ml, 14.6 mmol), diisopropylethylamine (2.54 ml, 14.6 ml) at room temperature. The reaction mixture was refluxed under nitrogen for 40 hours. After cooling, the reaction was then quenched with 100 ml water, extracted with dichloromethane 2×100 ml. The organic was dried (MgSO4) and removed in vacuo. The residue was purified by flash column chromatography over silica using a gradient 50% mixture of ethyl acetate and hexane to 100% ethyl acetate as eluant. Appropriate fractions were combined and the solvent was removed in vacuo to give the product as a yellow oil 0.9 g (Yield 35%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([O:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH:17]=[O:16])=[CH:19][CH:20]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(CO)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Product: COc1ccc(C(=O)OCc2ccc(C=O)cc2)cc1C(C)(C)C

Procedure:
In a manner similar to Example 1(d), by reaction of 7.6 g (34 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 4.6 g (34 mmol) of 4-hydroxymethylbenzaldehyde, 5.6 g (51%) of the expected aldehyde, melting point 75°-6° C., are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:52]([NH2:56])[CH:53]([CH3:55])[CH3:54]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:56][CH2:52][CH:53]([CH3:55])[CH3:54])=[O:20])[CH:17]=2)[NH:12][N:11]=1
Reactant: CC(C)CN
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)CNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 19 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (200 mg, 0.55 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (231 mg, 0.61 mmol) and isobutylamine (60 μL, 0.61 mmol); (71 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7–8.8 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.3–7.5 (m, 2H), 3.2 (m, 2H), 2.0 (m, 1H), 1.0 (d, 6H), ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CN.C[CH2:21][N:22](C(C)C)C(C)C>C(#N)C>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([CH2:21][NH2:22])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CC#N
Product: NCc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 2-(2,6-difluoro-3-nitrophenyl)pyridine (1.0 g, 4.2 mmol), methylamine (2.24 mL, 4.24 mmol, 2M in THF) and DIPEA (0.75 mL, 4.2 mmol) in acetonitrile (10 mL) was stirred overnight at RT. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-40% EtOAc/cyclohexane) to afford the title compound as a yellow solid (0.89 g, 84%). 1H NMR (CDCl3, 400 MHz): δ 8.74 (1H, ddd, 5.0, 2.1, 1.0 Hz) 8.46 (1H, br s) 8.27 (1H, dd, 9.5, 6.2 Hz), 7.80 (1H, td, 7.8, 2.1 Hz), 7.47 (1H, dq, 4.0, 1.2 Hz), 7.34 (1H, dd, 9.5, 8.2 Hz), 2.36 (3H, d, 5.3 Hz)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[C:5]([N:24]=O)=[C:4]([NH:26][C:27](=O)[CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC=CC=1C>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:24]=[C:27]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[NH:26]2)=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:21])([F:20])[F:22])=[CH:14][CH:15]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)Nc1nc(N)nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c1N=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)NCCCc1nc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc2[nH]1
Temperature: 25 °C
Yield: 107 %

Procedure:
Nitroso-pyrimidine 39 (Example 22, 1.84 g, 3.3 mmol) and triphenylphosphine (1.89 g, 7 mmol) in 20 mL o-xylene are heated to reflux for 10 h. After cooling to room temperature the solvent is removed in vacuo and the remaining residue redissolved in ethyl acetate. The residue is adsorbed on SiO2 and purified by flash column chromatography (ethyl acetate/ethanol 1:0 to 10:1) to yield the title compound as a colorless solid (1.04 g, 3.53 mmol, 50.4%). 1H-NMR (400 MHz, DMSO-d6): δ=7.46 (d, J=8.1, 2H, ArH), 7.28 (d, J=8.1, 2H, ArH), 6.85 (t, J=5.3, 1H, CONH), 6.41 (s, 2H, NH2), 5.41 (s, 2H, OCH2), 4.38 (s, 2H, CH2), 2.93 (q, J=6.5, 2H, CH2), 2.60 (t, J=7.1, 2H, CH2), 1.76 (qt, J=7.1; 2H, CH2), 1.35 (s, 9H, (CH3)3) ppm. MS (ESI) m/z 524.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of tert-butyl{4-chloro-2-[(trimethylsilyl)ethynyl]phenoxy}acetate (Intermediate 2, 17.70 g; 52.2 mmol) in THF (180 mL) was treated with tetrabutylammonium fluoride trihydrate (16.48 g; 52.2 mmol). The reaction mixture was stirred for 4 hours, then ethyl acetate (450 mL) was added and the organic phase was washed with water (750 mL) then with brine (750 mL), dried over MgSO4, filtered and concentrated under vacuum to give a brown oily residue which was purified by flash chromatography (silica) eluting with cyclohexane containing increasing amounts of ethyl acetate. The title compound was obtained as a brown oil which solidified after prolonged standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH3:28][NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[NH:29][CH3:28]
Reactant: CN
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: CNC(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with methylamine at 22° C. to give the title compound as a white solid. MS: 389.1 ([M−H]−).