Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([F:17])([F:16])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([F:17])([F:16])[C:8]2=[O:18])[CH2:4]1
Reactant: Clc1nc2ccccc2s1
Reactant: N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cccnc32)C1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C1N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncccc2C1(F)F
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1-(Trans-3-aminocyclobutyl)-3,3-difluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrobromide (0.084 g, 0.262 mmol), 2-chlorobenzothiazole (0.0534 g, 0.315 mmol), and N,N-diisopropylethylamine (0.183 mL, 1.050 mmol) were mixed in DMSO (0.5 mL) in a sealed tube. The reaction mixture was stirred at 120° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.030 g, 0.081, 30.7% yield) as a white solid. M+1: 373.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.49 (m, 2 H) 3.19-3.30 (m, 2 H) 4.48-4.58 (m, 1 H) 5.10 (quin, J=8.36 Hz, 1 H) 7.04 (t, J=7.53 Hz, 1 H) 7.21-7.26 (m, 1 H) 7.29 (dd, J=7.34, 5.38 Hz, 1 H) 7.43 (d, J=7.82 Hz, 1 H) 7.70 (d, J=7.24 Hz, 1 H) 8.20 (dd, J=7.43, 1.37 Hz, 1 H) 8.51-8.56 (m, 2 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].[C:24](Cl)([O:26][CH2:27][CH:28]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25].Cl>O.O1CCOCC1.CCOC(C)=O>[C:24]([CH:2]([NH2:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:25]
Reactant: NCc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(C(=O)OCC1c2ccccc2-c2ccccc21)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 5 °C

Procedure:
Cool to 5° C. a mixture of 2′-aminomethylbiphenyl-4-carboxylic acid (Preparation D, Step 5) (1.14 g, 5.0 mmol) and Na2CO3 (1.33 g, 12.5 mmol) in water:dioxane (2:1, 70 mL). Add Fmoc-Cl (1.3 g, 5.0 mmol) and stir at ice-bath temperature for 4 hours, then overnight at room temperature. Pour into a mixture of warm EtOAc (1 L) and 1N aqueous HCl (100 mL) and stir vigorously. Separate organic layer, dry (MgSO4), and concentrate in vacuo until solids appear. Collect the title compound, m.p. 215-218° C. MS (Cl+/CH4) m/z 450 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:53]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[O:21])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)O)cs2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)N3CCCCCC3)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
3-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.075 g, 0.24 mmol) was dissolved in DMF (2 mL). Triethylamine (0.72 mmol), HATU (0.26 mmol) and homopiperidine (0.26 mmol) were added and the reaction stirred at room temperature overnight. The reaction mixture was purified directly by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.066 g). LCMS m/z 393.26 [M+H]+ RT=4.05 min (Analytical Method 4).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([OH:12])[CH2:7][CH2:6]2
Reactant: O=C1CCc2cc(C(F)(F)F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
To a solution of 5-(trifluoromethyl)indan-1-one (0.7 g, 3 mmol) in THF (5 mL) cooled in an ice bath was added sodium borohydride (0.1 g, 3 mmol) followed by MeOH (1 mL). After being stirred for 30 min, the reaction was quenched with aqueous NaHCO3. The resulting solution was extracted with EtOAc twice. The extracts were washed with brine, dried (MgSO4), filtered and concentrated. The crude material was purified by flash chromatography on silica eluting with 20% EtOAc/hexane to afford the desired product (0.65 g, 92%) as an oil. LC/MS calculated for C10H9F3O: (M+H)+ 203. found 185.1 (M+H—H2O)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][N:7]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)[CH2:3][OH:4].C1([O:25][C:26](=O)[NH:27][C:28]2[N:29]([CH3:35])[N:30]=[C:31]([CH2:33][CH3:34])[CH:32]=2)C=CC=CC=1>CS(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH:9]2[CH2:10][N:7]([CH2:6][CH2:5][C@H:2]([NH:1][C:26]([NH:27][C:28]3[N:29]([CH3:35])[N:30]=[C:31]([CH2:33][CH3:34])[CH:32]=3)=[O:25])[CH2:3][OH:4])[CH2:8]2)=[CH:17][CH:16]=1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(C)n1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Solvent: CS(C)=O
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.45 g, 2 mmol) and (5-Ethyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (0.49 g, 1.66 mmol) in DMSO (5 ml) is stirred at ambient temperature for 1 hour, then partitioned between water and ethylacetate. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by recrystallisation from hot ethylacetate to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].[NH3:21]>O>[NH2:21][C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20]
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Reactant: N
Solvent: O
Product: CCCN1CC(C)=C(N)C2=C1N1CN(OC)C=C1C=N2
Temperature: 130 °C

Procedure:
10 g of intermediate A1 and 200 ml of an aqueous solution of NH3 (32%) are mixed in an autoclave and heated up to 130° C. for 8 hours. The reaction mixture is diluted with 200 ml water. The precipitated reaction product is separated washed with water and dichloro methane and dried at reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH:16]=[O:17].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:16]([OH:20])=[O:17]
Reactant: COc1ccccc1C1CCCCC1CC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccccc1C1CCCCC1CC(=O)O
Yield: 84 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-acetaldehyde (0.336 g, 1.45 mmol), and acetone (10.0 mL). Add dropwise Jones reagent until color goes from green to orange and persists for several minutes (approximately 1.0 mL). Then concentrate on rotovap then add ethyl acetate and wash excess chromium away with brine washes. Dry over anhydrous sodium sulfate, concentrate to yield the titled compound (0.301 g, 84%). TLC Rf=0.13 in 20% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (m, 1H), 7.0 (m, 1H), 6.8 (m, 2H), 3.8 (s, 3H), 3.3 (m, 1H), 2.6 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.6 (m, 8H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][C@@H:31]([OH:36])[C:32]([O:34]C)=[O:33])=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>CO>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:29][CH2:30][C@@H:31]([OH:36])[C:32]([OH:34])=[O:33])=[O:28])=[CH:37][CH:38]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2nc3ccccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Example 7 (0.1 mmol, 50 mg) in 2 mL of MeOH was added LiOH (0.5 mmol, 12 mg). H2O was added dropwise until the reaction became slightly cloudy, then the mixture was sonicated to dissolve the LiOH. The reaction was stirred at 40° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was taken up in dioxane/H2O and acidified with TFA. Purification by reverse-phase HPLC (Condition A), followed by lyophilization, afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 7.79 (d, 2H), 7.58 (m, 1H), 7.39-7.52 (overlapping m, 5H), 4.86 (s, 2H), 4.34 (m, 1H), 3.87 (s, 3H), 3.52-3.84 (overlapping m, 3H), 2.16 (m, 2H), 1.99 (m, 2H), 1.84 (m, 2H), 1.31 (m, 2H), 1.14 (m, 1H), 0.92 (s, 9H). MS (ESI): m/z 487 (M+H). MS (ESI): m/z 507 (M+H). HPLC A: 1.84 min.
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:27]([C:30]1[S:31][C:32]([C:35](O)=[O:36])=[CH:33][N:34]=1)([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:27]([C:30]1[S:31][C:32]([C:35]([N:5]2[CH2:6][C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[O:2][CH2:3][CH2:4]2)=[O:36])=[CH:33][N:34]=1)([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CC(C)c1ncc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.694 g) in DMF (13 mL) was treated with triethylamine (1.3 mL), followed by 2-isopropylthiazole-5-carboxylic acid (example 55, step b) (0.406 g) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g). The resulting mixture was stirred at RT for 16 h. DMF was removed in vacuo. The residue was taken up in EtOAc (40 mL) and washed with saturated sodium bicarbonate solution (2×40 mL), water (40 mL) and brine (40 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The viscous orange oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a viscous orange oil. Yield 0.765 g.
Reaction SMILES: [CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24](=[NH:41])[NH2:25])=[CH:22][CH:23]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C1CCCC1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccco2)C1
Yield: 78.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-furanboronic acid (102 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (150 mg, 78.5%) as an oil.
Reaction SMILES: [CH2:1](Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:10]([C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][N:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:17]=2[CH:31]=1)(=[O:12])[CH3:11]>CC(C)=O>[C:10]([C:13]1[CH:14]=[CH:15][C:16]2[N:22]([CH2:1][CH3:2])[C:21](=[O:23])[CH2:20][N:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:17]=2[CH:31]=1)(=[O:12])[CH3:11]
Reactant: CCBr
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Temperature: 25 °C
Reaction time: 71 h

Procedure:
14.2 ml of ethyl bromide and 27.2 g of potassium carbonate are added to 13.6 b (45.9 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 400 ml of acetone. The mixture is stirred at room temperature for 71 hours, filtered and evaporated in vacuo. The residue is taken up in methylene chloride, the organic phase is washed with water, dried and evaporated. From methylene chloride/cyclohexane there is obtained 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 154°-156°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][C:34](=[O:43])[N:35]3[CH2:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1.Cl[C:45]1[C:50]([O:51][CH3:52])=[CH:49][N:48]=[CH:47][N:46]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[C:28]([CH2:27][O:26][CH:14]3[CH:13]([C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:45]5[C:50]([O:51][CH3:52])=[CH:49][N:48]=[CH:47][N:46]=5)=[CH:8][CH:9]=4)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15]3)[CH:37]=2)[CH2:32][CH2:33][C:34]1=[O:43]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCN)cc3)cc21
Reactant: COc1cncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCNc4ncncc4OC)cc3)cc21
Temperature: 90 °C
Reaction time: 20 h

Procedure:
The mixture of 0.200 g of tert-butyl 4-[4-(4-aminobutoxy)phenyl]-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate, 0.058 g of 4-chloro-5-methoxypyrimidine, 0.0064 g of (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl, 0.387 g of sodium tert-butoxide and 0.0028 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex in 10 ml of toluene is stirred under argon at 90° C. over 20 hours. The reaction mixture is cooled, admixed with brine (20 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=4.60.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O-]CC.[Na+].Br[CH2:14][C:15]([OH:17])=[O:16]>C(O)C>[C:15]([CH2:14][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])([OH:17])=[O:16]
Reactant: O=C(O)CBr
Reactant: CCOP([O-])OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)(CC(=O)O)OCC
Yield: 154.6 %

Procedure:
A mixture of 4.0 ml (0.031 mole) of diethyl phosphite, 6.68 g (0.093 mole) of 94% sodium ethoxide, and 4.32 g (0.031 mole) of bromoacetic acid in 50 ml of absolute ethanol was heated under reflux for 1 h. Solvent was removed at reduced pressure, and the residual solid was triturated with ethyl acetate and 15 ml of conc hydrochloric acid with shaking and portionwise addition of water until all the solid was dissolved. The ethyl acetate layer was separated, dried (over MgSO4), and evaporated to give 9.4 g of residual liquid diethyl carboxymethylphosphonate; 1H NMR spectrum confirmed the structure of this compound which is disclosed by Martin and Griffin, J. Org. Chem., 30, 4034-4038 (1965).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1.CN1CCOCC1.ClC(OCC(C)C)=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCCc1ccc(Br)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NCCc1ccc(Br)cc1
Reaction time: 0.67 h

Procedure:
To a solution of N-Boc-glycine (175 mg) in tetrahydrofuran (2 mL), N-methylmorpholine (165 μL) and isobutyl chloroformate (131 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, 2-(4-bromophenyl)ethylamine (100 μL) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((4-bromophenethyl)amino)-2-oxoethyl)carbamate (R5).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH:14]=O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:17][CH:18]1[O:23][CH:22]([CH3:24])[CH2:21][NH:20][CH2:19]1.C1(C)C=CC=CC=1.[H][H]>[Pd].O>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14][N:20]2[CH2:19][CH:18]([CH3:17])[O:23][CH:22]([CH3:24])[CH2:21]2)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CC1CNCC(C)O1
Reactant: CCC(C)(C)c1ccc(CC(C)C=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)(C)c1ccc(CC(C)CN2CC(C)OC(C)C2)cc1

Procedure:
230 G. of 3-(p-tert.-amyl-phenyl)-2-methyl-propionaldehyde and 137 g. of 2,6-dimethylmorpholine are heated at reflux in 1000 ml. of toluene for 16 hours in a water-separator under nitrogen gasification until the water-cleavage has been completed. 17.5 G. of 5% palladium/carbon are added at room temperature under nitrogen gasification and the mixture is subsequently hydrogenated until the hydrogen uptake has been completed. Then, the catalyst is removed by filtration and the toluene is evaporated in vacuo. By distillation of the residue, there is obtained pure 4-[3-(p-tert.-amyl-phenyl)-2-methyl-propyl]-2,6-dimethylmorpholine having a boiling point of 134° C./0.036 Torr.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:22](OC(C)(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH:25]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16])[CH3:24]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
6-Phenyloxindole (0.053 mg, 0.25 mmol) and dimethylformamide di-t-butylacetal (0.08 mL, 0.32 mmol) were combined and dissolved in DMF. The reaction mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the resulting residue was triturated with diethyl ether. The solids were collected by filtration (50 mg, 75% yield).). 1H NMR 400 MHz (DMSO-d6) mixture of E and Z isomers: δ10.09 (s, 1H); 10.02 (s, 1H); 7.59-7.51 (m, 4H); 7.45-7.22 (m, 10H); 7.10-7.05 (m, 2H); 6.98 (s, 1H); 6.91 (s, 1H); 3.29 (s, 12H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>CN(C=O)C>[CH2:20]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1cn(Cc2ccccc2)cn1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A solution of 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) in DMF (2 mL) was added over 10 min to a suspension of NaH (20 mg, 0.47 mmol) in DMF (1 mL) at room temperature and after 30 min benzyl bromide (83.5 mg, 0.49 mmol) was added. After 2 h at room temperature, the mixture was poured into aqueous acetic acid (10%) and extracted with ethyl acetate. The organic extracts were then washed with water and brine, and then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1) afforded the title compound (88 mg, 63%) which was obtained as a colourless gum. MS: m/e=316.1 [M+H]+.