Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH3:17])=[CH:11][CH:10]=1.N1C=CC=CC=1>C(O)C>[CH3:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:2][OH:3])[CH2:16][CH3:17])=[CH:11][CH:10]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(OCCOC)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NO)c1ccc(OCCOC)cc1
Yield: 96.7 %

Procedure:
Hydroxylamine hydrochloride (2.27 g, 32.7 mmol) was added to a stirred solution of 1-(4-(2-methoxyethoxy)phenyl)propan-1-one (3.4 g, 16.3 mmol) and pyridine (3.87 g, 49.0 mmol) in ethanol (25 mL) and the mixture heated at reflux for 4 hours then allowed to cool. Most of the ethanol was removed by concentration, and the residue was partitioned between water and dichloromethane. The layers were separated and the aqueous phase extracted 2× with dichloromethane. The combined extracts were washed twice with water, then with sat brine and dried over magnesium sulfate. The solvent was removed by concentration, and then the residue was dissolved in toluene and again concentrated; this process was repeated once more, and the residue was dried under in vacuo to afford 3.52 g of the product as a cream-colored crystalline solid; mp 74-80° C.; mass spec ES+m/z=224 (m+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([OH:57])=[O:56])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:63](=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([O:57][CH3:63])=[O:56])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 84.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 25m (0.45 g, 0.57 mmol) in a methanol/tetrahydrofuran mixture (v/v=6/5, 22 mL) was added concentrated sulphuric acid (0.05 mL) at room temperature. The mixture was warmed up to 60° C. and stirred for 14 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 at room temperature and extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=6/1 to give the title compound 25n as a pale yellow solid (0.38 g, 84.4%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ(ppm): 7.48 (m, 1H), 7.47 (m, 2H), 7.41 (m, 4H), 7.33 (m, 7H), 7.25 (m, 3H), 7.21 (m, 4H), 7.16 (m, 2H), 7.08 (m, 2H), 6.87 (m, 2H), 5.01 (s, 2H), 4.81-4.75 (m, 3H), 4.78 (m, 1H), 4.63 (d, 1H), 4.52 (d, 1H), 4.26 (d, 1H), 4.19 (m, 2H), 4.09 (m, 1H), 4.01 (m, 2H), 3.87 (m, 1H), 3.74 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: COC1C=CC([N:9]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:11]([O:19][C:20](=[O:22])[CH3:21])[C:10]2=[O:23])=CC=1>C(#N)C.O>[C:20]([O:19][C@H:11]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:9][C:10]1=[O:23])(=[O:22])[CH3:21]
Reactant: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@@H]1C(=O)N[C@@H]1c1ccccc1

Procedure:
The above procedure may, in turn, be followed by modification of the lactam formed, should a different lactam starting material be desired. For example, a cis-1-p-methoxy-phenyl-3-acetoxy-4-phenylazetidin-2-one racemate prepared as above, in acetonitrile at a temperature such as -10° C. to -5° C., may be treated with a solution of ceric ammonium nitrate in water to yield a cis-3-acetoxy-4-phenylazetidin-2-one racemate. The latter compound may, for example, further be hydrolyzed, e.g., with aqueous potassium hydroxide, to yield cis-3-hydroxy-4-phenylazetidin-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O.[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=2)[N:20]=1>C(O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH:25]=2)[N:20]=1
Reactant: OB(O)c1ccccc1O
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3O)ccc2n1
Temperature: 80 °C

Procedure:
39.8 mg of 2-hydroxybenzeneboronic acid, 100 mg of potassium carbonate, 4.2 μl of water and 9.8 mg of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) are added to a solution of 100 mg of 2-amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline in 3 ml of ethanol under argon. The mixture is heated at 80° C. for 12 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)c(F)c1
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzaldehyde (0.42 g, 3.00 mmol) in DCM (15 mL) was added pyrrolidine (0.26 g, 3.60 mmol). After stirring for 20 min, sodium triacetoxyborohydride (0.76 g, 3.60 mmol) was added and the reaction mixture was stirred overnight. The mixture was then diluted with DCM and transferred to a separatory funnel. Water was added, basified to pH 9-10 with a 0.1 M solution of NaOH and extracted 6 times with DCM. The organic layer was dried (phase separator) and concentrated in vacuo. There was obtained 0.55 g (94%) of 31A as a solid. 1H NMR (500 MHz, CDCl3): δ 1.85 (s, 4H), 2.70 (s, 4H), 3.60 (s, 2H), 6.25 (m, 2H), 7.00 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]=[CH:1][C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(C=Nc2ccc(F)cc2)cc1
Yield: 101.2 %

Procedure:
tert-Butyl (4-formylphenoxy)acetate (21.6 g, 0.09 mol) was dissolved in dry toluene (150 ml) and 4-fluoroaniline (8.8 ml, 0.091 mol) was added. The mixture was refluxed in a Dean-Stark apparatus for 23 hours, cooled and concentrated under reduced pressure. Addition of hexane and concentration under reduced pressure afforded 30.0 g (quant. yield) of the title compound as an off-white solid. NMR (200 MHz): 1.5 (s, 9H), 4.6 (s, 2H), 7.0-7.2 (m, 6H), 7.8 (d, 2H), 8.4 (s, 1H).
Reaction SMILES: [N:1]1([CH:6]=[CH:7][C:8]#N)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1(C=CCC)CCCC1.C(O)(=O)C.[ClH:23]>C(Cl)(Cl)Cl>[Cl:23][C:6]1[CH:7]=[CH:8][C:4]([CH2:3][CH3:2])=[CH:5][N:1]=1
Reactant: Cl
Reactant: N#CC=CN1CCCC1
Agent: CCC=CN1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
19.3 g of β-pyrrolidino-acrylonitrile were added at -10° C. to 30 g of pyrrolidino-butene from A4 in 50 ml of chloroform. The mixture was allowed to warmto RT, and 50 ml of acetic acid were added dropwise. After stirring at RT for 15 hours, the mixture was cooled to -10° C., and dry hydrogen chloride gas was introduced. Aqueous workup gave 2-chloro-5-ethylpyridine as the main product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:22]4[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:13]=2)[N:22]2[C:17]=1[C:18]([NH2:23])=[N:19][CH:20]=[N:21]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CN1CCN(c2cc(-c3ccc4c(N)ncnn34)ccn2)CC1
Solvent: C1CCOC1
Product: CN1CCN(c2cc(-c3cc(Br)c4c(N)ncnn34)ccn2)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
To a cooled (−20° C.) solution 7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (250 mg, 0.81 mmol) in tetrahydrofuran (5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (115 mg, 0.40 mmol) in four portions over 15 min. The mixture was allowed to stir (−20° C.) for 4 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (10 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (2×20 mL). The combined organics were filtered to remove a fine precipitate and the filtrate was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 0% to 25% acetonitrile in water to obtain 60 mg (19%) of the desired product as a yellow foam. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, 1 H), 8.14 (dd, 1 H), 7.89 (s, 1 H), 7.14 (s, 1 H), 6.90 (d, 1 H), 3.55-3.50 (m, 4 H), 2.40-2.34 (m, 4 H), 2.20 (s, 3 H); ES-MS m/z 388.12 [M+H]+, HPLC RT (min) 1.38.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[Cl:12][C:13]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16].ClCCl>CN1CCCC1=O>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:18]([NH:17][C:15](=[O:16])[C:14]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:13]=1[Cl:12])=[O:19]
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Nc1ccc(C(=O)O)cc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Yield: 22.7 %

Procedure:
150 mg (1 mmol) of 3,4-diaminobenzoic acid were dissolved in 2 ml of N-methyl-2-pyrrolidinone and, at 0° C., 1 ml (1.2 mmol) of the 2-chloro-4-fluorobenzoyl isocyanate/dichloromethane solution prepared in stage a was added. The resulting precipitate was filtered off with suction. The crude mixture (500 mg) was purified by column chromatography (dichloromethane/methanol=98/2 to 93/7). 80 mg (25%) of the desired product were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](O)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (480 mg, 2.0 mmol) was reacted with trans-4-aminocyclohexanol (287 mg, 2.5 mmol) to afford the desired product (500 mg, 78%) as an orange-red solid: 1H NMR (500 MHz, CDCl3) δ 10.90 (s, 1H), 8.95 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.10 (tdt, J=11.2, 8.0, 3.9 Hz, 1H), 3.76 (tt, J=10.0, 4.3 Hz, 1H), 2.68 (s, 3H), 2.33-2.24 (m, 2H), 2.13-2.04 (m, 2H), 1.63-1.41 (m, 8H); ESI MS m/z 320 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[OH-].[Na+]>O>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(F)ccc1-c1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)ccc1-c1ncccn1
Temperature: 72 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 5-fluoro-2-pyrimidin-2-yl-benzoic acid methyl ester (1.72 g, 7.407 mmol) in 2-methyl-THF (20 mL) was added sodium hydroxide (0.74 g, 18.517 mmol) and water (20 mL). The mixture was heated to 72° C. and stirred for 2 h. The layers were separated and the aqueous layer was extracted with additional MTBE. A 50% HCl(aq) solution was then dripped into the aqueous layer until a pH of 1 was reached. The resulting solids were filtered to provide the desired product as an off-white solid (1.34 g, 83% yield). 1H NMR (400 MHz, CD3OD): 8.82 (d, J=5.0 Hz, 2H), 7.89 (dd, J=8.6, 5.4 Hz, 1H), 7.53 (dd, J=9.0, 2.7 Hz, 1H), 7.39 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.O(C(C(F)(F)F)(C(F)(F)F)C(OCC)=O)C1C=CC=CC=1>>[O:6]([C:7]([C:13]([F:14])([F:15])[F:16])([C:17]([F:18])([F:19])[F:20])[C:8]([OH:10])=[O:9])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCOC(=O)C(Oc1ccccc1)(C(F)(F)F)C(F)(F)F
Product: O=C(O)C(Oc1ccccc1)(C(F)(F)F)C(F)(F)F

Procedure:
The above process is repeated except that the ethyl 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate is replaced by ethyl 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate (13 g.) and the residue obtained by evaporation of the ethereal extract is purified by distillation at 10-3 mm. pressure, crystallisation from petrol (b.p. 30°-40° C.) at -65° C. and redistillation to give 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionic acid, b.p. 68°-70° C. at 10-3 mm., m.p. 6°-8° C. (8 g.).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23][O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:23][O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-CBZ-D-phenylalanine (47.3 g, 0.158 mmol) in DMF (300 mL) at 0° C., was added L-proline-methylester.HCl (25.0 g, 0.151 mmol), 1-hydroxybenzotriazole hydrate (20.28 g, 0.166 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.8 g, 0.166 mmol) and 4-methylmorpholine (16.0 g, 0.159 mmol). The reaction mixture was stirred for 8 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (1.2 L) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed as follows: KHSO4 (0.25 M, 2×200 mL), water (1×200 mL), saturated aqueous NaHCO3 (2×200 mL) and saturated NaCl (1×200 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give title compound, 60.9 g (98%), as an oil. MS (M+H)+ =411+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd]>[C:26]([C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]=1[OH:25])[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1cc(C(=O)N2CCN(Cc3ccccc3)CC2)cc(C(C)(C)C)c1O
Agent: [Pd]
Product: CC(C)(C)c1cc(C(=O)N2CCNCC2)cc(C(C)(C)C)c1O

Procedure:
In tetrahydrofuan (100 mL) was dissolved the compound (5.08 g, 12.4 mmol.) obtained in (1) above. To this solution was added 10% palladium/carbon (600 mg), and the resulting mixture was stirred under hydrogen atmosphere. The reaction mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1), to give the desired compound as a white crystalline product (1.50 g, yield: 38%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](N2CCOCC2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[N:5]=[C:6]([C:33]2[CH:34]=[C:29]([C:26](=[O:28])[CH3:27])[CH:30]=[CH:31][CH:32]=2)[N:7]=1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a mixture of compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.5 g, 1.54 mmol) and 3-acetyl benzene boronic acid (0.125 g, 0.31 mmol) in DMF (10 mL) was added palladium tetrakis triphenyl phosphine (0.053 g, 0.046 mmol) and 2M Na2CO3 solution (1.3 g, 12.34 mmol) at temperature in the range of 20-40° C. The reaction mixture was heated for 12 hours under nitrogen atmosphere. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate (3×10 mL). Combined the organic layers were concentrated and the residue was purified by column chromatography using 15% ethylacetate in petroleum ether to afford the desired compound (0.125 g, 20%) as a white solid.
Reaction SMILES: NC1C=C(OC)C(Cl)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:31][C:32]1[C:33]([O:57][CH3:58])=[CH:34][C:35]2[N:41]=[C:40]3[N:42](CC=C)[NH:43][C:44]([CH3:45])=[C:39]3[N:38]=[C:37]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:55])[C:36]=2[CH:56]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:31][C:32]1[C:33]([O:57][CH3:58])=[CH:34][C:35]2[N:41]=[C:40]3[NH:42][NH:43][C:44]([CH3:45])=[C:39]3[N:38]=[C:37]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:55])[C:36]=2[CH:56]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(Cl)c(OC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1Cl
Product: COc1cc2c(cc1Cl)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
7-chloro-5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVcc) was prepared by reacting 0.0023 moles of (2-amino-5-chloro-4-methoxyphenyl)-(2-chlorophenyl)-methanone (Xcc) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 7-chloro-5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVcc) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=373.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:1][CH2:2][CH:3]2[O:8][C:7]3[C:9]4[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=3[S:5][CH2:4]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:22][CH:21]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC(CO)O2
Reactant: O=C=Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
To a solution of 2-(hydroxymethyl)-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (0.13 g, 0.50 mmol) in N,N-dimethylformamide (1.5 mL) was added 1-fluoro-4-isocyanatobenzene (0.024 mL, 0.55 mmol) and potassium carbonate (0.026 g, 0.50 mmol). The mixture was stirred at 40° C. for 3 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 10% methanol in EtOAc) to give the product as a purple solid (0.051 g, 26%). M.p.=235-237° C.; 300 MHz 1H NMR (DMSO-d6) δ: 9.89 (s, 1H), 7.89 (d, J=7.5, 1H), 7.71 (br. s, 2H), 7.50 (m, 3H), 7.12 (m, 2H), 4.78 (m, 1H), 4.53 (m, 2H), 3.18 (m, 2H); LCMS: 400 [M+H].
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:35])=[CH:26][CH:27]=1)[CH3:21]
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(4-Ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.37 min; [M+H]+=506.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28](Cl)(=[O:39])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:28]([O:29][C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)=[O:39]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.5 g, 3.57 mmol), and DMAP (0.436 g, 3.57 mmol) were dissolved in DCM (50 ml), and 4-nitrophenyl carbonochloridate (0.863 g, 4.28 mmol) was added portion wise. The mixture was stirred at RT overnight. After 18 hours, the solvent was evaporated and the crude purified by silica gel flash chromatography (petroleum ether:EtOAc 3:7) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)-ethyl)pyridine 1-oxide (1.609 g, 2.75 mmol, 77% yield, MS/ESI+ 585 [MH]+).