Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=O)=[CH:28][CH:27]=1)([O-:25])=[O:24].O>O1CCOCC1>[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](=[S:10])[NH2:32])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Solvent: O
Product: NC(=S)c1ccc([N+](=O)[O-])cc1
Yield: 119.3 %

Procedure:
6.06 g (15 mmol) of Lawesson reagent is added to a solution of 4.15 g (25 mmol) of 4-nitrobenzamide in 100 ml of 1,4-dioxan. The reaction mixture is heated under reflux for two hours. After the solution has returned to ambient temperature, it is poured into 150 ml of water and extracted with 5 times 100 ml of ethyl acetate. The organic solution is dried over magnesium sulphate, filtered and concentrated under vacuum in order to produce a yellow oil which is purified on a silica gel column (eluant: heptane/ethyl acetate 1/1). The pure fractions are collected and concentrated under vacuum. 3.26 g of a yellow powder is obtained with a yield of 72%. Melting point: 165-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36](=[O:44])[N:35]([CH3:34])[CH3:45])[CH2:43][CH2:42]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (4 mL) was added N,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride (72 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 73.4 mg (64%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=616.3, RT=2.41 min. 1H NMR (400 MHz, CD3OD-d4) δ: (ppm) 9.09 (dd, 1H, J=1.6, 7.2 Hz), 8.66-8.64 (m, 2H), 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=2.8 Hz), 7.57 (dd, 1H, J=2.8, 8.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.4, 7.2 Hz), 6.63 (t, 1H, J=73.6 Hz), 5.29 (s, 2H), 3.84-3.77 (m, 4H), 3.75 (s, 2H), 3.08 (s, 3H), 3.06-2.96 (m, 7H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:3]=1[C:4]([O:6]C1C=CC=CC=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:27]([C:25]1[N:26]=[C:22]([NH:21][C:4](=[O:6])[C:3]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:2]=2[OH:1])[S:23][CH:24]=1)=[O:28]
Reactant: COC(=O)c1csc(N)n1
Reactant: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
In 250 mg of xylene were suspended 250 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) and 144 mg of methyl 2-amino-1,3-thiazole-4-carboxylate (4a) in a stream of argon, which was then heated to reflux (at 140° C.) for 7 hours. The reaction was not completed. After cooling, methanol was added, followed by stirring for one hour. The precipitated crystal was collected by filtration and dried under reduced pressure at 60° C. to provide 170 mg of the same compound (5a) as that of Example 4 at a yield of 55%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].CC(O)C.C(=O)=O.[Br:17]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:17][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:9]
Reactant: BrBr
Reactant: Cc1ccc(O)cc1C
Agent: O=C=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(O)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 3,4-dimethylphenol (2.48 g, 20.3 mmol, 1 equiv) in DCM (200 mL) at −78° C. (IPA/dry ice) was added dropwise bromine (1.05 mL, 20.3 mmol, 1 equiv). After 1 h, 1 N Na2SO3 was added and the cold bath was removed. After warming to ambient temperature, the DCM layer was separated, dried (Na2SO4), and concentrated in vacuo to provide the product (4.09 g, 100%) as a yellow solid. Regioselectivity>10:1, use as is. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 6.83 (s, 1H), 5.26 (s, 1H), 2.20 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:6]([N:13]1[C:14]([CH2:17][OH:18])([CH3:19])[CH2:15][O:16][CH2:2][C:3]1=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CO)(CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(CO)COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (14.0 ml) was added dropwise to a mixture of 2-benzylamino-2-methyl-1,3-propanediol (28.5 g), potassium carbonate (30.3 g) in dichloromethane (150 ml) and water (150 ml) at 0° C., and the whole was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane and the extract was washed successively with water, 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tert-butanol (400 ml) and the solution was added potassium tert-butoxide (16.38 g) portionwisely and the whole was refluxed for 30 minutes. After cooling, the solvent was removed by evaporation and ethyl acetate and water were added thereto. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:1) as an eluent to give 4-benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.89 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:17]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1-c1ccccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2ccccn2)cc1

Procedure:
The title compound was prepared according to the general procedure using 4-tert-butyl-benzenesulfonyl chloride and 4-chloro-2-pyridin-2-yl-phenylamine and purified by preparative HPLC. MS: (M+H)/z=401.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][C@@H:26]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:25][CH2:24]2>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:35]([O:34][C:33]([NH:32][CH2:31][C@H:26]1[CH2:25][CH2:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)[CH:22]=2)[O:27]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCc2cc(I)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC(=O)OC(C)(C)C)O3)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
A solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Example 15, 1.67 g, 6.36 mmol) in 130 mL toluene and 27 mL 1,4-dioxane was degassed with argon for 10 minutes. tert-Butyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylcarbamate (Example 12, 1.65 g) and 265 mg (3 mol %) Pd(dppf)Cl2 were then added, and the solution was degassed with argon for an additional 5 minutes. Finally, 26.5 mL of 2M aqueous sodium carbonate was added and the solution was stirred at 85° C. for 16 hours. This mixture was then cooled to ambient temperature, filtered through a pad of Celite®, and concentrated in vacuo. The product was then purified by Biotage (100% methylene chloride to 3% MeOH: methylene chloride) to obtain 1.40 g of product. m/z=397.9 [M+].
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[CH2:3]([N:2]([CH3:1])[CH2:17][C:18]([CH3:19])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)CN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Put 12.118 g (100 mmol) N-methylbenzylamine with 16.584 g (120 mmol) potassium carbonate in 100 ml toluene. Add dropwise 11.103 g (120 mmol) chloroacetone and stir overnight under reflux. Then cool to RT, filter to remove the salt and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 8:2), obtaining 9.0 g (50.8% of theor.) of the target compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CC#N>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1cccc(Br)n1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CCN(c2cccc(C=O)n2)CC1
Temperature: 110 °C
Yield: 31.8 %

Procedure:
A suspension of 6-bromopicolinaldehyde (1.50 g, 8.10 mmol), 1-methylpiperazine (2, 4.04 g, 40.0 mmol), potassium carbonate (4.46 g, 32.0 mmol) and anhydrous CH3CN (10 mL) was placed in a sealed vessel and the mixture was heated at 110° C. for 17 h. The mixture was diluted with water (50 mL) and brought to pH 7 using 2 N aq. HCl (15 mL). The resulting solution was extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with brine (200 mL). The solution was dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography eluting with 0-5% CH3OH in CH2Cl2 to afford the title compound (0.528 g, 32%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.84 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.27 (d, J=7.0 Hz, 1H), 6.85 (d, J=7.0 Hz, 1H), 3.67-3.65 (m, 4H), 2.55-2.52 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH:30]=O>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][N:19]([CH2:30][C:26]5[S:27][CH:28]=[CH:29][C:25]=5[CH3:24])[CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Br)ccc2n1C1CCN(C2CCNCC2)CC1
Reactant: Cc1ccsc1C=O
Product: Cc1ccsc1CN1CCC(N2CCC(n3c(=O)[nH]c4cc(Br)ccc43)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 18, using 5-bromo-1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one and 3-methyl-2-thenaldehyde.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.[H][H]>CO.[C].[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[NH:2][CH3:1])=[CH:13][CH:14]=1
Reactant: CNc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1ncnc2c1ncn2-c1ccc(N)cc1
Yield: 71.1 %

Procedure:
In 1,000 mL of methanol, 13.0 g (48 mmol) of methyl-[9-(4-nitrophenyl)-9H-purin-6-yl]amine was suspended, and 1.8 g of 10% palladium carbon was added thereto, and the suspension was stirred in a hydrogen atmosphere at 60° C. for six hours. The palladium carbon was removed by Celite filtration, and the product was concentrated under reduced pressure, and the obtained crude product was purified by a silica gel column (ethyl acetate:methanol=9.1) to obtain 8.2 g (70%) of a target product as a pale yellow solid.
Reaction SMILES: [CH2:1]=O.[Br:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][NH2:14])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1>C(O)=O>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]2[C:5]=1[CH2:1][NH:14][CH2:13][CH2:12]2
Reactant: COc1cc(Br)cc(CCN)c1
Reactant: C=O
Solvent: O=CO
Product: COc1cc(Br)c2c(c1)CCNC2
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Paraformaldehyde (660 mg; WAKO) was added to a formic acid (50 mL) solution of Intermediate 4 (4.33 g) at 50° C. and the resulting mixture was stirred as it was for 13 hours and 30 minutes. The solvent was evaporated under reduced pressure followed by the addition of dichloromethane (100 mL) and 1 N aqueous sodium hydroxide solution (100 mL) to extract the reaction mixture, and the aqueous layer was further extracted with dichloromethane. The organic layer was combined and dried and then the solvent was evaporated under reduced pressure to give the title compound (4.49 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>O>[CH2:24]([O:31][C:32]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10][CH2:9]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(=O)C2(CCN(Cc3ccccc3)CC2)c2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 15.1 g of 1'-benzyl-1-methyl-2-oxoindoline-3-spiro-4'-piperidine, 33.5 g of benzyloxycarbonyl chloride and 530 ml of toluene was refluxed for 6 hours. The resulting mixture was poured into water and extracted with ethylacetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thus obtained oil was washed with n-hexane to give 1'-benzyloxycarbonyl-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH:16](=O)/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH:18]=[CH:17][CH:16]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C/C=C/c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(N=CC=Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
p-Anisidine (12.32 g) is dissolved in 160 ml of methylene chloride and 20 g of anhydrous magnesium sulfate is added. The mixture is cooled in an ice bath and 13.22 g of transcinnamaldehyde is added. The mixture is stirred under nitrogen for 2 hours and then filtered. The filtrate is evaporated to give a solid. The crude product is recrystallized from methylene chloride-petroleum ether to give 20.96 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:59]=[CH:58][C:6]([CH2:7][O:8][C:9](=[O:57])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:56])[N:25]([CH2:31][C:32]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:35]=[C:34]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:33]=2)[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(O[N:82]1[C:87](=[O:88])[CH2:86][CH2:85][C:83]1=[O:84])=[N+](C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:57])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:56])[N:25]([CH2:31][C:32]2[CH:33]=[C:34]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH:35]=[C:36]([O:38][CH2:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH:37]=2)[CH2:26][CH2:27][C:28]([O:30][N:82]2[C:87](=[O:88])[CH2:86][CH2:85][C:83]2=[O:84])=[O:29])=[CH:58][CH:59]=1
Reactant: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)ON2C(=O)CCC2=O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
15-[(3,5-Bis-tert-butoxycarbonylmethoxybenzyl)-(2-carboxyethyl)carbamoyl]pentadecanoic acid 4-methoxybenzyl ester (190 mg, 0.23 mmol) was dissolved in THF (5 mL). The mixture was cooled with an ice bath. Diisopropylethylamin (0.047 mL, 0.28 mmol) and O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (83 mg, 0.28 mmol) was added. The mixture was stirred under nitrogen at 0° C. After 30 minutes the ice cooling was removed and the mixture was stirred for an additional 3 hours. Solvent removed in vacuo. The crude product was dissolved in ethyl acetate (50 mL), washed with aqueous phosphate buffer (pH=5.5) (3×25 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo to yield the title compound (163 mg) which was used in subsequent step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:18][CH2:17][CH:16]([O:15][C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[C:12]([F:11])([F:26])[F:27])[CH2:21][CH2:20]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Temperature: 82.5 °C

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.6 g, 6.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine (1.2 g, 7.6 mmol), and DBU (2 mL, 13 mmol) in DMF (25 mL) was heated at 80-85° C. for 2 h. The EtOAc extract was washed three times with water, dried (MgSO4) and concentrated. CombiFlash chromatography (120 g, 20-40% EtOAc in hexanes in 20 min, 70 mL/min, 18 mL/fraction) gave the desired product as a yellow powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([F:19])[CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:25]([O-])([O-:27])[O-:26]>C1COCC1>[C:14]([C:13]1[CH:17]=[CH:18][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][C:2]([B:25]([OH:27])[OH:26])=[CH:3][C:4]=3[CH:9]=2)=[CH:11][C:12]=1[F:19])(=[O:15])[NH2:16]
Reactant: [O-]B([O-])[O-]
Reactant: NC(=O)c1ccc(-c2ccc3occc3c2)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccc3oc(B(O)O)cc3c2)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Intermediate 20 (100 mg 0.4 mmol) was dissolved in THF (10 ml) and this mixture was cooled to −78° C. under N2 atmosphere. n-BuLi (0.5 ml, 1.3 mmol) was added to the above mixture and stirred at same temperature for 20 mins Reaction mixture warmed to 0° C. and stirred for 2 hrs. After that trisopropyl borate (88 mg, 0.47 mmol) was added and stirred the reaction for 16 h at rt. Reaction mass quenched with 2N HCl worked it up (EtOAC/H2O) to afford the titled compound (110 mg) as a crude. It was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[N:19]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:19]1([CH:23]2[CH2:28][CH2:27][N:26]([CH2:11][C:9]3[S:8][C:6]4[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[C:5]=4[N:10]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: C1CN(C2CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
To a solution of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (308 mg, 1.08 mmol) in DCE (8 mL) was added 4-azetidin-1-ylpiperidine (166 mg, 1.19 mmol). The resulting mixture was stirred at RT for 10 min then sodium triacetoxyborohydride (297 mg, 1.40 mmol) was added and stirring was continued for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH and concentrated in vacuo to give the title compound as an off-white solid (263 mg, 60%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22]>O1CCCC1>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:32])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 292°-293° C.
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[OH:20]O.O>CO>[CH2:1]([S:3]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20])[CH3:2]
Reactant: OO
Reactant: CCS[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Solvent: O
Solvent: CO
Product: CCS(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.224 g of (3R,4S)-4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of methanol is added 0.16 ml of 30% aqueous hydrogen peroxide and the mixture is stirred at room temperature for 4 hours. Then, 0.1 ml of 30% aqueous hydrogen peroxide is added, and the mixture is further stirred for 4 hours, followed by addition of 10 ml of water. Extraction is carried out with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of (3R,4S)-4-ethylsulfinyl-3-phenoxyacetamido-2-oxoazetidine.