Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[NH2:14][CH2:15][C:16]1([C:27]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:19]2[C:20]3[O:24][CH:23]=[CH:22][C:21]=3[CH:25]=[CH:26][C:18]=2[CH2:17]1>ClCCl.C(N(C(C)C)CC)(C)C.O>[OH:32][C:27]1([C:16]2([CH2:15][NH:14][C:11]([C@@H:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)=[O:12])[C:19]3[C:20]4[O:24][CH:23]=[CH:22][C:21]=4[CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Reactant: NCC1(C2(O)CCCC2)Cc2ccc3ccoc3c21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NCC1(C2(O)CCCC2)Cc2ccc3ccoc3c21)[C@H]1COc2ccccc2O1
Reaction time: 48 h

Procedure:
A solution of 762 mg of (2R)-2,3-dihydrobenzo[1,4]dioxin-2-ylcarboxylic acid chloride is added, at 0° C., to 900 mg of the compound obtained in Step A in 30 ml of dichloromethane and 1.2 ml of diisopropylethylamine. After 48 hours at room temperature, the reaction mixture is diluted with water and extracted with dichloromethane. Conventional treatment of the organic phases enables, after evaporation under reduced pressure, the expected product to be isolated in the form of a meringue.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[CH:13][C:14](=[C:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[OH:15])[CH3:2].[Br:27]Br>C(Cl)Cl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[C:13]([Br:27])[C:14](=[C:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[OH:15])[CH3:2]
Reactant: BrBr
Reactant: CCN1C(=CC(O)=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21
Solvent: ClCCl
Product: CCN1C(=C(Br)C(O)=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21

Procedure:
A suspension of 2-[(1-ethyl-2(1H)-quinolylidene)-1-hydroxyethylidene]indan-1,3-dione (1.72 g, 0.005 mol) in methylene chloride (25ml) is stirred as bromine (1.76 g, 0.011 mol) in methylene chloride is added in one lot. The solid dissolves initially, and a new solid precipitates. After 5 minutes the product is collected and washed with methylene chloride. Yield 3.25 g (98%)
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:14])=[CH:15][CH:16]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCNCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCN(CCc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.110 g, 0.37 mmol) in methylene chloride (3.7 mL) were added N-hexyl-2-phenylethylamine (0.080 g, 0.39 mmol) and DMAP (0.045 g, 0.37 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.071 g, 0.37 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.125 g (70%) of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1)=[S:17].[OH-].[K+]>O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6]>[NH:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[C:16]1[S:17][C:5]2[C:6]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:15]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)c1nc2ccccc2[nH]1
Agent: [Fe+6]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccccc4[nH]3)nc12
Yield: 46.7 %

Procedure:
To a suspension of 0.19 g of benzoimidazole-2-carboxylic acid (1.0 mmol) in 4 ml DMF was added 0.21 g of CDI (1.3 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 0.25 g of 2-methoxy-5-morpholin-4-yl-phenylamine (1.2 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with methylene chloride. The combined organic phases were dried on sodium carbonate, evaporated and the residue was stirred in hot ethyl acetate. After filtration and trying 0.27 g 1H-benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (63%) were obtained as a yellow solid; M.p.: 236–237° C. 0.2 g of 1H-Benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.71 mmol) was taken up in toluene (15.0 ml) and treated with 0.28 g of Lawesson reagent (0.71 mmol). The reaction mixture was heated to reflux for 2 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 1:2, then ethyl acetate). 0.22 g of 1H-Benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (86%) was obtained as a yellow solid; M.p.: 240–241° C. 0.19 g of 1H-Benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.52 mmol) were taken up in water (5.0 ml) and treated with 0.116 g KOH (2.0 mmol) and 0.68 g of potassium hexacyano ferrate (2.0 mmol) at reflux for 24 h. After cooling to ambient temperature water (10 ml) was added and the mixture was filtered. The residue on the filter was dissolved in methanol and subjected to column chromatography (silica gel, methylene chloride/methanol 99:1). One obtained 0.089 g of 2-(1H-benzoimidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (39%) as a yellow solid; M.p.: 284–286° C.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=[O:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1C(=O)N([Cl:21])C(=O)C1>CC#N>[Cl:21][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:10][C:11]([OH:13])=[O:12])[CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)Cn1ccc2cccnc21
Solvent: CC#N
Product: O=C(O)Cn1cc(Cl)c2cccnc21
Temperature: 65 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To a suspension of 2-(1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (100 mg) in MeCN (10 mL) was added NCS (91 mg) and the reaction mixture was stirred at 60° C. overnight and at 65° C. for 20 h. The solvent was removed in vacuo, the residue was taken up in DCM and the resulting precipitate was filtered off. The precipitate was further washed with DCM and dried in vacuo. 92 mg of grey solid was obtained. LC-MS (B): tR=0.66 min; [M+H]+: 211.02.
Reaction SMILES: CC(C)([O-])C.[K+].FC1C=CC=CC=1CC#N.Cl[C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]#[C:27][CH3:28])[N:21]=[CH:20][N:19]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:25]([O:24][C:22]1[N:21]=[CH:20][N:19]=[CH:18][CH:23]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: CC(C)(C)[O-]
Agent: N#CCc1ccccc1F
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC#CCOc1ccncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 40 ml of tetrahydrofuran was suspended 4.61 g of potassium t-butoxide, to which 4.44 g of (2-fluorophenyl)acetonitrile was added under ice cooling. Then, a solution of 5.00 g of 4-chloro-6-(2-butynyloxy)pyrimidine in 20 ml of tetrahydrofuran was added at 0° C., followed by stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 6.40 g of 4-α-cyano-2-fluorobenzyl)-6-(2-butynyloxy)pyrimidine (the present compound (145)).
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:16][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=2)[CH:3]([OH:2])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 4-fluorobenzoyl chloride (70 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (152 mg, 83%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[C:21]([Cl:28])=[N:22][C:23]([CH3:27])=[N:24][C:25]=1[Cl:26].CC([O-])(C)C.[K+]>O1CCCC1>[Cl:15][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:2]([N:24]2[C:25]([Cl:26])=[C:20]([NH2:19])[C:21]([Cl:28])=[N:22][CH:23]2[CH3:27])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1N=C(Cl)C(N)=C(Cl)N1c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 1 h
Yield: 117 %

Procedure:
6.71 g (0.022 mole) of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene and 3.56 g (0.020 mole) of 5-amino-4,6-dichloro-2-methylpyrimidine are dissolved in 50 ml of tetrahydrofuran. The solution is cooled to -30° C. and, at this temperature, a solution of 4.6 g (0.041 mole) of potassium tert-butylate in 50 ml of tetrahydrofuran is added dropwise. After 1 hour at -30° to 0° C., the mixture is extracted with water and ethyl acetate while adding 10 ml of acetic acid. The extracts are dried over sodium sulfate and concentrated, affording 10.5 g of an oil as crude product. This product is purified by chromatography through a column of silica gel using a mixture of 3 parts of petroleum ether and 1 part of ethyl acetate. The solvent is removed by rotary evaporation, affording 8.3 g of product as residue. Recrystallisation from a mixture of toluene and cyclohexane yields 6.80 g (69.2% of theory) of yellow crystals with a melting point of 134°-136° C.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[F:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[CH:31]=[CH:32][C:33](O)=[O:34].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[CH:31]=[CH:32][C:33]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=1)=[O:34]
Reactant: COC(=O)[C@@H](N)Cc1cn(C(C)C)c2ccccc12
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C(C)C)c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 93.4 %

Procedure:
The same procedures as in Example 146 were carried out from the compound obtained in Example 144 (0.7 g), triethylamine (0.4 mL), 2-fluorocinnamic acid (0.44 g), WSC.HCl (0.50 g), and methylene chloride (20 mL), to give the captioned compound (0.9 g, 98%) as an oily product.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][O:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:54]3[CH2:55][CH2:56][CH:51]([O:50][CH3:49])[CH2:52][CH2:53]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methoxy piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42].CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CC[C@@H](N)CO
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CC[C@H](CO)Nc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, (R)-2-aminobutan-1-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (R)-2-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ylamino]-butan-1-ol. MS: (ES+) 461.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1.O.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[Br:1][C:15]1[CH:16]=[C:10]([F:9])[CH:11]=[C:12]([CH3:17])[C:13]=1[NH2:14]
Reactant: Cc1cc(F)ccc1N
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)cc(Br)c1N
Reaction time: 8 h

Procedure:
A solution of N-bromosuccinimide (18.7 g, 0.105 mol) in 70 mL of N,N-dimethylformamide was added dropwise to a solution of 4-fluoro-2-methylaniline in 70 mL of N,N-dimethylformamide at 20° C. The reaction mixture was stirred overnight. The dark solution was poured into a mixture of water (1000 mL), brine (50 mL) and ethyl acetate (300 mL). The mixture was transferred into a separatory funnel, shacked and separated. The aqueous phase was extracted with ethyl acetate (4×150 mL). The combined organic layers were washed with water (5×100 mL), brine (2×100 mL), dried with sodium sulfate, filtered and concentrated. The 1H NMR spectrum of the crude material showed at least 95% purity. The product was further purified on silica gel pad (eluent system ethyl acetate/n-hexane: 1/8). The pure fractions were combined and evaporated to give 14.9 g of product. The impure fractions were combined, concentrated, redissolved in diethyl ether (30 mL) and extracted with 5% hydrochloric acid (5×10 mL). The acidic phase was basified with aq. potassium hydroxide and extracted with diethyl ether to provide 0.8 g of the title compound. Total yield was 15.7 g (77%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][Mg]Cl>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:11][C:10]([OH:12])([CH3:13])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
In a dry round-bottomed flask, 1-Boc-3-azetidinone (0.70 g, 4.1 mmol) was dissolved in THF (20 mL). The solution was cooled to 0° C. and methylmagnesium chloride (3.0 M solution in THF, 2.0 mL, 6.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with 10 mL saturated NH4Cl, diluted with 5 mL water and extracted with 100 mL EtOAc (2×). The combined organic layers were washed with 10 mL water and 10 mL brine then combined, dried over sodium sulfate, filtered and concentrated to afford 757 mg (99%) of 3-hydroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]1([CH2:10][CH2:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)C>[C:15]1([CH2:14][CH2:13][C:12](=[O:21])[CH2:11][CH2:10][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:1]([O:21][CH3:12])=[O:2]
Reactant: C[O-]
Agent: O=C(CCc1ccccc1)CCc1ccccc1
Agent: [Na+]
Solvent: CCOCC
Product: COC=O
Yield: 220 %

Procedure:
To a suspension of sodium methoxide (6 g) in ethylether (80 ml), a mixture of 1,5-diphenyl-3-pentanone (24 g, 0.1 mole) obtained in above (1) and methyl formate (6.7 g, 0.11 mole) was added dropwise at 1°-2° C., stirring was continued for 1 hour at the same temperature and allowed to stand overnight at room temperature. The reaction mixture was poured into cold H2O (300 ml), and aqueous layer was separated, acidified to ph 1 with 5% sulfuric acid and extracted with ethylether (100 ml×3). The organic layer was separated, washed with H2O (100 ml×2), dried over anhydrous MgSO4 and evaporated to give 12.7 g of the title compound as a pale yellow oil. The product was found to have keto-form and enol-form in molar ratio of ca. 1:1 based on 1HNMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][CH3:29]
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added ethyl chloroformate (97.5 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 10%-35%, 25 min) to give the title compound (240 mg, 58%) as TFA salt. 1H NMR DMSO 400 MHz δ 9.99 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.42 (q, 3H), 7.20 (d, J=8.0 Hz, 1H), 7.11 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 6.48 (s, 1H), 6.35 (q, 1H), 4.84 (s, 2H), 4.50 (s, 2H), 4.00 (q, 2H), 1.17 (t, 3H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([N:14]([CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:4]([O:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:15])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: CN(Cc1ccccc1)CC(C)(C)CO
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reaction time: 1.5 h

Procedure:
One gram of diketen was added dropwise to a stirred solution of 3-(N-benzyl-N-methylamino)-2,2-dimethyl propanol in 1 ml of benzene at 70° C. Sturing was continued for 1.5 hours at 70° C. after the addition. The solvent was distilled off to leave an oily residue. The residue was chromatographed over silica gel to afford 2.8 g of desired 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (oily substance).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+:16]=[N-:17])[CH3:11].CC(O)(C)C>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:17]=[N:16]1)[CH3:11]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-ethynylpyridine (100 mg, 0.73 mmol) and ethylazidoacetate (0.41 ml, 0.73 mmol) were taken up in water (1.5 ml) and 2-methylpropan-2-ol (1.5 ml) at room temperature. Aqueous solutions of copper(II) sulfate pentahydrate (9.08 mg, 0.036 mmol) in 1 mL of water and L-sodium ascorbate (28.8 mg, 0.145 mmol) in 1 mL of water were sequentially added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-65% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[N+]1CCCC1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.C(Cl)(Cl)Cl.CC(O)=[O:42]>C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[CH2:13][CH:14]1[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][C:15]1=[O:42])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(CC2C(=[N+]3CCCC3)CCc3ccccc32)cc1OCc1ccccc1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C1CCc2ccccc2C1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A solution of 1-[1-(3-benzyloxy-4-nitrobenzyl)-3,4-dihydro-1H-naphthalen-2-ylidene]-pyrrolidinium bromide (700 mg, 1.59 mmol) in a mixed solvent of 10 mL H2O, 1 mL CHCl3 and 2 mL CH3COOH is stirred at RT for 3 h. The solution is diluted with CH2Cl2 and the organic layer is washed well with water, brine and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 33-50% EtOAc/hexane as eluent to give the title compound as a yellow liquid. NMR (CDCl3): 7.70-7.68 (d, J=8.34 Hz, 1H), 7.40-7.29 (m, 5H), 7.23-7.15 (m, 3H), 6.96-6.94 (dd, J=6.31 Hz, 1 H), 6.57-6.55 (m, 2H), 4.96 (s, 2H), 3.75-3.72 (t, J=6.07 Hz, 1H), 3.34-3.29 (q, J=6.82 Hz, 1H), 3.19-3.14 (q, J=5.30 Hz, 1H), 2.88-2.82 (m, 1H), 2.57-2.46 (m, 3H). (M−1)−=386.