Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>N1C=CC=CC=1>[C:25]([O:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(C)C(=O)OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
170 mg of dimethylaminopyridine and 3.4 mg of pyridine are added to 3.0 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate. 1.66 ml of isobutyryl chloride are added dropwise thereto. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed in succession with 20 ml of citric acid, water; sodium bicarbonate solution and water. After drying and evaporation of the ether phase there are obtained 3.9 g of t-butyl (S)-3-isobutyroxymethyl-1-piperidinecarboxylate, Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated 30 ml of methanol are added to the residue and saturated sodium bicarbonate solution is then added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. There are obtained 2.82 g of (S)-3-iso-butyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt, Rf=0.4 (Takeda solution).
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].Cl.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C.O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:5]3[C:6]4[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=4[CH2:12][CH2:13][C:4]=3[C:1]([CH3:2])=[N:33]2)=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc2c(c1)C(=O)C(C(C)=O)CC2
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(OCc3ccccc3)cc1)CC2
Yield: 32.1 %

Procedure:
2-Acetyl-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (72.5 mg, 0.33 mmol) and 4-benzyloxyphenylhydrazine hydrochloride (90 mg, 0.36 mmol) were heated in ethanol at 70° C. for 2.5 days. The reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, dried over MgSO4, and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 42 mg of the desired product. LC-MS (C26H24N2O2 calculated 396) m/z 397 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][C:20]([CH2:25][CH3:26])([CH2:23][OH:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C:20]([NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])([CH2:23][OH:24])[CH2:25][CH3:26]
Reactant: CCC(N)(CO)CO
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: CCC(CO)(CO)NC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(1,1-Bis-hydroxymethyl-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.47 mmol of 2-amino-2-ethyl-propane-1,3-diol. LC/MS [5.93 min; 460 (M+1)]
Reaction SMILES: [Br-].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH2:33]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH2:44][CH2:45][CH:46]=O)[CH2:40][CH2:39]1)[CH2:34][CH2:35][CH2:36][CH3:37].O>COC(C)(C)C>[CH2:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH:46][CH2:45][CH2:44][C@H:41]2[CH2:40][CH2:39][C@H:38]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:43][CH2:42]2)=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCC=O)CC1
Agent: [Br-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC[C@H]1CC[C@H](CCC=Cc2ccc(OCCCC)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
A mixture of 54 g of (4-butyloxyphenyl)methyl-triphenylphosphonium bromide and 450 ml of absolute t-butyl methyl ether was treated with 12 g of solid potassium t-butylate at 0° C. and while gassing with nitrogen. After completion of the addition the reaction mixture was stirred at 0° C. for a further 15 minutes (whereby a deep orange coloration resulted) and then treated within 30 minutes at 0° C. with a solution of 15 g of 3-(trans-4-pentylcyclohexyl)propionaldehyde in 150 ml of absolute t-butyl methyl ether. Subsequently, the reaction mixture was stirred at room temperature overnight and then poured into 1000 ml of water and extracted three times with 200 ml of diethyl ether each time. The organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with hexane/toluene (vol. 4:1) gave 21 g of 1-butyloxy-4-[4-(trans-4 -pentylcyclohexyl)-1-butenyl]benzene (cis/trans mixture). Recrystallization from ethanol gave pure trans isomer with m.p. (C-SB) 46° C., SB --SA 74° C., SA --N 76° C. and cl.p. (N--I) 91° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:16](S(C)=O)=[C:15]([CH2:20][CH3:21])[C:13](=[O:14])[NH:12][C:10]1=[S:11])(=O)C.[C:22]1([SeH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].Cl>CCO>[CH2:20]([C:15]1[C:13](=[O:14])[NH:12][C:10](=[S:11])[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:16]=1[Se:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: CCc1c(S(C)=O)n(CCCCOC(C)=O)c(=S)[nH]c1=O
Reactant: [SeH]c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c([Se]c2ccccc2)n(CCCCO)c(=S)[nH]c1=O
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred suspension of 1-(4-acetoxybutyl)-5-ethyl-6-(methylsulfinyl)-2-thiouracil (0.33 g, 1.00 mmol) and benzeneselenol (0.11 mL, 1.04 mmol) in EtOH (5 mL) was added 1N methanolic NaOH solution (3.00 mL) at room temperature under a nitrogen atmosphere. After the mixture was stirred for 2 h, 3N HCl in EtOH (1.00 mL) was added and the reaction mixture was evaporated to dryness. The residue was purified by flash column chromatography on silica gel with MeOH-CHCl3 (5:95) as eluent to give 0.23 g of the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 3 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (90 mg, 0.289 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (62 mg, 0.304 mmol), DL-10-Camphorsulfonic acid (84 mg, 0.362 mmol) and isopropanol (3 mL) in a microwave tube. Microwaved reaction at 120° C. for 20 minutes. Evaporated off solvent and purified with normal phase chromatography to yield an off-white solid, 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-3,N-dimethyl-benzamide (4.2 mg, 3%). LCMS: m/z=479.37 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.06 (d, 1H, J=1.3 Hz), 7.39 (m, 4H), 7.27 (m, 1H), 7.18 (s, 1H), 7.14 (s, 1H), 6.66 (d, 1H, J=8.6 Hz), 6.10 (m, 1H), 2.92 (m, 3H), 2.34 (m, 2H), 2.25 (s, 3H), 2.05 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].O.[CH2:68]([OH:72])[CH2:69]CC>C(OC(=O)C)(=O)C>[C:68]([NH:1][CH2:2][C@H:3]1[O:7][CH:6]([O:8][C@@H:9]([C@@H:49]2[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@H:5]([O:64][CH3:65])[C@H:4]1[OH:66])(=[O:72])[CH3:69]
Reactant: CCCCO
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CO[C@H]1C(O[C@H](C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CNC(C)=O)[C@@H]1O
Reaction time: 0.58 h

Procedure:
A suspension of 39.0 mg (41.2 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid in 2.0 ml of acetic anhydride is placed in an ultrasonic bath (Branson 1200) at room temperature for 35 minutes. Water (2 ml) and n-butanol (2 ml) are added to the reaction mixture and the volatile materials removed under reduced pressure to a residue which is suspended in 2 ml of acetone and the suspension filtered through glass wool. The desired product (the acetone insoluble product) is recovered as a white solid by dissolving in 2 ml water followed by lyophylization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide as a solid in quantitative yield. MS: 294 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]Br.[Mg].[C:13]([NH:20][C:21]([CH3:25])([CH3:24])[CH:22]=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCOCC>[C:13]([NH:20][C:21]([CH3:25])([CH:24]=[CH:9][CH:3]1[C:2]([CH3:11])([CH3:1])[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])[CH3:22])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC1(C)CCC(C)(C)C1CBr
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent beings to form. The remainder of the alkyl bromide is then added and the mixture is stirred until all of the magnesium has dissolved. At 0° C. a solution of N-Boc-2-amino-2-methylpropanal is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCl, extracted with ether and the extracts are evaporated. The residue dissolves in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated as shown by thin layer chromatography. Water is added and the mixture extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[NH:13]1[CH:17]=[N:16][N:15]=[N:14]1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:14]1[N:15]=[N:16][CH:17]=[N:13]1
Reactant: c1nnn[nH]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Cn1ncnn1)c1ccc(Cl)cc1Cl
Yield: 42.7 %

Procedure:
A solution of 15.9 g (71 mmol) of 2,2',4'-trichloroacetophenone in 100 ml of methylene chloride was slowly added dropwise while cooling with ice to a solution of 4.98 g (71 mmol) of tetrazole and 14.4 g (142 mmol) of triethylamine in 100 ml of methylene chloride and heated under reflux for 16 hours. The reaction mixture was added to 100 ml of water and extracted three times with 100 ml of methylene chloride each time. The combined organic phases were dried over magnesium sulphate and concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). There were obtained 4.75 g (26%) of 1-(2,4-dichloro)-2-tetrazol-1-yl-ethanone and 7.80 g (43%) of 1-(2,4-dichlorophenyl)-2-tetrazol-2-yl-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]([O-:16])([O-])=O.[K+].[K+].C(Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[C:13]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)ccc1OC(=O)c1ccccc1

Procedure:
A mixture of methyl 5-chloro-2-hydroxy-benzoate (2.5 g, 13.4 mmol), K2CO3 (3.7 g, 26.8 mmol) and benzyl bromide (2.98 g, 17.4 mmol) in acetone (30 ml) was refluxed for 12 hours. After cooling, acetone was evaporated. EtOAc (100 ml) was added and filtered. The organic layer was then washed with 1M HCl (1×80 ml), brine (2×80 ml) and dried with Na2SO4. After filtration and evaporation of the solvent, yellow semi-solids were obtained (3.2 g). 1H NMR (d6-acetone) δ=7.73 (1H, d); 7.60-7.30 (1H+5H, m); 7.28 (1H, d); 5.30 (2H, s) and 3.90 (3H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C[C:11]1[C:16]([C:17]([O-:19])=O)=[C:15](C)[C:14]([C:21]([O-:23])=O)=[C:13](C)[C:12]=1[C:25]([O-:27])=O.Cl>CC(C)=O.O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:25]([C:12]1[CH:11]=[C:16]([C:17](=[O:19])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:15]=[C:14]([C:21](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:13]=1)=[O:27]
Reactant: CC(=O)C(C)(C)C
Reactant: Cc1c(C(=O)[O-])c(C)c(C(=O)[O-])c(C)c1C(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1cc(C(=O)CC(=O)C(C)(C)C)cc(C(=O)CC(=O)C(C)(C)C)c1
Reaction time: 7 h
Yield: 52.7 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 2.29 gm (57 mmol) of 60% sodium hydride, 5.24 gm (52 mmol) of pinacolone, 4.0 gm (15.8 mmol) of trimethyl-1,3,5-benzenetricarboxylate, and 40 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and the refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N aqueous hydrochloric acid was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Acetone was added to the crude product, and recrystallization afforded 3.8 gm of the target compound as yellow crystals (yield: 52%).
Reaction SMILES: [CH:1]1([N:7]([CH2:26]COC(=O)C)[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([C:22](=O)C)[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:33][C:34](=O)[C@H:35]([CH2:37][OH:38])[NH2:36].COC(=O)[CH:43](CO)[NH2:44]>>[CH:1]1([N:7]([CH3:26])[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:16](=[CH:17][CH:18]=2)[N:19]=[C:43]2[NH:44][C:34](=[O:33])[CH:35]([CH2:37][OH:38])[N:36]2[CH2:22]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C(N)CO
Reactant: CC(=O)OCCN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C(C)=O)c1)C1CCCCC1
Reactant: COC(=O)[C@@H](N)CO
Product: CN(C(=O)CCCOc1ccc2c(c1)CN1C(=N2)NC(=O)C1CO)C1CCCCC1

Procedure:
Proceeding in a like manner but substituting the appropriate aldehyde of formula (6) as prepared in Preparation 4, or the appropriate ketone of formula (8) as prepared in either Preparation 6 or 9, and either L-serine methyl ester or a racemic mixture of D,L-serine methyl ester or similar ester, there are prepared the following exemplary compounds:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].Br[CH2:12][C:13]1[C:18]2[N:19]=[C:20]([N:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:12][C:13]1[C:18]2[N:19]=[C:20]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2c(CBr)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(OCC)[C@H](C)NCc1cccc2sc(NC(=O)OC(C)(C)C)nc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 140.8 %

Procedure:
To the solution of (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 442 mg (3.00 mmol) in acetonitrile 5 ml, 4-bromomethyl-2-bis(tert-butoxycarbonyl)aminobenzothiazole (Compound XXI-1) 133 mg (0.30 mmol) and potassium carbonate 62 mg (0.45 mmol) were added and stirred at 65° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 100 ml and washed with water 100 ml and brine 100 ml. The organic phase was dried with magnesium sulfate 1 g and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound 173 mg (yield 71%).
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]=[C:37](C(Cl)(Cl)Cl)[O:36][N:35]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-:44].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:19][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][C:37](=[O:44])[O:36][N:35]=4)=[CH:24][CH:23]=3)[C:8](=[O:18])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(-c3ccccn3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(-c3ccccn3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
A mixture of 6-ethyl-3-pyridin-2-ylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.48 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.078 g, 16%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:28]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:28]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1cccnc1C(C)Br
Product: Cc1cccnc1C(C)Sc1c(Cl)ccc2c1CCNCC2
Product: Cl

Procedure:
Use a method similar to the Preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with (±)-2-(1-bromoethyl)-3-methyl-pyridine. Use a method similar to the General Procedure 1-5, basic workup, and a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z: 333 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]Cl)=[CH:3][CH:2]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:11]=[N+:12]=[N-:13])=[CH:3][CH:2]=1
Reactant: ClCCCc1ccncc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCc1ccncc1
Temperature: 65 °C

Procedure:
A solution of 2-3 (7 g, 41.2 mmol) in DMSO (150 mL) was treated with sodium azide (2 g, 45.3 mmol) and heated to 65° C. for 72 h. The solution was diluted with EtOAc, washed with H2O and saturated NaHCO3. The H2O washing was basified to pH11 and extracted with EtOAc. The organic layers were combined, dried with brine and MgSO4, filtered and evaporated to give 2-4 as a yellow oil.