Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]2[CH2:16][CH2:15]2)[CH2:12][N:11]2[N:17]=[C:18]([I:23])[C:19]([C:20]([OH:22])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:20]([C:19]1[C:18]([I:23])=[N:17][N:11]2[CH2:12][CH:13]([CH:14]3[CH2:15][CH2:16]3)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C:10]=12)(=[O:22])[NH2:27]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C1CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a stirred solution of Intermediate 348F (0.75 g, 1.731 mmol) in DMF (4.0 mL) was added NH4Cl (0.463 g, 8.66 mmol), HATU (1.316 g, 3.46 mmol) and DIPEA (1.512 mL, 8.66 mmol) and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (24 g REDISEP® column, eluting with 65% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 348G as a colorless liquid (0.51 g, 68%). MS(ES): m/z=433 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 6.83-7.50 (m, 2H), 5.07 (d, J=18.13 Hz, 1H), 4.50 (d, J=18.51 Hz, 1H), 4.20 (d, J=2.27 Hz, 2H), 3.84 (br. s., 1H), 1.43 (s, 9H), 0.89 (d, J=9.82 Hz, 1H), 0.47 (d, J=7.93 Hz, 2H), 0.27-0.40 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH2:14][CH2:13]1)=[N:9][C:8]([O:28][CH3:29])=[CH:7][CH:6]=2.Cl.O1CCOCC1>CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1)=[N:9][C:8]([O:28][CH3:29])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(N3CCN(CCNC(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(N3CCN(CCN)CC3)c2n1
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl (2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)carbamate (725 mg, 1.79 mmol) in MeOH (9 mL) at 25° C. was added dropwise a 4M solution of HCl in dioxane (3.1 mL, 12.53 mmol). After 12 h, the solution was concentrated the residue neutralized using excess MP carbonate resin in DCM affording the free amine which was used without further purification: LCMS (ES) m/e 306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.[C:13]([O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=2[CH3:33])=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(OC(=O)C1C=CC=C(OC2C=CC(NC3C4C=C(F)N=CC=4N=CN=3)=CC=2C)C=1)(C)(C)C>>[C:13]([O:17][C:18](=[O:34])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:9]3[C:4]4[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=4[N:6]=[CH:7][N:8]=3)=[CH:28][C:27]=2[CH3:33])=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: Cc1cc(N)ccc1Oc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from 6-Fluoro-3H-pyrido[3,4-d]pyrimidin-4-one and 4-(4-Amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester by a procedure analogous to the synthesis of 3-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-benzoic acid tert-butyl ester above. LRMS: 447.3/391.2 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 10.03 (s, 1H), δ 8.90 (s, 1H), δ 8.65 (s, 1H), δ 8.24 (s, 1H), δ 7.75-7.87 (m, 4H), δ 7.07 (d, J=8.73, 1H), δ 6.90-6.93 (m, 2H), δ 2.12 (s, 3H), δ 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Cl)[CH:13]=[CH2:14].[NH4+].[Cl-]>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:14][CH:13]=[CH2:12]
Reactant: COCC(=O)c1ccccc1
Reactant: C=CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)(COC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methoxy-1-phenyl-ethanone (5.00 g) dissolved in tetrahydrofuran (50 mL) was added to 2 M allylmagnesium chloride in tetrahydrofuran (21 mL) at room temperature. The solution was stirred at room temperature for 3 h and then 10% aqueous NH4Cl solution (50 mL) was added. The resulting mixture was extracted with tert-butyl methyl ether (3×50 mL) and the combined extracts were washed with water (50 mL) and brine (50 mL). The solvent was evaporated to afford the title compound as a colorless oil.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[CH:10].[N:17]([C:20]1[S:21][C:22]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[C:23]([CH3:25])[N:24]=1)=[N+:18]=[N-:19]>>[CH2:29]([NH:28][C:26]([C:22]1[S:21][C:20]([N:17]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:19]=[N:18]2)=[N:24][C:23]=1[CH3:25])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#Cc1cccnc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(-c3cccnc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 3-ethynylpyridine to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 13% yield: mp 117-119° C. (methanol/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.04 (t, J=3.0 Hz, 1H), 8.42 (d, J=6.0 Hz, 1H), 7.71 (d, J=6.0 Hz, 1H), 7.39-7.27 (m, 7H), 4.48 (d, J=6.0 Hz, 2H), 2.66 (s, 3H); MS (ES+) m/z 377.3 (M+1).
Reaction SMILES: [CH2:1]([NH:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][N:10]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])=[O:8])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.[C:46]1([CH3:56])[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1.CNCC(O[K])=O.OS([O-])(=O)=O.[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:5]([S:52]([C:49]1[CH:50]=[CH:51][C:46]([CH3:56])=[CH:47][CH:48]=1)(=[O:54])=[O:53])[NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:11][N:10]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])=[O:8])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NNCC(C)C)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: CNCC(=O)O[K]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)c3ccc(C)cc3)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Temperature: 25 °C
Yield: 124.8 %

Procedure:
(step 3) 4.3 g (3.15 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N′-isobutyl-hydrazide in 450 ml CH2Cl2 were treated with 5.6 ml (32.6 mmol, 4 eq) N-ethyldiisopropylamine, 3.1 g (16.3 mmol, 2 eq) p-toluene sulfonyl chloride and 100 mg (0.8 mmol, 0.1 eq) DMAP at 0° C. and was stirred at RT over night. 2.05 g (16.1 mmol, 2 eq) MeNHCH2CO2K were added and, the solution was stirred at RT for 1 h, 1M KHSO4 solution was added and, the phases were separated. The organic layer was extracted with sat. NaHCO3 and, the inorganic layers were washed with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Purification of the crude residue by flash chromatography with hexane:ethyl acetate 2:1 as eluent yields 2.68 g (48%) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N′-isobutyl-N′-(4-methyl-benzenesulfonyl)-hydrazide, which was directly subjected to the following reaction.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])(=O)[CH3:2].Cl.[CH2:23]([O:25][NH2:26])[CH3:24].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:23]([O:25][NH:26][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])[CH3:2])[CH3:24]
Reactant: CCON
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C)cc2)CC1=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(C)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 Gram of 2-acetyl-5-[2-(4-methylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 60 ml of ethanol, and after adding 0.25 g of ethoxyamine hydrochloride and 0.26 g of triethylamine, the resulting solution was stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. After removing chloroform, the product obtained was purified by thin layer chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 0.4 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-methylphenylthio)ethyl]cyclohexane-1,3-dione [Compound (2)].
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=12>C(Cl)(Cl)Cl.O=[Mn]=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=12
Reactant: OCc1ccn2ccnc2c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccn2ccnc2c1
Temperature: 60 °C

Procedure:
To a solution of imidazo[1,2-a]pyridin-7-yl-methanol (1 eq.) in chloroform was added MnO2 (10 eq.). The dark suspension was heated at 60° C. for 30 min, filtered through a pad of celite and the solvent removed under reduced pressure to afford imidazo[1,2-a]pyridine-7-carbaldehyde which was used as such without further purification.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].C(N(CC)CC)C.[C:24]12([C:34](Cl)=[O:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>O1CCCC1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:34]([C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:35])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
2.93 g (0.010 mol) of L-alanyl-L-proline ethylamide hydrobromide were dissolved in 50 ml of tetrahydrofuran and the mixture was cooled to 0° C. There were then added 2.8 ml (0.020 mol) of triethylamine followed by 2.15 g (0.010 mol) of 1-adamantoyl chloride. The mixture was stirred at 0° C. for 0.5 hour and at room temperature for 2 hours and then evaporated to dryness. The oily residue was dissolved in ethyl acetate and the solution washed successively with 0.5-N hydrochloric acid, water, 5% sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The resulting oil was crystallised from ethyl acetate/petroleum ether to yield 2.2 g (59%) of N-(1-adamantylcarbonyl)-L-alanyl-L-proline ethylamide of melting point 116°-118° C; [α]D20 =-88.1° (c=0.99% in methanol).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:5]([C:12]([NH2:14])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[OH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:5]([C:12]([NH2:14])=[O:13])[S:6][C:7]=1[N:27]1[CH2:28][CH2:29][O:30][CH:25]([CH2:24][OH:23])[CH2:26]1)#[N:2]
Reactant: OCC1CNCCO1
Reactant: CS(=O)(=O)c1sc(C(N)=O)c(-c2ccc(Cl)cc2Cl)c1C#N
Product: N#Cc1c(N2CCOC(CO)C2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 70.1 %

Procedure:
4-cyano-3-(2,4-dichlorophenyl)-5-(methylsulfonyl)thiophene-2-carboxamide (0.013 g, 0.0346 mmol) was dissolved in 2-hydroxymethylmorpholine (0.300 g, 2.56 mmol) and the solution was heated at 60° C. overnight. The residue was concentrated in vacuo and column chromatography was performed and yielded the title compound 87 (0.010 g, 66%) as a white solid. LCMS: (FA) ES+ 412, 414, 416. 1H NMR (400 MHz, d4-methanol) δ: 7.68 (s, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 4.08-3.92 (m, 3H), 3.88-3.56 (m, 4H), 3.16-3.04 (m, 2H).
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[C:27](=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[CH3:19][C:17]([C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:18].[CH3:27][O:9][C:7]1[CH:8]=[CH:2][C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: Cc1cc(O)ccc1O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: COc1ccc(O)cc1
Temperature: 180 °C
Reaction time: 0.08 h

Procedure:
To a 1 L glass reaction vessel, methylhydroquinone (1.07 moles, 133.14 g), bisphenol-A (0.03 moles, 6.28 g) and diphenyl carbonate (1.19 moles, 254.50 g) were added. The system was purged and backfilled with nitrogen three times. After heating the system to about 180° C., the system underwent a modified series of the 11 segments described in Table 1 where Segments 7 and 9 were shortened to about 5 minutes and the temperature for Segment 11 was 310° C. After a total of almost 3 hours, the polymer was stranded to give about 124 g and about 132 g each for two batches.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].C1COCC1.[N:35]1([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O.CCCCCC>[O:29]=[C:4]1[C:3](=[CH:2][NH:47][C:44]2[CH:43]=[CH:42][C:41]([CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:46][CH:45]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 200 mg, 0.4945 mmol) and THF (5.0 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (87.1 mg, 0.494 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 52% yield (0.144 g, 0.256 mmol).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[CH2:20]2)=[O:17])[NH:13][C:12]1=[O:37])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:45]([C:48]1[CH:58]=[CH:57][C:51]([CH2:52][O:53][CH2:54][CH2:55]Cl)=[CH:50][CH:49]=1)([O-:47])=[O:46].P([O-])([O-])([O-])=O>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[CH2:20]2)=[O:17])[N:13]([CH2:55][CH2:54][O:53][CH2:52][C:51]2[CH:57]=[CH:58][C:48]([N+:45]([O-:47])=[O:46])=[CH:49][CH:50]=2)[C:12]1=[O:37])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
57.7 mg (0.105 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-([(S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl)-2-azetidinone and 33 mg (0.33 mmole) of triethylamine were dissolved in 3 ml of methylene chloride. To the solution were added 73 mg (0.30 mmole) of p-nitrobenzyloxyethyl chloride, with ice-cooling under a nitrogen atmosphere. The mixture was stirred for 1 hour and then poured into a 0.1M phosphate buffer solution (pH 7.2). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride. The solvent was distilled off and the residue was purified by column chromatography through 1.3 g of silica gel, to give 67.8 mg (yield 83%) of the desired product as an oil from the fraction eluted with mixtures of benzene and ethyl acetate in volume ratios from 12:1 to 4:1.
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].Br[CH2:19][Cl:20]>>[C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:19][Cl:20])=[O:7]
Reactant: O=C([O-])CCCCC(=O)OCc1ccccc1
Reactant: ClCBr
Product: O=C(CCCCC(=O)OCc1ccccc1)OCCl
Temperature: 0 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To 350 ml of bromochloromethane cooled to 0° C. is added 67 g (0.14 mole) tetrabutylammonium salt of benzyl adipate half ester and the mixture is stirred overnight at 0° C. then allowed to warm to room temperature. The excess bromochloromethane is evaporated in vacuo, 400 ml ethyl ether is added to the residue and the mixture is stirred to form crystals of tetrabutylammonium bromide. The crystals are removed by filtration, washed with ether, stirred with ethyl acetate (300 ml) for one hour and refiltered and washed with ethyl acetate. The combined filtrates are evaporated in vacuo, the residue purified by chromatography on silica gel (1 kg), eluting with 2:1 hexane/ethyl acetate, to yield 19.1 g (48%) of the title compound. 1H--NMR (CDCl3) ppm (delta): 1.58-1.9 (m, 4H), 2.2-2.62 (m, 4H), 5.13 (s, 2H), 5.68 (s, 2H), 7.38 (s, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH3:27])[CH2:8][CH:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][C:13]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:15]=2)[O:10]1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.CO.[OH2:34].OOS([O-])=O.[K+].[OH2:41]>>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:8][CH:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][C:13]([S:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:41])=[O:34])=[CH:14][CH:15]=2)[O:10]1)[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CN(CC1CC(=O)c2ccc(Sc3ccccc3)cc2O1)C(=O)OC(C)(C)C
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of methyl-(4-oxo-7-phenylsulfanyl-chroman-2-ylmethyl)-carbamic acid tert-butyl ester (200 mg, 0.5 mmol) in a mixture acetonitrile/methanol/water (1/1/1, 30 mL) was added oxone (922 mg, 1.5 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was then diluted with water and the solid was filtered off. The filtrate was concentrated in vacuo to give (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (186 mg, 86% yield) as yellow glass which was used without further purification for deprotection in the next step.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9](=[O:30])[C@H:10]([C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([OH:29])([CH2:22]3)[CH2:20]1)[CH2:26]2)[NH:11]C(OC(C)(C)C)=O)#[N:2].[C:31]([O-:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+]>>[NH2:11][C@@H:10]([C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][C:21]([OH:29])([CH2:27]3)[CH2:20]1)[CH2:28]2)[C:9]([N:4]1[C@H:3]([C:1]#[N:2])[CH2:8][C@H:7]2[C@@H:5]1[CH2:6]2)=[O:30].[C:31]([O-:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Agent: O=C([O-])c1ccccc1
Agent: [Na+]
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
A coupling reaction is then used to couple (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, (Formula 3) methanesulfonic acid salt to (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Formula J) in the presence of 1-hydroxybenzotriazole (HOBT) or other known coupling agent to produce 3-(aminocarbonyl)-αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula K). Formula K compound is subjected to dehydration by treating compound K with organic base such as pyridine or triethylamine and trifluoroacetic anhydride, and then subjecting the reaction to hydrolysis by cooling to from about 0 to about 10° C. and adding sodium hydroxide or other strong base such as KOH or LiOH to form Compound L. 3-cyano-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula L), which is then deprotected (and treated with sodium benzoate) to form the dipeptidyl peptidase IV inhibitor (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, benzoate (1:1) (Formula M).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([C:14](=[O:25])C2C=CC(C(C)(C)C)=CC=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]2[C:9](=[O:11])[C:8]3[C:7](=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:13][CH:12]=3)[C:14](=[O:25])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)c2cc(C(C)(C)C)ccc2C(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2c(c1)C(=O)c1cc(C(C)(C)C)ccc1C2=O
Temperature: 150 °C
Yield: 69 %

Procedure:
Into a 500 ml flask having the egg plant shape equipped with a condenser, 200 ml of polyphosphoric acid was placed and heated at 150° C. Then, 32 g (95 mmole) of 4-t-butyl-2-(4-t-butylbenzoyl)benzoic acid was added in small portions, and the resultant mixture was stirred at the same temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into ice water, and the resultant mixture was treated by liquid-liquid extraction with chloroform. After being dried with magnesium sulfate, the extract was concentrated under a reduced pressure by a rotary evaporator. The obtained crude crystals were recrystallized from hexane, and 21 g of the anthraquinone compound of the object compound was obtained (the yield: 69%; yellow crystals).