Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@H:43]([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[K+].[CH3:48][N:49]([CH3:53])[C:50](Cl)=[O:51]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@H:43]([O:45][C:50](=[O:51])[N:49]([CH3:53])[CH3:48])[CH3:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 100 mg of (R)-1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propan-2-ol (diastereomer 1) (from example 34b) in 10 ml tetrahydrofuran, are added 35 mg of potassium hydride and 0.14 ml of N,N-dimethylcarbamoyl chloride at room temperature. The reaction mixture is stirred for one additional hour, diluted with water and extracted with tert-butyl methyl ether. The combined organic phases are dried and concentrated under reduced pressure to afford the crude title compound. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.37 (EtOAc-heptane 2:1); Rt=5.44.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](O)[C:7]3[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>P(Cl)(Cl)(Cl)=O>[Cl:17][C:6]1[C:7]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:8]=2[N:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: Cc1nn(C)c2c(O)nc(C3CC3)nc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c2c(Cl)nc(C3CC3)nc12
Yield: 89.2 %

Procedure:
A mixture of 5-cyclopropyl-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol (14.3 g, 0.07 mol) and 18 g (0.088 mol) phosphorus pentachloride in 150 ml of phosphorus oxychloride is stirred under reflux for seven hours and evaporated in vacuo. The residue is dissolved in methylene dichloride and stirred with a saturated aqueous solution of NaHCO3. The organic layer is separated, dried (MgSO4), and evaporated in vacuo to give 13.9 g (84%) of 7-chloro-5-cyclopropyl-1,3-dimethyl-pyrazolo[4,3-d]pyrimidine, mp 87°-90° C. from heptane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1>CS(C)=O>[N+:28]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8]2)=[CH:22][CH:23]=1)([O-:30])=[O:29]
Reactant: c1ccc(C2CNCCO2)nc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCOC(c3ccccn3)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)morpholine (0.1 g, 0.609 mmol) in dimethylsulfoxide (5 mL) was added triethylamine (0.17 mL, 1.2 mmol). The resulting solution was stirred for 10 min at room temperature, and then 6-chloro-3-nitropyridin-2-amine (105 mg, 0.609 mmol) was added. The reaction mixture was heated at 110° C. for 4 h, and then was cooled to room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (80% ethyl acetate in petroleum ether) to afford the title compound (0.1 g, 55%). MS (ES+) (M+H) 302.25.
Reaction SMILES: C([Sn](CCCC)(CCCC)[O:6][Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])CCC.Cl[Si:29](Cl)([CH3:31])[CH3:30]>>[CH2:16]([Sn:7]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[O:6][Si:29]([O:6][Sn:7]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH2:18][CH3:19])([CH3:31])[CH3:30])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(Cl)Cl
Product: CCCC[Sn](CCCC)(CCCC)O[Si](C)(C)O[Sn](CCCC)(CCCC)CCCC
Temperature: 180 °C

Procedure:
Hexabutyldistannoxane (2 equiv.) was slowly added dropwise with stirring to dimethyldichlorosilane (19), followed by heating to 180° C. for 4 hours and vacuum distillation to give bis(tri-n-butylstannyloxy)dimethylsilane 24. Equimolar amounts of 23 and 24 in THF were stirred at room temperature for 4 hours before cyclosiloxane 25 was isolated by distillation.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:8][C:7]([CH3:24])([CH3:23])[CH:6]1[CH2:25][CH2:26][CH2:27][CH:28]([CH2:29][OH:30])[CH:5]21.[ClH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:8][C:7]([CH3:23])([CH3:24])[CH:6]2[CH2:25][CH2:26][CH2:27][CH:28]([CH2:29][OH:30])[CH:5]32)=[O:42])[CH2:34][CH2:33]1
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1C(CO)CCCC1C(C)(C)N2
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccccc1)c1cc2c(cc1OC(=O)CCCN1CCOCC1)C1C(CO)CCCC1C(C)(C)N2
Temperature: 25 °C

Procedure:
To a 25° C. solution of 5,6,6a,7,8,9,10,10a-octahydro-2-hydroxy-10-hydroxymethyl-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)benzo[c]quinoline (626 mg., 1.5 mmole) in dry methylene chloride (25 ml.) is added 4-morpholinobutyric acid hydrochloride (0.315 g., 1.5 mmole) and the mixture stirred at room temperature under a nitrogen atmosphere. A 0.1 M solution of dicyclohexylcarbodiimide in methylene chloride (12.5 ml., 1.5 mmole) is added dropwise and the mixture stirred for 6 hours. It is then cooled in ice, filtered and evaporated to give the title product which is purified as the free base by column chromatography on silica gel.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18]C(=O)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)[CH3:22])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 18.7 g (59.7 mmol) of trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester in 110 ml of methanol was added 41.25 g (298.5 mmol) of potassium carbonate. The reaction mixture was then stirred for 2 hours at room temperature. The excess of potassium carbonate was removed by filtration and the methanol was removed by evaporation under reduced pressure. The crude residue was partitioned between ether, 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 2:1 v/v mixture of hexane and ethylacetate as the eluent giving 13.9 g (86.0%) of pure trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS 272 (MH+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[CH3:16][C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:20]1[CH:21]=[N:22][C:17]([CH3:16])=[CH:18][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: Cc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccc(-c2c(C(C)O)oc(=O)c3ccccc23)cn1
Yield: 29 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.55 g, 2.04 mmol), 6-methylpyridin-3-ylboronic acid (0.550 g, 2.0 mmol), Pd(PPh3)4 (0.118 g, 0.102 mmol) and Cs2CO3 (1.06 g, 3.27 mmol) to afford the title compound (0.163 g, 28%)
Reaction SMILES: [CH3:1][S-:2].[Na+].[C:4]1([CH2:10][CH2:11][CH2:12]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH2:10][CH2:11][CH2:12][S:2][CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCc1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCCCc1ccccc1

Procedure:
Sodium methanethiolate (6 mmol, 0.42 g) and 3-phenylpropyl bromide (5 mmol, 1 g) in methanol were refluxed overnight. After removal of solvent, diethyl ether was added, washed with H2O and evaporated to give 3-phenylpropylmethyl sulfide. It was then reacted with equivalent amount of bromoacetic acid in acetonitrile (5 mL) at room temperature under N2 overnight, affording S-methyl-3-phenylpropylsulfoniumylacetic acid bromide as a white powder. It was then subjected to the general procedure 1 to give compound 585 as a white powder (0.75 g, 36% overall yield). Anal. (C12H19NaO7P2S.0.5 C2H5OH) C, H.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.Cl[CH:14]([F:16])[F:15].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:14]([F:16])[F:15])=[C:6]([F:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)c1ccc(OC(F)F)c(F)c1
Yield: 82.7 %

Procedure:
A solution of 3-fluoro-4-hydroxy-benzoic acid methyl ester (2 g, 11.75 mmol), chlorodifluoromethane (10.6 g, 122.6 mmol, 10.4 eq.) and K2CO3 (1.94 g, 14.1 mmol) was heated in an autoclave for 6 hrs. at 160° C. After cooling the mixture was treated with excess Na2CO3 and extracted with EtOAc. The organic phase was washed twice with satd. NaCl then dried and evaporated to afford the title compound (2.14 g, 83% yield) as an orange oil. MS: m/e=220 (M+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:31]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:47]([CH:44]2[CH2:45][CH2:46][N:41]([C:39]([O:38][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:40])[CH2:42][CH2:43]2)=[O:48])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCc1nccnc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) in DCM (27.0 mL) was treated with and N-(3-dimethylaminopropyl)-Al-ethylcarbodiimide hydrochloride (3.2 g, 0.017 mol), 1-hydroxybenzotriazole (1.5 g, 0.011 mol) and 1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol). The mixture was stirred at rt overnight then diluted with DCM (30 mL), washed with sat. NaHCO3 (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material thus obtained was chromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding 3.38 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.68-1.78 (m, 2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m, 2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m, 5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z 389.17 [MH+].
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:66])[CH3:67])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (130 mg) in acetonitrile (4 ml) was added a solution of 2% HF in aqueous acetonitrile (200 μl), and the mixture stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (65 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH3:17].C([O-])(=O)C.[NH4+:22]>CN(C)C=O>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:22][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH3:17]
Reactant: CCOC(=O)c1coc2c1C(=O)N(CC)CC2
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)N(CC)CC2
Temperature: 115 °C
Yield: 53.6 %

Procedure:
A mixture of ethyl 4-oxo-5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-3-carboxylate (3.66 g, 15.4 mmol) and ammonium acetate (5.94 g, 77.1 mmol) in N,N-dimethylformamide (30 mL) was heated at 115° C. for 23 hours. The mixture was cooled, concentrated in vacuo, ice water added, and the precipitate collected and dried to give ethyl 4-oxo-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylate (1.95 g). The aqueous filtrate was extracted 2X with ethyl acetate, the combined organic layers dried over magnesium sulfate, filtered, and concentrated in vacuo to afford additional ester (0.68 g). The combined materials were treated with aqueous 5N sodium hydroxide (75 mL) in dioxane (10 mL) at reflux for 2 hours. After cooling in an ice water bath, the mixture was acidified with aqueous hydrochloric acid, and concentrated in vacuo. Ethyl acetate was added, the mixture filtered, and the organic layer concentrated in vacuo. Trituration with ethyl acetate afforded 4-oxo-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (0.84 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C:5]([CH:18]=[CH2:19])(O)[C:4]=2[CH:3]=1.[NH2:20][C:21]([NH2:23])=[S:22].C(O)(C(F)(F)F)=O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C:5]3([CH2:18][CH2:19][S:22][C:21]([NH2:23])=[N:20]3)[C:4]=2[CH:3]=1
Reactant: C=CC1(O)c2cc(Br)ccc2Oc2ccc(I)cc21
Reactant: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: NC1=NC2(CCS1)c1cc(Br)ccc1Oc1ccc(I)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol (0.50 g, 1.16 mmol) and thiourea (0.18 g, 2.33 mmol) in acetic acid (2.00 mL) was added TFA (4.00 mL). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc, followed by a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (10%-100% EtOAc/hexane) to provide 0.36 g of 2′-bromo-7′-iodo-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:27]([O:26][C:24]([NH:23][C:20]1[S:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:31])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:22][CH:21]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(NC(=O)OC(C)(C)C)s3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ncc(NC(=O)OC(C)(C)C)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of [6-(5-tert-butoxycarbonylamino-thiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (270 mg, 0.6 mmol) in THF (7 mL) was added LiOH (76 mg, 1.8 mmol) in water (3.5 mL). The mixture was stirred at room temperature for 3 h and acidified by 1N HCl to pH 3. The mixture was extracted by ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by HPLC affording the title compound (100 mg, 40%) as a white solid. 1H NMR (CD3OD) δ 7.29 (s, 1H), 7.19 (s, 1H), 6.75 (s, 1H), 5.69 (dd, 1H), 3.19 (m, 1H), 2.40 (s, 3H), 2.35 (m, 1H), 1.52 (s, 9H). MS found: (M+H)+=421.20.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([C@H:20]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[C:21](O)=[O:22])[CH3:19])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:57]([O:61][C:62]([N:64]([CH3:78])[NH:65][C:66](=[O:77])[C@H:67]([NH:75][CH3:76])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:63])([CH3:60])([CH3:59])[CH3:58].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:57]([O:61][C:62]([N:64]([CH3:78])[NH:65][C:66](=[O:77])[C@H:67]([N:75]([C:21](=[O:22])[C@H:20]([N:18]([C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH3:19])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:76])[CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:63])([CH3:58])([CH3:60])[CH3:59]
Reactant: CN[C@H](Cc1ccccc1)C(=O)NN(C)C(=O)OC(C)(C)C
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of (2R)-2-[N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino]-3-naphthalen-2-ylpropionic acid (0.6 g, 1.33 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.18 g, 1.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.25 g, 1.33 mmol) and the mixture was cooled to 0° C. Then N-methyl-N'-((2R)-2-(methylamino)-3-phenylpropionyl)hydrazinecarboxylic acid tert-butyl ester (0.34 g, 1.11 mmol) and diisopropylethylamine (0.25 ml, 1.44 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The product was chromatographed on silica (40 g) with heptane:ethyl acetate (2:1) to give 0.53 g (64%) of N'-[(2R)-2-(N-((2R)-2-[N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylamino]-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionyl]-N-methylhydrazinecarboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([OH:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=O.CC(O)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C@H:19]([CH2:18][C:16]2[N:15]=[N:14][N:13]([C@H:9]3[C:10]4[C:5](=[CH:4][C:3]([CH2:1][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:12][CH:11]=4)[CH2:6][CH2:7][CH2:8]3)[CH:17]=2)[C:20]([OH:22])=[O:21])(=[O:25])=[O:26])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn(C3CCCc4cc(C=O)ccc43)nn2)C(=O)O)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CN5CCCCC5)ccc43)nn2)C(=O)O)cc1
Reaction time: 2 h

Procedure:
(2R)-3-(1-(6-Formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)-propanoic acid (85.8 μM, 1 eq) piperidine (3 eq) and HOAc (3 eq) were heated to 40° C. for 3 d. Additional portions of piperidine (3 eq) and HOAc (3 eq) were then added. After 2 h, MP-BH4 was added and the reaction mixture was allowed to stir for 3 days. The reaction mixture was concentrated and was purified using reverse phase conditions C18 (0-100% acetonitrile/water) to afford the title compound. MS (m/z): 538.2 (m+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=2)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29])=[CH:23][CH:22]=1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: COc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).