Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[CH3:34][C:35]1[CH:36]=[N:37][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[N:37]=[CH:36][C:35]([CH3:34])=[CH:40][N:39]=3)[CH2:42][CH2:43]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: Cc1cnc(C2(N)CC2)nc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.025 g (48%). 1H NMR (400 MHz, CD3OD): δ 8.58 (d, J=0.8 Hz, 2H), 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 1.82-1.79 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ −77.67 (TFA), −112.34, −122.75 LCMS: (ES+) m/z=583.2 (M+H)+
Reaction SMILES: [C:1](=[O:53])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:42])[C@@H:12]([NH:20][C:21](=[O:41])[C@@H:22]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[C:37](=[O:38])[CH:36]=[CH:35][C:34]2=[O:39])[CH:23]([CH3:25])[CH3:24])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1.[N:54]1([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(OCC)C>CS(C)=O>[O:39]=[C:34]1[CH:35]=[CH:36][C:37](=[O:38])[N:33]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C@H:22]([C:21]([NH:20][C@H:12]([C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([N:57]2[CH2:56][CH2:55][N:54]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58]2)=[O:53])=[CH:9][CH:8]=1)=[O:42])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[NH2:19])=[O:41])[CH:23]([CH3:24])[CH3:25])=[O:40]
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
Step 1 4-((S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-nitrophenyl carbonate 58 (30 mg, 0.041 mmol) was reacted with tert-butyl piperazine-1-carboxylate (5.3 mg, 0.0287 mmol) in anhydrous DMSO under argon atmosphere at room temperature (FIG. 7d). The reaction mixture was stirred for 1 h, until disappearance of the starting material (HPLC-MS analysis). Diethyl ether (80 ml) was then added to the reaction mixture and the precipitate thus obtained was collected by filtration to give N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[({[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}oxy)methyl]phenyl}-N5-carbamoyl-L-ornithinamide 59 as a yellow solid, 22.0 mg) was isolated and used without further purification in the next step. MS (ESI): 785 [M+H]+. Retention time=4.87 min (method 1).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][CH:6]1[O:11][CH:10](Br)[CH:9]([O:13][C:14]([CH3:16])=[O:15])[CH:8]([O:17][C:18]([CH3:20])=[O:19])[CH:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[CH2:25]([OH:28])[CH:26]=[CH2:27]>>[C:14]([O:13][C@@H:9]1[C@@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]1[O:28][CH2:25][CH:26]=[CH2:27])(=[O:15])[CH3:16]
Reactant: C=CCO
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Product: C=CCO[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
Acetobromogalactose (2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide) was mixed with allyl alcohol and mercuric cyanide via the Koenigs-Knorr glycosylation to obtain allyl β-D-galactopyranoside tetraacetate. This was followed by oxidation with 3-chloroperoxybenzoic acid in dichloromethane to obtain 2,3-epoxypropyl-β-D-galactopyranoside, 2,3,4,6-0-tetracetate.
Reaction SMILES: [Si]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([Cl:35])=[N:24][N:25]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(OCC)(=O)C>C1COCC1>[Cl:35][C:23]1[C:22]2[C:26](=[CH:27][C:19]([OH:18])=[CH:20][CH:21]=2)[N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:24]=1
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(Cl)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Tert-butyl 6-(tert-butyldiphenylsilyloxy)-3-chloroindazole-1-carboxylate (17.415 g) which can be prepared according to the method described in Reference example 38, etc. was dissolved in dehydrated THF (150 mL), added with 1 mol/L-TBAF-THF solution (42 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.), and stirred overnight at room temperature. The reaction solution was added with ethyl acetate and the organic layer was washed once with brine, once with water, and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was added with n-hexane (150 mL) and the suspension was subjected to ultrasonication treatment. The precipitate was filtered to obtain the title compound (6.3815 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]([F:10])([F:9])[F:8])[NH:6][CH2:5][CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:8][C:7]([F:10])([F:9])[CH:2]([NH:6][CH2:5][CH2:4][OH:3])[CH3:1]
Reactant: CC1(C(F)(F)F)NCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(NCCO)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 2-methyl-2-(trifluoromethyl)oxazolidine (39) (5.58 g, 36.0 mmol, Eq: 1.00) in tetrahydrofuran (30 ml) at 0° C. was added lithium aluminum hydride (2M solution in tetrahydrofuran) (18.0 ml, 36.0 mmol, Eq: 1.00) and the reaction mixture was stirred at room temperature for 1 hr, quenched slowly with 1 ml of cold water, stirred for 20 min. Then 1 ml of 1N NaOH aq. solution was added and the reaction mixture was stirred for 10 m in. 3 ml of water were added and the reaction mixture was stirred for 1 hr. Granular salt was formed. The white solid was filtered off, washed with diethyl ether (100 ml). The mixture was concentrated to obtain a crude product 2-(1,1,1-trifluoropropan-2-ylamino)ethanol (40) (oil, 5.50 g, 35.0 mmol, 97.3% yield) which was used as such in the next step.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][C:18]#[C:19][CH2:20][CH2:21][CH3:22])[CH:12]=O.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CCCC#COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 75.3 %

Procedure:
Piperidine (0.45 mL, 4.6 mmol) was added to a suspension of 3-methoxy-4-(pent-1-ynyloxy)benzaldehyde (1.0 g, 4.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.93 g, 4.2 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-methoxy-4-(pent-4-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.2 g, 75%) as a pale yellow crystalline solid; mp 166.5-167.5° C.; δH (400 MHz, DMSO-d6) 1.89 (p, J=7.6 Hz, 2H, CH2), 2.32 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.81 (t, J=2.4 Hz, 1H, CCH), 3.84 (s, 3H, OCH3), 4.06 (t, J=7.6 Hz, 2H, OCH2), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.17 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (dd, J5′,6′=8.0, J2′,6′=2.0 Hz, 1H, H6′), 7.37 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 14.5, 27.7, 55.7, 66.7, 71.7, 83.6, 110.7, 112.7, 116.6, 120.0, 120.3, 122.6, 122.7, 127.4, 131.1, 134.0, 141.1, 141.6, 149.2, 149.8, 164.1, 169.4; HRMS (ESI) calculated for C22H21NO5 [M+H]+ 380.1492. found 380.1493; vmax 755, 1257, 1506, 1584, 1657, 2929, 3266, 3519 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=2[F:17])=[CH:4][C:3]=1[O:21][CH3:22].CN(C)C=[O:26]>O.[Cu]Cl.[Pd](Cl)Cl>[C:15]([C:13]1[CH:12]=[CH:11][C:10]([F:17])=[C:9]([CH:14]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:19]=[CH:20][C:2]([Cl:1])=[C:3]([O:21][CH3:22])[CH:4]=1)=[O:18])(=[O:26])[CH3:16]
Reactant: C=Cc1ccc(F)c(C(=O)NCc2ccc(Cl)c(OC)c2)c1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C(C)=O)ccc2F)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of copper(I) chloride (464 mg) and palladium(II) chloride (83.2 mg) in a mixture of dimethylformamide (42 mL) and water (6 mL) was stirred for an hour under oxygen atmosphere (1 atm) at ambient temperature. To the mixture was added N-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinylbenzamide (1.50 g). After stirring for 6 hours at 60° C., the mixture was partitioned between ethyl acetate and 1N-hydrochoric, acid. The separated organic layer was washed with water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (2:1 to 1:1) to give 5-acetyl-2-fluoro-N-(4-chloro-3-methoxybenzyl)benzamide as colorless powders (719 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([CH:16]=[CH:15][CH:14]=[C:12](O)[CH:11]=1)[OH:10].Cl.NC1C=CC(C)=CC=1.[OH-].[Na+]>C(OCC)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[CH:11]=[C:9]([OH:10])[CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(Nc2cccc(O)c2)cc1
Temperature: 160 °C
Yield: 74.1 %

Procedure:
A reaction mixture of p-toluidine (13.4 g, 126.2 mol), resorcinol (10 g, 90.8 mmol) and p-toluidine HCl (1.3 g, 9.0 mmol) was heated at 160° C. for 48 h with an oil bath. After cooling to room temperature, the reaction mixture in 500 mL of diethyl ether was treated with 2N NaOH to give precipitated materials and filtered under reduced pressure. The collected solid was treated with glacial acetic acid until completely dissolved, and the solution was extracted with diethyl ether (2×200 mL). The ether layer was washed with water (2×150 mL), dried over MgSO4, and concentrated under reduced pressure to give a dark-brown oil, which was purified by flash column chromatography using EtOAc/hexane (40:60). The resulting oil was crystallized from CH2Cl2/hexane to yield 13.4 g (74%) of the title compound as a dark brown solid. Mp 86-88° C. (lit 91° C. )
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[C:8]1(O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)(Cl)=O>O>[C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([O:5][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: Oc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C(CC(=O)Oc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Malonic acid (11 g, 106 mmol) was mixed with phenol (20 g, 212 mmol) at 0° C. under nitrogen and phosphorus oxychloride (11.5 mL, 123 mmol) was added dropwise to the solid mixture. The resulting mixture was stirred at 0° C. for 5 mins, and then heated at reflux for 5 h, causing the solid to melt and an orange solution to form. The reaction was cooled to room temperature, and then poured onto 100 mL water and extracted with diethyl ether (3×75 mL). The combined organics were washed with brine, dried over MgSO4, concentrated in vacuo to an orange oil of the title compound. (27 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:13]([O:12][C:10]([NH:9][C:3]([CH3:8])([CH2:2][NH:1][S:28]([C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[Cl:20])(=[O:30])=[O:29])[C:4]([O:6][CH3:7])=[O:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)C(C)(CN)NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
0.103 g (0.341 mmol) of methyl 3-amino-2-benzyloxycarbonylamino-2-methylpropionate, 0.109 g (0.443 mmol) of 2,4 dichlorobenzenesulfonyl chloride and 0.237 ml (1.36 mmol) of DIEA are dissolved in 2 ml of DCM. The mixture is stirred at room temperature overnight. 2 ml are added to the reaction solution, and then the organic phase is separated off and dried over MgSO4, and the solvent is removed in vacuo. The crude product is purified by chromatography on 4 g of SiO2, EtOAc/DCM as eluent (gradient of 0-40%). 0.081 g of the desired product is obtained as an oil. MW=474 (calculated, monoisotopic), measured value: (M+H)+ 475.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1.O[N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:37]=[C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35](=[O:36])[N:27]1[O:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.6 %

Procedure:
Diethyl azodicarboxylate (17.4 g, 100 mmol) was added to a solution of (R)-tert-butyl 3-hydroxypyrrolidin-1-carboxylate (9.40 g, 50.0 mmol), 2-hydroxyisoindoline-1,3-dione (8.16 g, 50.0 mmol) and triphenylphosphine (26.2 g, 100 mmol) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 5/95 to 12.5/87.5) to give (S)-tert-butyl 3-(1,3-dioxoisoindoline-2-yloxy)pyrrolidin-1-carboxylate (6.74 g, 41%) as a white solid: LCMS: 277 [M−55]+.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([CH2:25]Br)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:27]([C:21]1[CH:22]=[C:23]([CH2:25][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:24]=[CH:19][CH:20]=1)#[N:28]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C#N)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-m-tolunitrile (1.0 g, 4.9 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL of DMF was stirred at 25° C. for 24 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was dried in vacuo to afford 1.18 g (82%) of the 9-[(3-cyanophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.65-7.2 (m, 6H), 7.15 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 2226, 1729, and 1646. MS (ES) m/e 357, 359.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][OH:20])([CH3:18])[CH2:13]3)[O:7][C:6]=2[CH:21]=1.[H-].[Na+].I[CH3:25].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][O:20][CH3:25])([CH3:18])[CH2:13]3)[O:7][C:6]=2[CH:21]=1
Reactant: C[C@]1(CO)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@]1(C)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
[(S)-1-((S)-7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol (2.5 g, 8.5 mmol) in tetrahydrofuran (10 ml) was added slowly to a mixture of sodium hydride, 60% in oil (1.354 g, 33.9 mmol) and tetrahydrofuran (15 ml). The reaction mixture was heated at 60° C. for 2 hours after the mixture was cooled down and iodomethane (0.685 ml, 11.0 mmol) in tetrahydrofuran (3 ml) was added. The mixture was stirred at RT for 1 hour, water (25 ml) was added carefully and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness. Ethyl acetate (20 ml) was added to the evaporation residue and was made acidic with aq HCl. The layers were separated and the water layer was made basic with aq NaOH and extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness to yield 2.34 g (89%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH2:11])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>CC(C)=O.O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCN
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)NCCCSc2nnnn2C)cc1
Reaction time: 2 h
Yield: 43.8 %

Procedure:
1-Methyl-5-(3-aminopropylthio)-1,2,3,4-tetrazole (0.9 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). To the mixture is added potassium carbonate (0.7 g) and thereto is added dropwise with stirring 4-methoxybenzoylchloride (1.1 g) under ice-cooling. Stirring is continued for 2 hours under ice-cooling. After acetone is distilled off, water is added to the resulting residue and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and then the residue is purified by column chloratography (Wakogel C-200), followed by eluting with chloroform to give 1-methyl-5-{3-[N-(4-methoxybenzoyl)amino]propylthio}-1,2,3,4-tetrazole (0.7 g), colorless needles (ethyl acetate-ethanol), m.p. 118°-122° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>>[N+:22]([C:21]1[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ncccc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.51 mmol) and 2-bromo-3-nitropyridine (113 mg, 0.56 mmol) according to the general procedure IF to give 84 mg (53%) of a red solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:8): Rf=0.16 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 8.84 (dd, J=4.7, 1.6 Hz, 1H), 8.39 (dd, J=8.3, 1.6 Hz, 1H), 7.64-7.59 (m, 2H), 7.44 (dd, J=8.3, 4.7 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 3.68 (s, 3H), 2.99 (t, J=7.7 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.0, 153.5, 146.8, 143.0, 137.6, 132.8, 132.5, 128.6, 122.5, 119.3, 98.0, 85.0, 51.7, 35.2, 30.9; ESI-MS m/z 333.1 (M+Na+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-:13].[K+].CN(C)C=O>O>[F:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
93 g (0.5 mol) of 4-chloro-3-nitrobenzaldehyde and 58 g (1 mol) of potassium fluoride are suspended in 250 mol of dimethylformamide. The reaction mixture contains 0.02% of H2O. The mixture is stirred for one hour at 160° C. and the dimethylformamide is evaporated off in vacuo. The residue is cooled and stirred with 200 ml of water, the mixture is extracted with methylene chloride and the organic phase is dried. After the methylene chloride has been evaporated off, 83 g of 4-fluoro-3-nitrobenzaldehyde with a content of 90.2% are obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([OH:19])[CH2:17][OH:18])=[N:14][CH:15]=1)[CH3:9].[S:20](Cl)(Cl)=[O:21]>ClCCl>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:17][O:18][S:20](=[O:21])[O:19]2)=[N:14][CH:15]=1)[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(C(O)CO)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C2COS(=O)O2)nc1
Reaction time: 1 h

Procedure:
4.98 mL (0.0387 mol) triethylamine was added to a solution of 3 g (0.017 mol) 1-(5-ethyl-pyridin-2-yl)-ethan-1,2-diol dissolved in 60 mL dichloromethane at 0-5° C. To this 1.43 mL (0.019 mol) thionyl chloride was added drop wise in 15 min. and stirring was continued for 1 hr. Reaction mixture was quenched with 10% sodium bicarbonate solution. Product was extracted with dichloromethane, which was concentrated in vacuo to obtain titled product. Yield of the product was 3.44 g (90%).