Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:15][CH2:14][C@H:13]([N:16]([O:29][CH2:30][CH:31]=[CH2:32])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:12]=[C:11]1[CH3:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].SCC(O)=O.[Li+].[OH-]>CN(C)C=O.O>[Si:1]([O:8][CH2:9][C@H:10]1[NH:15][CH2:14][C@H:13]([NH:16][O:29][CH2:30][CH:31]=[CH2:32])[CH:12]=[C:11]1[CH3:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCON[C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-[(3R,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-1,2,3,6-tetrahydropyridin-3-yl]-2-nitro-N-(prop-2-en-1-yloxy)benzene-1-sulfonamide (Intermediate 146, 12 g, 24.11 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), 2-sulfanylacetic acid (4.4 g, 47.77 mmol, 2.00 equiv). This was followed by the addition of LiOH (5.8 g, 242.17 mmol, 10.00 equiv), in portions. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 5×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine and 2×200 mL of sodium bicarbonate (aq.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8.4 g (crude product) of the title compound as yellow oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:37]([O:39][C:40]([CH:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[NH:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1)=[O:41])[CH3:38]>CN(C)C=O>[CH2:37]([O:39][C:40]([CH:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[N:47]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1)=[O:41])[CH3:38]
Reactant: CCOC(=O)C1CCCC1NCc1ccccn1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(Cc1ccccn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Reaction time: 16 h
Yield: 25.3 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.10 g, 0.30 mmol) and N,N′-dicyclohexylcarbodiimide (0.068 g, 0.33 mmol) in N,N-dimethylformamide (10 mL) was treated with 2-[(pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester and stirred for 16 h. The mixture was filtered, the filtrate was concentrated in vacuo, and purified by flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0-10% methanol in dichloromethane) to afford the desired product, 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-pyridin-2-ylmethyl-amino}-cyclopentanecarboxylic acid ethyl ester (0.043 g, 0.076 mmol, 25.3%), as a pale white solid. LC-MS (ESI) calcd for C24H29N5O7S2 563.15, found 564.6 [M+H+].
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]1(Br)[CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrC1CCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCC1
Yield: 42429.7 %

Procedure:
Sodium (10.3 g, 0.44 mmol) was dissolved in dry ethanol (300 ml) under a nitrogen atmosphere and to the cooled solution (0° C.) was added diethyl malonate (71 g, 0.44 mmol). After stirring for 15 minutes cyclobutyl bromide (60 g, 0.44 mmol) was added and the solution was heated to reflux overnight. The cooled mixture was evaporated and the residue was partitioned between water and ether. The ether layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was distilled to give diethyl cyclobutylmalonate (40 g, 42%) (bp. 74°-75° C. at 0.5 mm Hg).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][C:5]3([O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[N:9]4[CH:1]=[CH:2][CH:3]=[C:4]34)[CH2:14][CH2:15]2)=[O:25])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (100 mg, 0.361 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (75.2 mg, 0.361 mmol), and triethylamine (110 mg, 151 μL, 1.08 mmol) were combined in DMF (3 mL) and HATU (137 mg, 0.361 mmol) was added. The reaction was stirred at room temperature for 1 h and was concentrated. The residue was purified by column chromatography (silica gel: 0-50% ethyl acetate in hexanes) to give (4-fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (113 mg, 73%). ESI-MS m/z calc. 430.1, found 431.1 (M+1)+; Retention time: 2.24 minutes (4 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1.CO.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][CH2:13][N:12]([CH:25]2[CH2:27][CH2:26]2)[CH2:11]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: NS(=O)(=O)c1cnc(OC[C@@H]2CNCCO2)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NS(=O)(=O)c1cnc(OC[C@@H]2CN(C3CC3)CCO2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 244B (250 mg), anhydrous methanol (6 mL), (1-ethoxycyclopropoxy)trimethylsilane (0.474 mL), and acetic acid (0.509 mL) was heated at 70° C. for 30 minutes. After cooling to ambient temperature, sodium cyanoborohydride (112 mg) was added and the mixture was stirred for 18 hours. Additional sodium cyanoborohydride (75 mg) was added and stirring was continued 18 hours. The reaction was concentrated and the residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product was isolated from the dried methylene chloride layer and was purified on silica gel and was eluted with a 1, 2.5, 5, 10% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][N:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CS([C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[N:26]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][O:33][C:27]1[CH:28]=[C:29]([O:31][CH3:32])[N:30]=[C:25]([O:1][C:2]2[C:3]([C:8]([O:10][N:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:26]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCCCC(CCCC)=NOC(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CCCC)=NOC(=O)c1ncccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of 6.3 g of 5-nonanylidenamino 3-hydroxypicolinate, 2.5 g of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 3.9 g of anhydrous potassium carbonate, 50 ml of N,N-dimethylformamide was added, and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction solution was poured into water and extracted with ethyl ether. The organic layer was further washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue thereby obtained was purified by silica gel column chromatography by using as a developing solvent a mixture of hexane/ethyl ether to obtain 5.2 g of the above identified compound as slightly yellow transparent viscous liquid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:24]=[CH:23]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 103.7 %

Procedure:
p-Toluenesulfonyl chloride (2 g) and tetrabutyl ammonium hydrogen sulfate (250 mg) were added to a toluene (20 ml) solution containing 5-chloroindole (1.52 g), followed by stirring at room temperature for 11 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:1), and a colorless solid of 5-chloro-1-tosyl-1H-indole (3.18 g) was thus obtained.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([OH:21])C=CC=CC=1.O.SCCCS(O)(=O)=O>>[C:1]1(=[O:21])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)CCCS
Solvent: O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 45 °C

Procedure:
9-Fluorenone (6.44 g, 0.0358 mol, 1.00 equiv.), molten phenol (70.0 g, 0.744 mol, 20.8 equiv.), and deionized water (1.93 g, 0.107 mol, 3.00 equiv.) is added to the reactor (reactor design 3). The reaction mixture is heated to 45° C. with stirring under a pad of nitrogen. 3-Mercaptopropanesulfonic acid (0.385 g, 2.47 mmol, 0.0690 equiv.) is added slowly over approximately 1 minute to the reaction mixture at 45° C. The reaction is monitored throughout the reaction period by collecting samples and analyzing by HPLC. The 9-fluorenone is found to be 4% consumed within 9 minutes, 13% consumed within 1 hour, 29% consumed within 3.5 hours, and 94% consumed within 20.5 hours. HPLC analysis (analytical method 3) gives the following relative area % analysis for the reaction products (fluorenone area not included) at 94% conversion:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1ccccc1O
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccccc1Oc1ccc(C=O)cc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a mixture of 4-fluoro-benzaldehyde (1.5 g, 12.08 mmol) and 2-isopropyl-phenol (1.64 g, 12.08 mmol) in anhydrous N,N-dimethyl acetamide (20 mL) was added granulated potassium carbonate (3.7 g, 26.58 mmol). The reaction mixture was stirred at 150° C. for 18 hours and was partitioned between ethyl acetate and brine. The ethyl acetate layer was washed with saturated aqueous hydrogenocarbonate solution, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (15% ethyl acetate in n-heptane) to yield 4-(2-Isopropyl-phenoxy)-benzaldehyde as a gum (2.25 g, 77%).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=O)(=[O:23])=[O:22])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1>O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]2[O:28][CH:29]=[N:2][N:3]=2)(=[O:23])=[O:22])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1-c1nnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Hydrazine hydrate (2.25 mL, 46 mmol) was added to a solution of methyl 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}benzoate (Example 38, 0.42 g, 1.0 mmol) in 1,4-dioxane (1 mL), stirred for 1 hour at room temperature then heated at 90° C. overnight. Solvent was removed in vacuo and the residue azeotroped using toluene. Triethyl orthoformate (10 mL) and a catalytic quantity of (±)-10-camphorsulfonic acid were added to the resultant crude hydrazide then stirred and heated at 90° C. overnight. Solvent was removed in vacuo, water (100 mL) added and extracted with ethyl acetate (2×75 mL). Extracts were washed with water and saturated brine then dried (MgSO4), filtered and evaporated to a yellow residue. Purification by flash column chromatography eluting with a 20-60% ethyl acetate/isohexane gradient gave 2-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)-1,3,4-oxadiazole (0.22 g, 51%). 1H NMR (500 MHz, d6-DMSO) δ 9.46 (1H, s), 8.59 (1H, s), 8.40 (1H, dd, J=1.0, 8.0 Hz), 8.37 (1H, s), 8.30 (1H, d, J=8.7 Hz), 8.20 (1H, d, J=8.8 Hz), 8.05 (1H, dd, J=1.7, 8.6 Hz), 8.00-7.96 (1H, m), 7.93-7.91 (3H, m), 7.87-7.85 (2H, m), 7.42-7.33 (2H, m); m/z (ES+) 431 [MH+].
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].O.[NH2:25][NH2:26]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH:25][NH2:26])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 8 h

Procedure:
A suspension of 0.35 g (1.1 mmol) of N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester in 7 ml methanol is treated with 83 mg (1.7 mmol) of hydrazine hydrate. The reaction mixture is refluxed for 2 h, then another portion of 300 mg (6 mmol) of hydrazine hydrate is added and reflux is pursued for another 8 h. The mixture is cooled and hold overnight in the frig. The precipitate is filtered off and recrystallised from methanol to yield 0.043 g (12%) of filthy, colorless needles. MS: m/e=318.3 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33](O)[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:50])[C@@H:47]([OH:49])[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:49][C@@H:47]([C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:50])[CH3:48])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)O)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=O.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:14]([CH3:13])[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(-c2cccc(Cl)c2)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.16 g yield starting from 3-chlorobenzhydrazide (0.52 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.48 g). MS (m/z): 262 [MH]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]([CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:19](=[O:21])[CH3:20])[N:14]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[N:13]=[CH:12]2)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]([CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[C:19](=[O:21])[CH3:20])[N:14]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[N:13]=[CH:12]2
Reactant: CC(=O)N(c1cc2c(cnn2C2CCCCO2)cc1OCc1ccccc1)C1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N(c1cc2c(cnn2C2CCCCO2)cc1O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of N-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide (1.7 g, 3.78 mmol) in EtOH (100 mL) and EtOAc (100 mL) is added Pd/C (1 g, 10% wt). After the reaction mixture is stirred at RT under H2 overnight, it is filtered and the filtrate is concentrated. The residue is purified by silica gel column chromatography eluting first with PE:EtOAc (1:1) and then EtOAc to give the product (1.2 g, 88.2% yield). MS (m/z): 360.2 (M+H).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.Br.[NH2:15][C:16]1([CH3:24])[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C>CN(C)C=O>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:15]([C:16]1([CH3:24])[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[CH2:11]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CC1(N)CCC(=O)NC1=O
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(N2Cc3cc(Br)ccc3C2=O)CCC(=O)NC1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (3.0 g, 10.0 mmol), 3-amino-3-methyl-piperidine-2,6-dione hydrobromide (2.2 g, 10.0 mmol) and triethylamine (2.0 g, 20 mmol) in N,N-dimethylformamide (10 mL) was heated to 90° C. under nitrogen. After 1 h, the mixture was cooled to rt and the solvent was removed in vacuo. The crude residue was purified by column chromatography (95:5 CH2Cl2: MeOH) providing 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-3-methyl-piperidine-2,6-dione (2.0 g, 61% yield); 1H NMR (DMSO-d6) δ 1.67 (s, 3H), 1.87-1.93 (m, 1H), 2.54-2.80 (m, 3H), 4.64 (d, J=17.9 Hz, 1H), 4.73 (d, J=17.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.1, 1.5 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 10.89 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CO.O1CCOCC1.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>[F:1][C:2]1[C:11]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1c(F)ccc(-c2cccc(F)c2)c1F
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A mixture of methyl 2,6-difluoro-3-(trifluoromethylsulfonyloxy)benzoate (3.0 g, 9.4 mmol, 1.0 eq), 3-fluorophenylboronic acid (1.57 g, 11.2 mmol, 1.2 eq), K2CO3 (5.2 g, 37.6 mmol, 4.0 eq) and Pd(PPh3)4 (543 mg, 0.47 mmol, 0.05 eq) in a mixture of MeOH (10 mL) and dioxane (30 mL) was heated to 80° C. under N2 overnight. After cooling, the resulting mixture was concentrated in vacuo and purified by flash column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (1.7 g, 68%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](=[N:12]/[C:13]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][C:14]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH3:11].C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>CN(C=O)C>[CH2:37]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](=[N:12]/[C:13]1[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)/[CH3:11])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C/C(=N\c1c(-c2ccccc2)cccc1-c1ccccc1)c1nc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(=N\c1c(-c2ccccc2)cccc1-c1ccccc1)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 0.70 g (1.87 mmol) N-[(1E)-1-(1H-benzimidazol-2-yl)ethylidene]-N-1,1′:3′,1″-terphenyl-2′-ylamine, 1.42 g (10.3 mmol) anhydrous K2CO3 and 0.35 g (2.06 mmol) benzylbromide in 4 ml anhydrous DMF was stirred at room temperature for 10 hours. The reaction mixture was then poured into 80 ml water, stirred for 10 min and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (3×25 ml) and dried over anhydrous Na2SO4. The solvent was evaporated to give an yellow oil which was triturated with 5 ml methanol at −78° C., filtered while cold washed with cold (−78° C.) methanol (2×2 ml) and dried under reduced pressure. Yield 0.56 g (66.2%). 1H NMR (250 MHz, CDCl3), δ, ppm: 2.07 (s, 3H), 5.51 (m, 2H), 6.90 (m, 2H), 7.22 (m, 19H), 7.78 (m, 1H).
Reaction SMILES: C[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:16](Cl)=[N:15][C:14]3[C:9]2=[CH:10][C:11]([Cl:19])=[C:12]([Cl:18])[CH:13]=3)[C@H:5]([OH:20])[C@@H:4]1[OH:21].[Br:22]C1NC2C=C(Cl)C(Cl)=CC=2N=1.C(OC1O[C@H](C)[C@@H](OC(=O)C)[C@H]1OC(=O)C)(=O)C>>[Br:22][C:16]1[N:8]([C@@H:6]2[O:7][C@H:3]([CH3:2])[C@@H:4]([OH:21])[C@H:5]2[OH:20])[C:9]2[CH:10]=[C:11]([Cl:19])[C:12]([Cl:18])=[CH:13][C:14]=2[N:15]=1
Reactant: CC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Agent: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O

Procedure:
2-bromo-5,6-dichloro-1-(5-deoxy-β-D-ribofuranosyl)benzimidazole (211) was prepared using the same method as that used for the preparation of compound 210, except that 2-bromo-5,6-dichlorobenzimidazole was condensed with the carbohydrate 206 instead of 207.