Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:20]=[C:19]3[C:14]([C:15](=[O:29])[C:16]([C:24]([O:26]CC)=[O:25])=[CH:17][N:18]3[CH2:21][CH2:22][F:23])=[CH:13][C:12]=2[F:30])[CH2:7]1)C)(=O)C.O.C(O)C>Cl>[F:30][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:11]=1[N:8]1[CH2:9][CH2:10][CH:6]([NH:4][CH3:1])[CH2:7]1)[N:18]([CH2:21][CH2:22][F:23])[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]2=[O:29]
Reactant: CCOC(=O)c1cn(CCF)c2nc(N3CCC(N(C)C(C)=O)C3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)C1
Yield: 65.9 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (26.7 g) obtained according to the Reference Example 2, 3-(N-acetyl-N-methylamino)pyrrolidine (15.5 g), triethylamine (10.0 ml), and ethanol (300 ml) was heated under reflux for one hour. The reaction mixture was concentrated to a half volume under reduced pressure. To the mixture was added water (200 ml), and the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 24.8 g of ethyl 7-[3-(N-acetyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 227°-229° C. A solution of the above ester (20.0 g) in 20% hydrochloric acid (120 ml) was heated under reflux for 3 hours. After the reaction was completed, water (60 ml) and ethanol (120 ml) were added to the reaction mixture, and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (800 ml) and the solution was treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of 27% aqueous ammonia. The crystals were collected by filtration, washed with water, and dried to give 11.0 g of the compound 4, m.p. 243°-245° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[CH:8]=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=1)[CH3:6])C.Cl.[NH2:26][OH:27].[OH-].[K+]>CO>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[NH:10][N:9]=[CH:8][C:7]=2[CH:5]([CH3:6])[C:4]([NH:26][OH:27])=[O:3])=[CH:13][CH:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1ccc(-c2[nH]ncc2C(C)C(=O)OCC)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCc1ccc(-c2[nH]ncc2C(C)C(=O)NO)cc1
Temperature: -5 °C
Reaction time: 24 h

Procedure:
10 g 5-(4-n-hexylphenyl)-1H-pyrazol-4-yl-propionic acid ethyl ester dissolved in 40 ml methanol are added rapidly to a solution of 4.2 g hydroxylamine hydrochloride and 5 g KOH in 40 ml methanol, pre-cooled to -5° C. After reaching room temperature, the reaction mixture is stirred for 24 hrs. The mixture is filtered and the solvent concentrated under vacuum. The residue is dissolved in ethyl acetate, washed with water, dried with Na2SO4 and solvent removed by evaporation under vacuum. The title compound is crystallised from ethyl ether/hexane: m.p.=150°-155° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:60])[C@H:3]([NH:55][C:56](=[O:59])[O:57][CH3:58])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][NH:30][C:31]([CH:33]4[CH2:37][CH2:36][C:35]5([CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[N:34]4[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=O)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C([O-])(=O)C.[NH4+:65]>O1CCOCC1>[CH3:60][CH:2]([CH3:1])[C@H:3]([NH:55][C:56](=[O:59])[O:57][CH3:58])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:65]=[C:31]([CH:33]5[CH2:37][CH2:36][C:35]6([CH2:38][CH2:39][O:40][CH2:41][CH2:42]6)[N:34]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])[NH:30][CH:29]=4)=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[N:15]=1)=[O:5]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4CCC5(CCOCC5)N4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)cc2)c[nH]1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c(C5CCC6(CCOCC6)N5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 110 °C
Yield: 13.7 %

Procedure:
To a solution of methyl ((1S)-2-methyl-1-{[(2S)-2-(4-{4′-[({[1-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-8-oxa-1-azaspiro[4.5]dec-2-yl]carbonyl}amino)acetyl]-4-biphenylyl}-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}propyl)carbamate (169) (71 mg, 0.09 mmol) in anhydrous dioxane (1 mL) was added ammonium acetate (66 mg, 0.86 mmol) and the reaction was degassed with nitrogen and heated to 110° C. for 48 h in a sealed tube. The reaction was purified by HPLC eluting with 10-90% water/acetonitrile/0.2% NH4OH to afford the title compound as an off-white solid (10 mg, 14% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56-7.86 (m, 9H) 7.16-7.44 (m, 2H) 6.88-7.09 (m, 1H) 5.72 (br. s., 1H) 5.09-5.21 (m, 1H) 4.03-4.28 (m, 1H) 3.80-4.04 (m, 6H) 3.42-3.71 (m, 9H) 2.11-2.56 (m, 8H) 1.88-2.11 (m, 6H) 0.80-1.06 (m, 12H). HRMS for C44H57N8O7 (M+H)+ calc: 809.4350, found: 809.4347. Purity (LC-MS): 93%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:24](Cl)=[O:25]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]4[CH:27]=[C:28]([Cl:30])[CH:29]=[C:21]([C:20]([F:32])([F:19])[F:31])[CH:22]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cc(Cl)cc(C(F)(F)F)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(Cl)cc(C(F)(F)F)c1
Yield: 29.8 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 3-trifluoromethyl-5-chlorobenzoyl chloride to afford the title compound (28 mg, 29.8%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=5.9 Hz), 6.94-6.96 (m, 1H, Harom), 7.45 (t, 1H, Harom-5, J=8.2 Hz), 7.59 (s, 1H, Harom-2), 7.63-7.65 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 8.12 (s, 1H, Harom′), 8.22 (s, 1H, Harom′), 8.30 (s, 1H, Harom′), 10.60 (s, 1H, NHamide), 11.20 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=5.07 minutes, m/z: 448.06 (M+H)+, calculated for C20H13N4O3F3Cl. HRMS (EI): m/z [M+H] calculated for C20H13N4O3F3Cl: 449.0628; found: 449.0619.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[N:9]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:8]3[CH2:7][N:6]=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:4]=2[CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:16][CH2:15][C:12]1[N:9]2[C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:6][CH2:7][C:8]2=[N:14][N:13]=1)(=[O:26])[CH3:25]
Reactant: OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 30 °C

Procedure:
1 g of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol is dissolved in 10 ml of absolute pyridine and treated with 1 ml of acetic anhydride. The solution is maintained at 30° C. for 15 hours and then evaporated under vacuum. The residue is partitioned between methylene chloride and water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. By recrystallization of the residue from ethyl acetate, there is obtained 9-acetoxymethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]-diazepine of melting point 191°-193° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C(Cl)Cl>[C:20]([O:19][C:17]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1)=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: OCC1CCCNC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5.0 g (43.4 mmol) of 3-hydroxymethyl-piperidine in 200 ml of CH2Cl2, was added 6.05 ml (43.4 mmol) of triethylamine (Et3N), followed by 9.8 ml (43.4 mmol) of (BOC2O). The reaction mixture was stirred for 1 hour at room temperature and then washed with 75 ml of a 0.1N hydrochloric acid solution (HCl), dried over Na2SO4, filtered and then concentrated in vacuo.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[N:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:13][O:11][C:10]([C:5]1[C:4]2[CH:3]=[N:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cccc2[nH]ncc12
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2[nH]ncc12
Temperature: 25 °C

Procedure:
Indazole-4-carboxylic acid (2.00 g, 12.3 mmol) was suspended in methanol (20 mL) and toluene (30 mL) at room temperature. A solution of 2 M trimethylsilyl diazomethane (12 mL, 24 mmol) in toluene was added slowly and the mixture was stirred at room temperature until the solution turned yellow. The reaction was quenched with concentrated acetic acid (5 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford 1H-indazole-4-carboxylic acid methyl ester.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][CH2:32][CH2:33]2>>[C:28]1([O:27][CH2:26][CH2:25][CH2:24][CH2:23][S:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:4]2)[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Reactant: BrCCCCOc1cccc2c1CCCC2
Product: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CSCCCCOc2cccc3c2CCCC3)S1

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0 g, 0.006 mol) and the bromide produced in Example 7 (1.7 g, 0.006 mol). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.5 g (77%) of the product as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][CH2:14]1>CN(C)C=O>[Cl:8][C:9]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@@H]2CCC[C@H](Cn3ccnc3)O2)c(Cl)c1
Yield: 69 %

Procedure:
As in Example 1(b), 16 mg of imidazole, 10 mg of 55% sodium hydride and 70 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran were reacted in dimethylformamide, to give 37 mg of the title compound in the form of a colourless oil.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C@@H:16]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:18][C:17]1([C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[C:50]([CH2:58][C:59]2[S:63][C:62]3[CH:64]=[CH:65][C:66]([F:68])=[CH:67][C:61]=3[CH:60]=2)[CH:49]=1)O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:8]([O:15][C@H:16]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:18][CH:17]1[C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[C:50]([CH2:58][C:59]2[S:63][C:62]3[CH:64]=[CH:65][C:66]([F:68])=[CH:67][C:61]=3[CH:60]=2)[CH:49]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC1(c2cc(Cc3cc4cc(F)ccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc2sc(Cc3cc(C4O[C@H](COCc5ccccc5)[C@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
In a nitrogen stream, triethylsilane (0.19 ml, 1.21 mmol) and a boron trifluoride-diethyl ether complex (0.14 ml, 1.11 mmol) were added to a solution of (3R,4R,5S,6R)-3,4,5-trisbenzyloxy-6-benzyloxymethyl-2-[3-(5-fluorobenzo-[b]thiophen-2-ylmethyl)-naphthalen-1-yl]tetrahydropyran-2-ol (770 mg, 0.93 mmol) in methylene chloride (10 ml) at 0° C. The reaction mixture was stirred at room temperature for two hours, and then a saturated sodium hydrogen carbonate aqueous solution was added. The obtained mixture was extracted with methylene chloride, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried with sodium sulfate. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (550 mg, 73%).
Reaction SMILES: Br[CH:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5](=[O:15])[C:4]2[C:16]([CH3:31])=[C:17]([CH:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[NH:22][C:21]3=[O:30])[NH:18][C:3]1=2.BrCC1C2C(=[O:50])N(CCN(CC)CC)CCC=2NC=1C=C1C2C(=CC=C(F)C=2)NC1=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:13]([N:10]([CH2:11][CH3:12])[CH2:9][CH2:8][N:6]1[CH2:7][CH2:2][C:3]2[NH:18][C:17]([CH:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[NH:22][C:21]3=[O:30])=[C:16]([CH2:31][OH:50])[C:4]=2[C:5]1=[O:15])[CH3:14]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(CBr)c2C1=O
Reactant: CCN(CC)CCN1CC(Br)c2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(CO)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 7-bromo-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one and 3-bromomethyl-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one in 10 ml of methanol was added with saturated potassium carbonate (2 ml). The mixture was stirred at room temperature overnight, added with water (20 ml) and extracted with the 6 to 1 mixture of dichloromethane and methanol (10 ml×4). The combined extracts were concentrated to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-hydroxymethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (13 mg, 72%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[OH-].[Na+].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Cl:20]>C(O)C>[ClH:20].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: COc1ccccc1S
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1SCc1ccccn1
Yield: 43 %

Procedure:
2-Methoxybenzenethiol (5 g) was added to a solution of sodium hydroxide (2.85 g) in ethanol (50 ml) and the resulting mixture was treated with 2-picolyl chloride, hydrochloride (5.7 g) in ethanol (25 ml) at 0° C. After 16 hours at ambient temperature the mixture was filtered through kieselghur and evaporated. The residue was converted into the hydrochloride in ether with ethereal HCl solution and this was recrystallised from propan-2-ol/acetone to give 2-(((2-methoxyphenyl)thio)methyl)pyridine, hydrochloride (4.0 g) mp 141°-3° C. (Found: C,58.5; H,5.4; N,4.9 C13H13NOS.HCl requires C,58.3; H,5.3; N,5.2%).
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CC(C)CCOCCCCOCCCCCCO
Reactant: CCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCc1ccc(OCCCCCCOCCCCOCCC(C)C)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
2.60 g (0.010 mol) of 6-(4-Isopentyloxybutyloxy)-hexanol are mixed with 1.22 g (0.010 mol) of 4-ethylphenol and 2.06 g (0.010 mol) of dicyclohexyl carbodiimide and the mixture is stirred at 100° C. over the course of 3 days. After cooling the residue is chromatographed with hexane/ethyl acetate (97:3) on silica gel, whereupon 1-ethyl-4-[6-(4-isopentyloxybutyloxy)-hexyloxy]-benzene is obtained, which according to thin layer chromatography and gas-chromatography is a pure oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][S:36]([CH3:35])(=[O:38])=[O:37])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine (100 mg, 0.257 mmol) was dissolved in dichloromethane (2.6 mL) and pyridine (0.208 mL, 2.57 mmol) before methanesulfonyl chloride (30 μl, 0.385 mmol) was added and stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with 1 N HCl (aqueous), washed with 1 N HCl (aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after purification via preparatory LC. MS (ESI) m/z: Calculated: 467.1; Observed: 468.1 (M++H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(N(C(C)C)C(C)C)C>[C:16]([O:18][CH2:19][CH2:20][NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][CH:9]=1)(=[O:17])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCNc1ccc(-c2noc(C)n2)cc1

Procedure:
Prepared analogously to Example 1k from 4-(5-methyl-1,2,4-oxadiazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl-diisopropylamine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]N(C=O)C>>[O:1]([C:8]1[CH:9]=[C:10]2[C:11]([CH:14]=[CH:18][NH:15]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Product: c1ccc(Oc2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 4-phenoxy-1-methyl-2-nitro-benzene (6 g, 26.2 mmol) and DMF dimethylacetal (15.6 g, 131 mmol) in 60 mL dry DMF and heat at 170° C. for 16 hours. Cool to room temperature and concentrate to dryness. Dissolve residue in 50 mL EtOAc and hydrogenate with 2 g 5% Pd/C and hydrogen for 3 hours at atmospheric pressure. Filter through celite and concentrate to an oil. Purify by chromatography using Hex/EtoAC to obtain a tan solid: ISMS 210 (M+1)
Reaction SMILES: C([O:3][C:4]([O:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:35])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[N:24][N:25]([CH3:34])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:14][CH:13]=1)[C:8]([NH2:10])=[O:9])=O)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[O:3]=[C:4]1[NH:10][C:8](=[O:9])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:35])/[CH:20]=[CH:21]/[C:22]3[CH:23]=[N:24][N:25]([CH3:34])[C:26]=3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:16][CH:17]=2)[O:6]1
Reactant: CCOC(=O)OC(Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1)C(N)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CC3OC(=O)NC3=O)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A mixture of 2-(ethoxycarbonyloxy)-3-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-propenoyl}amino)phenyl]propionamide (420 mg), 1,8-diazabicyclo[5.4.0]-7-undecene (266 mg) and acetonitrile (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated and diluted with ethyl acetate. The mixture was successively washed with a 1N aqueous hydrochloric acid solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give (2E)-N-{4-[(2,4-dioxo-1,3-oxazolidin-5-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide (293 mg, 77%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1cccc(F)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 3-fluorophenol (2.24 g, 20.0 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate (2.34 mL, 21.0 mmol), and the mixture is stirred at 70° C. for 18 h. The mixture is cooled to RT, Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled to give 3.2 g of the product 432.
Reaction SMILES: [CH:1]([Si:4]([O:11][CH2:12][C@@H:13]([OH:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:24]I>>[CH:8]([Si:4]([O:11][CH2:12][C@@H:13]([O:23][CH3:24])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:9])[CH3:10]
Reactant: CC(C)[Si](OC[C@@H](O)CNC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: CI
Product: CO[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Yield: 81 %

Procedure:
Using a procedure analogous to Example 57-B, (2S)-3-(t-butoxycarbonylamino)-2-hydroxypropyl triisopropylsilyl ether and methyl iodide gave the title compound (4.2 g, 81%).
Reaction SMILES: C(B1[O:7][CH2:6][CH2:5][O:4]1)C.[CH2:8]([OH:11])[CH2:9][OH:10]>>[O:10]=[CH:9][C@@H:8]([C@H:5]([C@@H:6]([C@@H:6]([CH2:5][OH:4])[OH:7])[OH:7])[OH:4])[OH:11]
Reactant: OCCO
Reactant: CCB1OCCO1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h
Yield: 72 %

Procedure:
20 ml of ethane-1,2-diol are added dropwise at 50° C. to 11 g of residue and at the same time the 2-ethyl-1,3,2-dioxaborolane formed is distilled off in vacuo (10 Torr). The excess ethane-1,2-diol is removed in vacuo (10-3Torr, bath 80° C.). Approximately 40 ml of hexane are added to the highly viscous residue, the mixture is stirred for about 30 minutes and the white glucose is filtered off. 5 g (72%) of pure D-glucose are obtained after drying, mp. 146° C.