Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:61](Br)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:61]([N:9]1[CH2:10][CH2:11][C:6]2[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([C:36]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:34]=[N:33][N:32]=4)=[CH:23][CH:24]=3)[C:7]=2[CH:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(Cc1ccccc1)CC2
Yield: 66.6 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.00 g), potassium carbonate (1.16 g), benzyl bromide (0.72 g) and dimethylformamide (10 ml) is stirred under ice-cooling for two hours. The mixture is diluted with ethyl acetate, and the solution is washed with water, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate) to give ethyl 5-benzyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.50 g) as a white foam.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C@:20]2([CH3:26])[CH2:24][O:23]C(=O)[NH:21]2)[CH:14]=[CH:13]3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)C.[OH-].[Li+].O>>[NH2:21][C@@:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][C:8]3[CH:27]=[CH:28][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH:11]=2)[CH:16]=1)([CH3:26])[CH2:24][OH:23]
Reactant: CC(C)Oc1ccc(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(R)-4-[6-(4-Isopropoxy-phenoxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (1.092 g, 0.002894 mol) was dissolved in ethanol (60 mL, 1 mol), followed by 4 M lithium hydroxide in water (30 mL, 0.1 mol). The reaction mixture was then heated at 80° C. for 5 hours. LCMS indicates no SM remains with mostly DP RT=1.26 min, M+1=352. All solvent was removed under reduced pressure. The solid was triturated with DCM, and the solvent was then washed with water. Organic was dried over MgSO4, filtered and concentrated to dryness. Residue was then placed on the high vac for 5 hours. 1H NMR and LCMS were consistent with structure. ESI-MS: 360 (M-16)+ 1H NMR (400 MHz, CHLOROFORM-d) δ=7.88-7.67 (m, 3 H), 7.50-7.21 (m, 5 H), 7.00 (m, 2 H), 6.45-6.13 (m, 1 H), 4.82-4.67 (m, 1 H), 4.43 (s, 2 H), 2.17 (s, 3 H), 1.46-1.28 (d, J=9.0 Hz, 6 H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: Cl
Product: COC(=O)c1cc(F)ccc1N
Temperature: 100 °C
Yield: 42 %

Procedure:
A solution of 2-amino-5-fluorobenzoic acid (9.29 mmol, 1.440 g) in a mixture of HCl/MeOH (3N, 30 ml) was heated at 100° C. overnight. The solvent was evaporated and the crude mixture was extracted between DCM and K2CO3 saturated aqueous solution. The organic phase was evaporated and the crude mixture was purified by chromatography over SiO2 with hexane/ethyl acetate mixtures affording 0.650 g (yield 42%) of the expected product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]1[C:39](=[O:40])[N:9]2[C:10]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:11](/[CH:14]=[CH:15]/[S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:12][S:13][C@H:8]12>O.C(O)=O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][CH:7]1[C:39](=[O:40])[N:9]2[C:10]([C:23]([OH:25])=[O:24])=[C:11](/[CH:14]=[CH:15]/[S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:12][S:13][C@H:8]12
Reactant: Cn1nnnc1S/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S/C=C/C1=C(C(=O)O)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1

Procedure:
A solution of the hydrochloried/hydrofluoride salt of diphenylmethyl 7-(imidazol-2-yl)amino-3-[2-(1-methyltetrazol-5-ylthio)-trans-vinyl]ceph-3-em-4-carboxylate (300 mg.) in a mixture of water (2 ml.) and formic acid (2 ml.) was heated to 40°-45° for 1.75 hours. The solvent was evaporated and the residue dissolved in the minium amount of a mixture of CH2Cl2, methanol and water. Precipitation by addition of isopropanol gave 7-(imidazol-2-yl)amino-3-[2-(1-methyltetrazol-5-ylthio)-trans-vinyl]ceph-3-em-4-carboxylic acid as a salt (73 mg.) having the following n.m.r. in d6DMSO+CD3COOD: 3.62 (m, 2H); 3.90 (s, 3H); 5.1 (d, 1H); 5.5 (d, 1H); 6.7 (d, 1H); 7.2 (d, 1H); 6.75 (s, 2H).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30](O)=[O:31])=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:20][CH:19]=1>>[S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:30]([C:25]2[C:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:28][N:27]([CH3:29])[N:26]=2)=[O:31])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: c1ccc2sc(CC3CCCCN3)cc2c1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2cc3ccccc3s2)n1
Yield: 2.4 %

Procedure:
The title compound (6 mg) was prepared from 2-benzo[b]thiophen-2-ylmethyl-piperidine D83 (133 mg) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (140 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(C[CH2:14][CH:15]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:19][C:18](=[O:28])[NH:17][CH2:16]1)(O)=O.[O:29]1CCCC1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]2[CH2:19][C:18](=[O:28])[NH:17][CH2:16][CH:15]2[CH:14]=[O:29])=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: O=CC1CNC(=O)CC1c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
DIBAL-H (4.03 ml, 6 mmol) was added gradually at a rate of 5.6 ml/hour, by means of a syringe pump, to a solution of 3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6-one (0.53 g, 2 mmol) in 4 ml tetrahydrofuran at −70° C. under an argon atmosphere. The reaction mixture was stirred for 1 hour at −70° C. then quenched with a solution of methanol (0.24 ml) in toluene (2 ml) at −70° C., followed by 0.12 ml water at 0° C. After 30 minutes stirring at ambient temperature, the gel which formed was destroyed by the addition of 1.5 ml brine and the reaction mixture was extracted with diethyl ether (50 ml). The organic phase was separated, dried with anhydrous sodium sulphate, filtered and evaporated to yield the title compound (0.2 g) as a yellow oil. The aqueous layer was basified with 10% aqueous sodium hydroxide and extracted with dichloromethane (20 ml). A further 0.08 g product was isolated from the dichloromethane extract.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][CH:24]([F:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][CH:24]([F:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][C@@H:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[C@@H:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:36])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(C(F)F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H](Cc1ccc(C(F)(F)F)cc1)[C@H](O)c1ccc(F)cc1)c1ccc(C(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-(difluoromethyl)-1-naphthalenecarboxylic acid (213 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the-title compound (410 mg, 83%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[C:9]1([C:15](=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=Cc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1cccnc1)c1ccccc1
Yield: 30.2 %

Procedure:
To a mixture of 4.3 g of 3-pyridinecarbaldehyde, 5.4 g of phenylacetic acid, and 11.4 ml of acetic anhydride, 5.6 g of triethylamine is added with stirring, and the mixture is stirred at 100° C. for 4 hours. The reaction mixture is alkalified with 10% aqueous sodium bicarbonate solution. The aqueous solution is warmed and filtered. The filtrate is adjusted to pH 4.5 with 10% hydrochloric acid, and the resulting precipitate is collected and recrystallized from ethanol to give 2.7 g of the title compound, m.p. 190°-192° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[C:13]([C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25](/[CH:29]=C4/C(=O)N(CC(O)=O)C(=O)S/4)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:43]([F:46])([F:45])[F:44])[CH:16]=1)#[N:14]>>[C:13]([C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25](/[CH:29]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:43]([F:46])([F:45])[F:44])[CH:16]=1)#[N:14]
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: N#Cc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CC(=O)O)C4=O)ccc32)c(C(F)(F)F)c1
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C#N)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Cyano-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-cyano-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 346) following General Procedure E.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[C:12](OC(=O)C)(=O)[CH3:13]>>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[N:11]=[C:12]1[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccnc1NCCO
Product: Cc1nc2cccnc2n1CCO
Yield: 59 %

Procedure:
2-(2-Hydroxyethylamino)-3-aminopyridine (3.4 g) was dissolved in acetic anhydride (140 ml) and stirred at reflux for 15 hours. The reaction mixture was cooled and the excess of reagent removed under reduced pressure. The dark brown oil was dissolved in ethanol (100 ml), 2N sodium hydroxide (50 ml) was added and the mixture was stirred for 15 minutes. The solution was acidified to pH5 using 2N hydrochloric acid and the solvents removed under reduced pressure. The residue was chromatographed over silica eluting with 10% methanol in ethyl acetate to yield the title compound (2.32 g, 59%) as a foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([Cl:8])[CH:5]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1
Reactant: CCOC(=O)CCc1cccc(N)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (67)(58 mg, 0.26 mmol) was coupled to aniline (124)(50 mg, 0.26 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:25][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH:13]2[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:25][CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][CH:13]3[CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.46 g, 7.96 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.11 g, 13.74 mmol) in EtOH (60 mL) was added Et3N (2.21 g, 21.84 mmol) and the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (50 mL) and water (50 mL), and extracted with EtOAc (150 mL×3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as a pale yellow solid (2.97 g, 100%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([Si:8]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([NH2:18])[CH:17]=[C:12]2[CH:11]=[CH:10]1)([CH3:7])[CH3:6].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:22]([Si:8]([CH:5]([CH3:7])[CH3:6])([CH:19]([CH3:21])[CH3:20])[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([NH:18][C:1](=[O:3])[CH3:2])[CH:17]=[C:12]2[CH:11]=[CH:10]1)([CH3:24])[CH3:23]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
Acetyl chloride (75 μL, 1.0 mmol) was added to a solution of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (230 mg, 0.8 mmol) and 4-dimethylaminopyridine (5 mg) in pyridine (1.6 mL). The mixture was stirred at RT for 24 h and a saturated solution of ammonium chloride (30 mL) and ethyl acetate (30 mL) were added. The separated aqueous layer was extracted with ethyl acetate (3×25 mL) and the combined organic layers were dried, filtered and concentrated to provide an oil which was purified by preparative HPLC to afford N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (140 mg, 53%) as an oil: LCMS; m/z 332 (M+H+). B. At RT under argon, a solution of borane-dimethylsulfide complex (665 μL, 6.6 mmol, 10 M) was added to N-methyl-N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (110 mg, 0.33 mmol) in THF (3.0 mL). The mixture was heated to 65° C. for 2 h., cooled down and a 6N hydrochloric acid solution was slowly added. The mixture was heated to 100° C. and vigorously stirred for 12 h., cooled down and a 6 N sodium hydroxide solution was added until pH 7 was reached. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried, filtered and evaporated to provide an oil which was purified through silica gel-SCX column (arylsulfonic acid with washes with methanol and 2N NH3 in methanol) to afford ethyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine. LCMS; m/z 203 (M+AcCN), 162 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:28][C:20]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=2[F:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of the bromide 41 (5.1 g, 20.5 mmol), potassium carbonate (5.65 g, 4 mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) was heated at 190° C. in diphenyl ether (25 ml) for 3 hrs. After cooling to room temperature it was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (eluent EtOAc:hexane, 3:1) to afford title compound 42 as a yellow solid (5.4 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.55 (d, J=5.28 Hz, 1H), 8.46 (dd, J=2.5 and 10.4 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J=8.4 Hz), 6.99 (d, J=5.47 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[CH:9](OCC)=[O:10]>>[CH:9]([NH:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:10]
Reactant: NCCc1ccco1
Reactant: CCOC=O
Product: O=CNCCc1ccco1

Procedure:
Here, 2-(2-amino-ethyl)furan (10.0 g, 0.090 mol) is refluxed with ethyl formate (80 ml, 1.0 mol) for 12 hours. The reaction product is concentrated by evaporation and distilled in vacuo.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][NH:13][C:12](=[S:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+].O.[CH3:22]I>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][N:13]=[C:12]([S:17][CH3:22])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)CC(=S)NCCS1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
The compound (2.00 g, 6.54 mmol) obtained in Example 4-0) was dissolved in tetrahydrofuran (11 mL). Potassium hydroxide (2.16 g, 39.72 mmol), water (7 mL), and methyl iodide (2.44 mL, 39.27 mmol) were added to the solution at room temperature, and the mixture was stirred for 1 h under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.09 g, quant.) in a yellow oily form.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[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.[C:28]1([S:38](Cl)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:38]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cccc2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 66 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 1-naphthalenesulfonyl chloride under the conditions used in example 2 giving 66% of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O-:9])=O)[C:2]=1[C:10]([O:12]C)=O.[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>CCO>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[C:7]([C:3]1[C:2]([C:10]([N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17])=[O:12])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: COC(=O)c1nccnc1C(=O)[O-]
Reactant: OCCNCCO
Solvent: CCO
Product: O=C(c1nccnc1C(=O)N(CCO)CCO)N(CCO)CCO
Yield: 71.6 %

Procedure:
Methyl pyrazine-2,3-dicarboxylate (2 g, 10.2 mmol) was dissolved in EtOH (5 mL). Diethanolamine (2.14 g, 20.4 mmol) was added and the mixture was heated under reflux for 5 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 8:2) to afford the title compound (2.5 g, 71.4%).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1.O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[C:11]3[CH2:22][CH2:21][CH2:20][C:12]=3[C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCC3
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc2c3c(c(OCC4CC4)nn12)CCC3
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylmethanol (1.78 ml) was initially charged in DMF (25 ml). Subsequently, the mixture was admixed with sodium hydride (541 mg) under argon and stirred at 45° C. for 0.5 h. Subsequently, 6-chloro-8,9-dihydro-7H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.017, 1.31 g) was dissolved in DMF (20 ml) and 11.25 ml of the alkoxide solution were added in portions at 45° C. over 90 min. Then the mixture was stirred at 45° C. for another hour. After adding a little water, the mixture was dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 528 mg of the title compound were obtained. LC-MS rt: 0.63 min [M+H]+: 246.1 (met. b)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][NH2:14])[CH2:6]2.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][NH:14][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:6]2
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(c1)CC(CN)CO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1COc2ccc(OC)cc2C1
Reaction time: 1 h

Procedure:
A solution of 0.4 g (2.06 mmol) of the amine obtained in Step B in 20 ml of anhydrous dichloromethane is cooled to 0° C. 1 ml (7.2 mmol) of triethylamine and also 0.38 g (3.6 mmol) of butyryl chloride are added in succession to the medium. After one hour of stirring under argon, the reaction mixture is acidified with a 1N hydrochloric acid solution; the aqueous phase is then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The title amide is obtained pure in the form of a white solid after passage over a silica column (eluant: petroleum ether/ethyl acetate 50/50).