Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[OH:28]N1C2C=CC=CC=2N=N1.[CH:38]([NH:40][CH:41]([CH2:45][CH3:46])[C:42]([OH:44])=[O:43])=[O:39].C1(N=C=[N:55][CH:56]2CCCCC2)CCCCC1>N1C=CC=CC=1.ClCCl>[CH3:26][O:25][C:24]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19](/[CH:18]=[CH:17]/[C:15]([CH2:14][C:12](/[CH:11]=[CH:10]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)=[O:13])=[O:16])[CH:27]=1.[CH:38]([NH:40][C:41]([NH:55][CH:56]=[O:28])([CH2:45][CH3:46])[C:42]([O-:44])=[O:43])=[O:39]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCC(NC=O)C(=O)O
Reactant: On1nnc2ccccc21
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(NC=O)(NC=O)C(=O)[O-]
Reaction time: 24 h

Procedure:
To a slurry of 1.85 g curcumin (5 mmole), 0.14 g 1-hydroxybenzotriazole (1 mmole) and 1.6 g N-formylaminobutyric acid in 5 ml pyridine and 50 ml dichloromethane was added 2.7 g dicyclohexylcarbodiimide (13 mmole). After stirring the mixture for 24 h at reflux, the solids were filtered off and washed thoroughly with dichloromethane. The filtrate was evaporated to yield 1.7 g curcumin-bis-formylaminobutyrate, m.p. 142-147° C. of approx. 80% purity.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=C(O)C1CCNCC1
Agent: [Pd]
Solvent: O
Product: CN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Isonipecotic acid (50 g, 0.387 mole) was dissolved in water (500 ml) and 37% formaldehyde (125 ml). 10% Palladium on carbon (50 g) was added and the mixture was shaken under a hydrogen atmosphere at 60 psi at room temperature for 18 hours.
Reaction SMILES: CC1C=CC(S(OC[C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4=[C:24]5[S:30][CH:29]=[CH:28][C:25]5=[N:26][CH:27]=[C:22]4[N:21]=[C:20]3[CH3:31])[CH2:15][O:14]2)(=O)=O)=CC=1.[C-:32]#N.[Na+].S(=O)(=O)(O)O.C[N:41]([CH:43]=O)C>CO>[CH3:31][C:20]1[N:19]([C@@H:16]2[CH2:15][O:14][C@@H:13]([CH2:32][C:43]#[N:41])[CH2:18][CH2:17]2)[C:23]2=[C:24]3[S:30][CH:29]=[CH:28][C:25]3=[N:26][CH:27]=[C:22]2[N:21]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c(C)nc4cnc5ccsc5c43)CO2)cc1
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a mixture of [(2R,5S)-5-(2-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]methyl 4-methylbenzenesulfonate (50.2 mg, 0.110 mmol) and sodium cyanide (9.1 mg, 0.19 mmol) in DMF (1.1 mL) was added 1.0 M sulfuric acid in DMF (9 μL, 0.009 mmol). The reaction solution was stirred at 50° C. overnight. After cooling, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (15.2 mg, 44%). LCMS calculated for C16H17N4OS (M+H)+: m/z=313.1. Found: 313.0.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:9]=[N:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12](=S)=[S:13].Cl>CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:12]([SH:13])=[N:11][N:10]=2)[N:9]=1
Reactant: Cc1ccc(NN)nn1
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nnc(S)n2n1
Yield: 85 %

Procedure:
To a solution of KOH (11.3 g, 0.202 mol) in methanol (100 mL) was added (6-methyl-pyridazin-3-yl)-hydrazine (25 g, 0.202 mol) at room temperature. The reaction mixture was placed in an ice-water bath and carbon disulfide (98 mL, 1.61 mol) was slowly added. The resultant yellow solution was heated to reflux overnight before removal of solvent. The yellow residue was acidified with 2 N aqueous HCl to pH˜4, filtered, and washed with water. Upon drying 33 g of 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol was obtained as a yellow powder (85% yield): 1H NMR (DMSO-d6): δ 2.5 (s, 3H), 7.28 (d, 1H), 8.05 (d, 1H), 14.66 (br s, 1H); MS (m/z) 167 [M+H+]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19]S(C2C=CC=CC=2)(=O)=O)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH3:29])[CH:6]=1)#[N:4].CC1CCCO1.[F:36][C:37]([F:53])([F:52])[C:38]1[CH:39]=[C:40]([NH:44][C:45]2[CH2:50][CH2:49][CH2:48][C:47](=[O:51])[CH:46]=2)[CH:41]=[CH:42][CH:43]=1>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19][C:46]2[C:47](=[O:51])[CH2:48][CH2:49][CH2:50][C:45]=2[NH:44][C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:36])([F:53])[F:52])[CH:39]=2)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:7]([CH3:29])[CH:6]=1)#[N:4]
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Reactant: Cc1cc(C#N)ccc1N(CS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1cc(C#N)ccc1N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 150 mg, 3.75 mmol) is added in portions to a mixture of tert-butyl (4-cyano-2-methylphenyl)(phenylsulfonyl)methylcarbamate (step 1, 1.88 g, 3.41 mmol) and 2-methyltetrahydrofuran (10 mL), and the mixture is stirred at room temperature for 30 min 3-(3-(Trifluoromethyl)phenylamino)cyclohex-2-enone (869 mg, 3.41 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the mixture is extracted with dichloromethane. The phases are separated, and the organic layer is concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 1.57 g; ESI mass spectrum [M+H]+=500; Retention time HPLC: 0.79 min (X012_S01).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:14](=[O:16])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:22]Br>C(O)(=O)C>[Br:22][C:15]1[C:14](=[O:16])[C:13]2([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[O:12][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(C2=CC(=O)C3(CCCCC3)O2)cc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCCC3)O2)cc1

Procedure:
50 mg of 2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,5]dec-2-en-4-one was reacted with bromine (0.5 ml) in the presence of 0.1 ml acetic acid to yield 68 mg of 3-bromo-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,5]dec-2-en-4-one by following a procedure similar to the procedure in Step 5 of Example 53. mp: 163-164° C. NMR: δ1.79 (m, 10H), 3.11 (s, 3H), 8.10 (d, J=8.1 Hz, 2H), 8.40 (d, J=8.1 Hz, 2H). IR (cm−1): 2936, 1709, 1583, 1316, 1149, 912, 744.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].O.C(O)(=O)C>C(O)C>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1N
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccccc1Oc1c(C(=O)O)[nH]c2ccccc12

Procedure:
1.6g of methyl-3-[o-aminophenoxy]-indole-2-carboxylate was dissolved in 10ml each of ethanol and water and refluxed for 10 min. The clear solution was acidified with acetic acid. The white precipitate was filtered and recrystallized from acetonitrile to give analytical material, mp. 217°-18°.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].FC(F)(F)C(O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]2[S:28][C:29]3[CH2:35][CH2:34][CH2:33][C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(O)[C:30]=3[N:31]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[N:23][C:22]([CH3:25])=N1.C(Cl)(Cl)[Cl:44]>>[N:1]([C:32]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:27]([NH:26][C:16]3[CH:17]=[CH:18][C:19]([N:20]4[CH:25]=[C:22]([Cl:44])[N:23]=[CH:24]4)=[C:14]([O:13][CH3:12])[CH:15]=3)[S:28][C:29]=2[CH2:35][CH2:34][CH2:33]1)=[N+:2]=[N-:3]
Reactant: ClC(Cl)Cl
Reactant: COc1cc(Nc2nc3c(s2)CCCC3(O)c2ccccc2)ccc1-n1cnc(C)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3c(s2)CCCC3(N=[N+]=[N-])c2ccccc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
Sodium azide (4.5 mg, 0.069 mml) and trifluoroacetic acid were sequentially added to a solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-ol (10 mg, 0.023 mmol, from example 81) in chloroform (0.1 mL). After stirring 4 h at rt, the reaction was diluted with chloroform and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo to afford 4-azido-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (6 mg, 57% yield). LC-MS (M+H)+ 459.33.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(Cl)=O.[CH3:12][C:13]1([CH3:35])[S:17][C@@H:16]2[C@H:18](NC([C@H](N)C3C=CC=CC=3)=O)[C:19](=[O:20])[N:15]2[C@H:14]1[C:32]([OH:34])=[O:33].N1C(=O)C=CN1>ClCCl.Cl>[CH3:12][C:13]1([CH3:35])[S:17][C@@H:16]2[CH2:18][C:19](=[O:20])[N:15]2[C@H:14]1[C:32]([OH:34])=[O:33]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Agent: O=c1cc[nH][nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
The pyrazolinone acid obtained in (b) (0.10 g, 0.46 mmol) in dry dichloromethane (5 ml) was treated with triethylamine (0.10 ml, 0.7 mmol) and the solution cooled to -20° and treated with thionyl chloride(0.040 ml, 0.56 mmol) in dichloromethane (0.5 ml). The solution was then stirred 30 min. at -10°. Anhydrous ampicillin (0.15 g., 0.43 mmol) in dichloromethane (5 ml) was meanwhile separately treated with triethylamine (0.07 ml, 0.5 mmol); the suspension was stirred 20 mins. when further triethylamine (0.06 ml) was added to give a solution. This was cooled to 0° and the above pyrazolinone solution added dropwise. The whole was stirred 90 mins. at room temperature; 1 drop of 5 N HCl was added, the solution concentrated to low volume, ethyl acetate and water were added and the pH of the aqueous layer adjusted to 7.5 with sodium bicarbonate solution. The aqueous layer was separated, acidified to pH 1.5 (5 N HCl) and extracted with ethyl acetate. Drying (Na2SO4) and evaporation of the organic layer gave a crude product which was triturated with ethyl acetate (0.5 ml) to leave the desired title product as the solid free penicillanic acid (10 mg.) δ ((CD3)2CO+D2O) 1.49, 1.55 (2×3H, 2s, (CH3)2), 2.54 (3H, s, CH3 --C=), 4.29 (1H, s, C3 -penicillanic proton), 5.56 (2H, m, C5 and C6 -penicillanic protons), 5.89 (1H, s, --CH--CON--), 7.58 (11 H, complex, aryl and ring NH protons), 8.14 (partially exchanged --C--NH--CO). The free acid was converted to the sodium salt by suspension in water, addition of dilute sodium bicarbonate solution until, on shaking, dissolution occurred at pH 6.5, and freeze-drying.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][C:13]=1[OH:19]>B(F)(F)F.CCOCC>[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15]([OH:16])=[C:17]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Oc1ccc(Cl)c(O)c1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1cc(Cl)c(O)cc1O
Reaction time: 2 h
Yield: 79.2 %

Procedure:
This compounds was synthesised in the same manner as described above. Phenylacetic acid (4.71 g, 34.6 mmol), 4-chlororesorcinol (5 g, 34.6 mmol), boron trifloride etherate (30 ml). After standing for two hours an orange precipitate formed. This was purified by flash chromatography to give the required compound as a white solid (7.2 g, 79.3%); Rf 0.9 hexane/ethyl acetate (20/80)].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[C:12]1[CH:17]=CC=C[C:13]=1[OH:18].CC(=O)OCC>CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:17][CH:12]1[CH2:13][O:18]1
Reactant: Oc1ccccc1Br
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cccc(OCC2CO2)c1
Reaction time: 0.08 h
Yield: 113.3 %

Procedure:
To a solution of NaH (416.2 mg, 17.34 mmol) in DMF (10 mL) was added 3-bromophenol (1.0 g, 5.78 mmol) at 9° C. and stirred for 5 minutes. To this mixture was added 2-bromophenol (1.2 g, 8.67 mmol) at 9° C. The reaction mixture was stirred for a further 16 h at 9° C. TLC (PE:EA=5:1) showed that the reaction was completed. The mixture was treated with water (50 mL) and extracted with EA (2×20 mL). The organic layer was washed with NaHCO3, brine (30 mL) then dried over Na2SO4 and concentrated to give 2-((3-bromophenoxy)methyl)oxirane (1.5 g, crude) as colorless oil which was used in next step without further purification. LCMS (m/z): 229.1/230.1 [M+H]+/[M+2H]+
Reaction SMILES: I[C:2]1C=CN=C(OC)[C:3]=1C1NC(C2C=CC=CC=2)=CN=1.[I:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[C:23]=1[C:30]1[N:31]([OH:41])[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:33][N:34]=1>>[CH2:2]([C:33]1[N:34]=[C:30]([C:23]2[C:24]([O:28][CH3:29])=[N:25][CH:26]=[CH:27][C:22]=2[I:21])[N:31]([OH:41])[C:32]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:3]
Reactant: COc1nccc(I)c1-c1ncc(-c2ccccc2)n1O
Reactant: COc1nccc(I)c1-c1ncc(-c2ccccc2)[nH]1
Product: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1

Procedure:
4-Iodo-2-methoxy-3-(5-phenyl-1H-imidazol-2-yl)-pyridine and 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol: Isonitrosoacetophenone (0.030 g, 0.114 mmol) was reacted as described for the synthesis of 4-ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol and gave 4-iodo-2-methoxy-3-(5-phenyl-1H-imidazol-2-yl)-pyridine (0.008 g, 19%) and 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol (0.007 g, 16%). 4-Iodo-2-methoxy-3-(5-phenyl-1H-imidazol-2-yl)-pyridine: LCMS (+ESI, M+H+) m/z 378; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.83 (3H, s), 7.17-7.97 (8H, m), 12.29 and 12.60 (1H, 2 br s). 2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol: : LCMS (+ESI, M+H+) m/z 378; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.82 and 3.92 (3H, 2 d), 7.19-8.05 (8H, m), 11.68 and 12.70 (1H, 2s).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[S:13](Cl)([CH3:16])(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][S:13]([N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:12][CH2:11]1)(=[O:15])=[O:14]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
An ice cold solution of 1-ethoxycarbonylmethylpiperazine (5 g, 29 mmol), mesyl chloride (3.37 mL, 43.5 mmol) and triethyl amine (6.05 mL, 43.5 mmol) in CH2Cl2 (150 mL) was stirred at 0° C. for 5 min then at rt for 30 min, then partitioned between CH2Cl2 and aq. sat. NH4Cl. The organics were washed with aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated to give 6.88 g of the title compound. MS (APCI) m/z 251 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:22])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:7]1[CH:23]=[CH:24][CH:25]=[CH:26][C:6]=1[N:5]2[CH3:27].[CH:28]1([CH2:31][O:32][C:33]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:34]=2[CH:35]=O)[CH2:30][CH2:29]1.[O-]CC.[Na+]>C(O)C>[CH:28]1([CH2:31][O:32][C:33]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:34]=2/[CH:35]=[CH:1]/[C:2]2[N:3]=[C:4]3[N:8]([C:9](=[O:22])[C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]=2[N:5]3[CH3:27])[CH2:29][CH2:30]1
Reactant: Cc1nc2n(C)c3ccccc3n2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3n(C)c4ccccc4n3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 92.5 %

Procedure:
The title compound was synthesized by condensation of Intermediate 25 (300 mg, 0.801 mmol) with 2-cyclopropylmethoxy-3-methoxy benzaldehyde (215 mg, 1.010 mmol) in presence of sodium ethoxide (108 mg, 1.610 mmol) in ethanol (25 ml) according to the procedure described in Example 24 to afford crude product which was purified by column chromatography to give 416 mg of the desired compound; 1H NMR (300 MHz, DMSO-d6) δ 0.23-0.32 (m, 2H), 0.49-0.56 (m, 2H), 1.12 (br s, 1H), 3.70-3.78 (m, 6H), 3.87 (s, 2H), 6.91-6.99 (m, 3H), 7.20-7.26 (m, 1H), 7.32-7.38 (m, 1H), 7.45-7.54 (m, 5H), 7.68 (d, J=8.4 Hz, 1H), 8.27 (d, J=16.2 Hz, 1H), 8.37-8.43 (m, 1H); APCI-MS (m/z) 562.49 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][OH:10])[C:5]([F:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([F:13])=[CH:4][CH:3]=1
Reactant: CC(O)(CO)c1nc(Br)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(COS(C)(=O)=O)c1nc(Br)ccc1F
Reaction time: 0.5 h

Procedure:
To a solution of 2-(6-bromo-3-fluoro-pyridin-2-yl)-propane-1,2-diol (18.29 g, 73.1 mmol) in dichloromethane (350 ml) was added triethylamine (20.39 ml, 146 mmol). Methanesulfonyl chloride (6.27 ml, 80 mmol) was added dropwise at 0° C. over 10 minutes. Stirring was continued at 0° C. for 30 minutes. The reaction mixture was washed with sat. sodium bicarbonate solution, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. 31.46 g (crude, used without further purification in the next step). LCMS RtH5=0.81 min. (ES+ 328, 330); 1H-NMR (360 MHz, CDCl3): 7.52 (dd, 1H), 7.41 (dd, 1H), 5.13 (s, 1H, OH), 4.61 (d, 1H), 4.45 (d, 1H), 3.05 (s, 3H, CH3SO2), 1.61 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]1[C@@H:67]([CH2:68][N:69]2[N:73]=[N:72][C:71]([CH3:74])=[N:70]2)[NH:66][C:65]1=[O:75]>C(Cl)Cl.CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:13]([NH:63][C@@H:64]2[C:65](=[O:75])[NH:66][C@@H:67]2[CH2:68][N:69]2[N:73]=[N:72][C:71]([CH3:74])=[N:70]2)=[O:15])[N:17]=1)=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: Cc1nnn(C[C@H]2NC(=O)[C@H]2N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Prepared in an analogous manner to example 4, step 3 using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (130 mg, 0.302 mmol), DIPEA (158 μL, 0.906 mmol) and HATU (138 mg, 0.362 mmol) in DCM:DMF (2:1, 3.0 mL) at 0° C. followed by a solution of (3S,4R)-3-amino-4-((5-methyl-2H-tetrazol-2-yl)methyl)azetidin-2-one (55 mg, 0.30 mmol) in DCM:DMF (2:1, 3.0 mL). After stirring at rt for 1 h it was concentrated in vacuo, dissolved in EtOAc, washed with water then brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM), affording the title compound (179 mg, 99%) as a solid. LCMS: Rt=0.93 min, m/z=594.3 (M+1) Method 2m_acidic.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[NH:17]([CH2:21][CH2:22][CH2:23]Br)[C:18]([CH3:20])=[O:19]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:23][CH2:22][CH2:21][NH:17][C:18](=[O:19])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)NCCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 70.7 %

Procedure:
191 mg of 3-(1-piperidinylmethyl)phenol was dissolved in 10 ml of ethanol, and 116 mg of potassium hydroxide was added. The mixture was heated under reflux, and a solution of 360 mg of 3-acetamino-1-bromopropane in 3 ml of ethanol. The reaction mixture was heated under reflux for 8 hours, and the solvent was distilled off under reduced pressure. Water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 205 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide as an oil. The resulting product coincided with the product obtained in Example 2.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>C(#N)C>[Cl:14][C:15]1[N:16]=[C:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 65 °C
Reaction time: 15 h
Yield: 89.9 %

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (5.07 g, 27.2 mmol), 2,6-dichloropyrazine (3.38 g, 22.7 mmol), and K2CO3 (4.09 g, 30.0 mmol) in acetonitrile (20 mL) was stirred at 65° C. for 12.5 h and for a further 15 h at room temperature. Ether was added and the suspension was filtered. Concentration in vacuo furnished the crude product as an oil that crystallized upon standing. Purification by chromatography on silica gel using ethyl acetate/n-hexane (6:4) as eluent gave 6.1 g (90%) of the title compound as a solid. HRMS m/z calcd for C13H19ClN4O2 (M)+ 298.1197, found 298.1211. Anal. (C13H19ClN4O2) C, H, N.