Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:11])=[O:10]
Reactant: OCCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCC(F)(F)F

Procedure:
3,3,3-Trifluoropropyl methanesulfonate was prepared by reaction of 3,3,3-trifluoropropanol with methanesulfonyl chloride by an analogous procedure to that used for Example 52 step 1.
Reaction SMILES: ClC(Cl)(Cl)COC(NC([N:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:26])C(C)C)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[C:19]1([CH2:18][C:17]([NH:16][CH:14]2[CH2:15][NH:12][C:13]2=[O:26])=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C(NC(=O)OCC(Cl)(Cl)Cl)N1CC(NC(=O)Cc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)NC1CNC1=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
1-[1-(2,2,2-Trichloroethoxycarbonylamino)-2-methylpropyl]-3-(2-phenylacetamido)-2-azetidinone (1.13 g.) was dissolved in a 90% acetic acid aqueous solution (20 ml.), and the solution was cooled to 5° C. Zinc powder (1.62 g.) was added dropwise to said solution in 5 minutes, and the mixture was stirred for 30 minutes. Furthermore, zinc powder (1.62 g.) was added to said mixture, and the mixture was stirred for 2 days. The reaction mixture was neutralized with a sodium bicarbonate aqueous solution, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution. The residue (0.65 g.) was subjected to preparative thin layer chromatography using silica gel [developing solvent; a mixed solvent of ethyl acetate, ethyl methyl ketone, water and formic acid (volume ratio 5:3:1:1)], isolated and purified to give 3-(2-phenylacetamido)-2-azetidinone (0.3 g.). Mp 190° to 192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].[O-]CC.[Na+].[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27]Br>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:29])[C:7]=1[CH2:13][CH3:14]
Reactant: COC(=O)CCBr
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nn(CCC(=O)OC)c(CC)c1Cc1cc(Cl)cc(Cl)c1

Procedure:
A solution of the pyrazole of Example 11 (198 mg, 0.70 mmol) in ethanol (1 ml) was treated with sodium ethoxide (21% w/v in EtOH) (261 μL, 0.81 mmol) and then methyl-3-bromopropionate (153 μL, 1.40 mmol) and heated at 70° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. Over a period of 3 days more sodium ethoxide (2.65 eq) and methyl-3-bromopropionate (6.0 eq) were added and the reaction was maintained under the same conditions. After cooling, the solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (5:1, by volume) to afford two products.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si]([O:15][CH2:16][C@H:17]([CH3:47])[O:18][C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH:35]=1)[C:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][O:31][CH3:32])[N:29]=1)=[O:23])(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[OH:15][CH2:16][C@H:17]([CH3:47])[O:18][C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([O:36][C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)[CH:35]=1)[C:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][O:31][CH3:32])[N:29]=1)=[O:23]
Reactant: COCc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COCc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)CO)c2)n1
Reaction time: 1 h
Yield: 55.7 %

Procedure:
TFA (2 mL) was added to a solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-[4-(methoxymethyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenoxy]benzamide (325 mg, 0.536 mmol) in DCM (4 mL) and water (1 mL) and the reaction was stirred for 1 h. The reaction was basified to pH7-8 with saturated aqueous sodium hydrogencarbonate and then extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered and evaporated and purified by column chromatography, eluting with 50% to 100% ethyl acetate in hexanes, to afford the title compound as a white foam (147 mg, 56%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:21]=1)([CH3:4])([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:10][C:9]=2[CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cc3cc(C(C)(C)C)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc2oc(-c3ccc(O)cc3)cc2c1
Temperature: 200 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
Compound 84 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and the crude product was purified by column chromatography (eluant 25% EtOAc/hexanes) to give a solid (0.18 g, 17%); Mp=172-174° C.; 1H NMR (DMSO-d6) δ 9.83 (s, 1H), 7.70 (d, 2 H, J=8.9 Hz), 7.56 (d, 1 H, J=1.7 Hz), 7.45 (d, 1 H, J=9.0 Hz), 7.32 (dd, 1 H, J=9.0 Hz, 2.1 Hz), 7.11 (s, 1 H), 6.87 (d, 2H, J=8.5 Hz); MS 265 [M−H]−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:34][CH3:35])[CH:6]([C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:34][CH3:35])[CH2:6][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OC)C(O)c1ccc(OCCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c2ccsc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c2ccsc12)OC
Reaction time: 4 h
Yield: 86.3 %

Procedure:
0.173 g of the above prepared 3-(4-{2-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-3-hydroxy-2-methoxy-propionic acid ethyl ester (0.31 mmol) was dissolved in 1.0 ml of trifluoroacetic acid, treated at 0° with 0.250 ml of triethylsilane (5 eq.) and then kept for 4 h at this temperature, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/AcOEt/NaHCO3 (pH of aq. layer ˜7.5), the organic layer washed with water and brine (pH of aq. phase˜8), dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=85/15) afforded 0.143 g of the title compound as white crystals of mp. 100-102°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11][Cl:12].[C-:20]#[N:21].[Na+]>CS(C)=O>[ClH:12].[NH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:20]#[N:21]
Reactant: NCCON=C(CCCCCl)c1ccc(Cl)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCCC(=NOCCN)c1ccc(Cl)cc1

Procedure:
10 mmol (3.3 gr) of 4',5-dichlorovalerophenone O-(2-amino ethyl)oxime hydrochloride, melting point 140° -141.5° C, were dissolved in 10 ml of dimethylsulphoxide. 25 mmol (1.2 gr) of sodium cyanide were added to said solution.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C([O+:10]([CH2:13][CH3:14])[CH2:11][CH3:12])C.O=[C:16]1[NH:21]CC[N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>>[CH2:13]([O:10][C:11]1[CH2:12][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16][N:21]=1)[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethyloxonium hexafluorophosphate (3.20 g, 28.0 mmol) was added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.54 g, 12.7 mmol) in CH2CL2 (31.7 mL) at 0° C., and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated NaHCO3, dried (Na2SO4), and concentrated to give tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate as an oil. LCMS (APCI+) M+H−t−Bu: 173 (40%); rt=3.14 minutes.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].[CH2:25](Br)[CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][CH2:27][CH:26]=[CH2:25])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNC[C@H]1CN(c2ccc(N3CCC(=CC#N)CC3)c(F)c2)C(=O)O1
Yield: 35 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (0.12 mmol), allyl bromide (0.18 mmol), and potassium carbonate (0.25 mmol) in tetrahydrofuran was heated at reflux temperature for 12 hours. Solvent evaporation and purification to provided the title compound in 35% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccccc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Combine 4-bromophenylboronic acid (6.064 g, 30.195 mmol), 2-iodo-phenylamine (5.532 g, 25.257 mmol), toluene, 2N Na2CO3 (13 ml, 26 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (0.849 g) and heat to 80° C. After 4 hours cool to room temperature and stir for 16 hours. Dilute the reaction with EtOAc and back extract water layer with EtOAc. Combine the organic layers and wash with H2O, and dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography (silica gel), eluting with first hexane and increasing up to 10% EtOAc/Hexane to afford 4′-bromo-biphenyl-2-ylamine (4.008 g, 64%). LCMS 247.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([OH:11])[CH:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[OH:11][C:5]1[CH:4]=[C:3]([CH2:2][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1ccc(CBr)cc1O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1O

Procedure:
4-Bromomethyl-2-hydroxybenzonitrile (0.222 g, 1.045 mmol) and imidazole (0.356 g, 5.23 mmol) were stirred in DMF (10 mL) at ambient temperature for 18 hr. The reaction mixture was concentrated in vacuo to remove the DMF, and the residue was chromatographed (SiO2, 2-5% CH3OH in CH2Cl2) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[F:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccccc2F)OC1(C)C
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(2-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[N:23]1([CH:28]2[CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH:28]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: c1ncn(C2CNC2)n1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 94.4 %

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (75 mg, 0.25 mmol) and 100 mg (0.5 mmol) of 3-(1,2,4-triazol -1-yl)azetidine hydrochloride in 3 ml of dry pyridine, in the presence of 152 mg (1 mmol) of DBU was heated under nitrogen at 75° C. overnight. The suspension was then evaporated to dryness and to the residue water was added and solid collected, washed with water and dried to give 95 mg (94%) of the desired product as a yellow solid. m.p. 293°-295° C. 1H NMR (TFA) δ: 9.79 (s, 1H), 9.1 (s, 1H), 8.88 (s, 1H), 6.12-5.88 (m, 1H), 5.45-5.05 (m, 4H), 4.44-4.16 (m, 1H), 1.53-1.18 (m, 4H). Anal. calcd. for C18H16F2N6O3 : C, 53.74; H, 4.01; N, 20.88. Found: C, 53.60; H, 4.08; N, 20.91.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1>>[I:1][C:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[NH:9][N:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1cnc2cn[nH]c2c1
Product: Ic1n[nH]c2cccnc12
Yield: 57.4 %

Procedure:
In the similar method as described in Production example 206, 9.5 g of N-iodosuccinimide was reacted on 5 g of 1H-pyrazolo[4,3-b]pyridine, to afford 5.9 g of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1.[CH3:28][CH:29](O)[CH3:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([O:27][CH:29]([CH3:30])[CH3:28])=[O:26])[CH:4]=[N:3]1
Reactant: CC(C)O
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 0 °C
Reaction time: 108 h
Yield: 0 %

Procedure:
A white suspension of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (90 mg, 248 mol.) and 2-propanol (23 l, 298 mol) in N,N-dimethylformamide (2 ml) is cooled to 0° C. A solution of 4-dimethylaminopyridine (15.2 mg, 124 mol, 0.5 eq.) and PYBROP (127 mg, 273 mol, 1.1 eq.) in N,N-dimethylformamide (2 ml) is dropwise added at 0° C. followed after 5 min by triethylamine (105 l, 745 mol). The white suspension is allowed to warm to room temperature giving a colorless clear solution and stirred for 4.5 days. The colorless solution is poured on water, neutralized to pH 7-8 with aqueous 1N hydrochloric acid and extracted with dichloromethane (3×70 ml). The combined aqueous layer is washed with water (3×50 ml), dried with magnesium sulfate and the solvent is removed in vacuo. Purification of the residue (77 mg) by chromatography on a 10 g silica cartridge (eluent heptane/ethyl acetate 30-60% 25′) affords isopropyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (10 mg, 9.96%) as a white solid. MS: m/z=405.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[C@H:9]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CO.[Pd]>[CH3:24][N:8]([C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a suspension of 5% Pd/C (4.60 g, 2.16 mmol) in ethanol (40 mL) was added slowly a solution of (S)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)pyrrolidine-1-carboxylate (7.2 g, 21.6 mmol) in methanol (20 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with methanol (60 mL). The filtrate was concentrated under reduced pressure to afford (S)-tert-butyl methyl(pyrrolidin-3-yl)carbamate (4.3 g, 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])([OH:17])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25]N1C(=O)CCC1=O.C(O)(=O)C.C1(C)C=CC=CC=1>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:25])=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])([OH:17])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccc(Cl)cc21
Yield: 88.2 %

Procedure:
A flask is charged with 2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 18) (10 g, 30.83 mmol), N-chloro succinimide (NCS) (4.12 g, 30.83 mmol), acetic acid (40 and toluene (20 mL). The orange suspension is then stirred over night and becomes a homogeneous solution. After the addition of about 5 mL of water, the solvent is removed on the rotavapor. To the residue, water is added, and the product is extracted with chloroform. After drying and removal of solvent 11 g of crude product is obtained which after chromatography on silica (toluene:ethyl acetate 1:1) gives the title product (9.76 g, 88%) as yellow foam. 1H-NMR (CDCl3, 300 MHz) δ 2.74, 3.08 (AB, 2H, 2J=16.3 Hz, CH2CONMe2); 4.85 (s, 2H, NCH2Ph); 6.32 (br s, 1H, OH); 6.58 (d, 1H, 3J=8.2 Hz, H-7); 7.10 (dd, 1H, 4J=2.0 Hz, H-6); 7.13-7.32 (m, 5H, Ph); 7.46 (d, 1H, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.77, 37.77 (N(CH3)2); 38.80 (CH2CONMe2); 44.27 (CH2Ph); 74.65 (C-3); 110.72 (C-7); 125.10 (C-4); 127.33 (Ph ortho-C); 127.90 (Ph para-C); 128.54 (C-5); 129.00 (Ph meta-C); 129.49 (C-6); 132.80 (C-9); 135.26 (C-15); 141.08 (C-8); 170.31 (C-11); 175.96 (C-2).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=4)=[CH:15][C:10]=3[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=4)=[CH:15][C:10]=3[CH:9]=[C:8]([C:29]([OH:31])=[O:30])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature overnight, heated at 50° C. for 1 hour, concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.30 g) as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CN(C)C=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:15][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 78.4 %

Procedure:
To a 3 liter flask were added 400 grams (2.32 mol) 2-chloro-1-(4-fluorophenyl)ethanone, 1 liter of N,N-dimethylformamide and 265 grams (3.23 mol) anhydrous sodium acetate. The mixture was stirred and heated to 90° C., and the reaction lasted 10 hours. After the reaction was completed, the heating was stopped. The reaction solution was cooled down to room temperature, and extracted with ethyl acetate (600 ml×6). The organic phases were combined, washed three times with brine, dried over anhydrous sodium sulfate and concentrated until dry. The residue was crystallized from the mixed toluene/petroleum ether solution and dried to obtain 357 grams (1.82 mol) compound A-1 with yield of 78.5%. 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H, CH3), 5.30 (s, 2H, —CH2—), 7.14-7.19 (m, 2H, Cpr-H), 7.93-7.97 (m, 2H, Cpr-H); MS (m/z): 197 [M+H].
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH:7]([NH2:9])[CH3:8])[CH3:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1.[OH-].[K+]>O.ClCCCl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:10][CH3:11])=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCN(CC)CCCC(C)N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: CCN(CC)CCCC(C)NC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture containing 970 g. (6.2 moles) of freshly distilled N1,N1 -diethyl-1,4 pentanediamine, 4 l. of 1,2-dichloroethane and 1 l. of water at 5°-10° C. there was simultaneously added dropwise a solution containing 5.95 moles of 4-chloro-2-nitrobenzoyl chloride in approximately 8 l. of 1,2-dichloroethane and a solution containing 410 g. (6.2 moles) of 85% potassium hydroxide in 1 l. of water. When the addition was complete the ice bath was removed and stirring was continued 0.5 hours at room temperature. The organic layer was separated, dried over anhydrous calcium sulfate and evaporated to dryness under vacuum. The residue was dissolved in 3 l. or 1,2-dichloroethane and the resulting solution was treated with decolorizing carbon and filtered. The filtrate was diluted to 6 l. with additional 1,2-dichloroethane to give a pale yellow solution of 4-choro-N-[4-(diethylamino)-1-methylbutyl]-2-nitrobenzamide which was divided into three equal portions which were used directly in the next step.