Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][CH2:44][CH3:45])[CH:42]=1)[C:37]([OH:39])=O)=[O:33].[CH2:46]([C:48]1[CH:63]=[C:62]([C:64](=[NH:67])[NH:65]O)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]>>[CH2:46]([C:48]1[CH:63]=[C:62]([C:64]2[N:67]=[C:37]([C:36]3[CH:40]=[C:41]([CH2:43][CH2:44][CH3:45])[CH:42]=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:65]=2)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCCc1cc(C=O)cc(C(=O)O)c1
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCCc1cc(C=O)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)c1
Yield: 37.8 %

Procedure:
The title compound (552 mg) was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-5-propyl-benzoic acid (582 mg, 3.03 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (985 mg, 3.03 mmol). LC-MS**: tR=0.78 min; [M+1]+=481.82; 1H NMR (D6-DMSO): δ 0.95 (t, J=7.3 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.71 (h, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 3.20-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.71-3.81 (m, 2H), 3.84 (d, J=4.8 Hz, 2H), 3.93-4.01 (m, 1H), 5.31 (d, J=5.0 Hz, 1H), 5.55 (t, J=5.3 Hz, 1H), 7.70 (t, J=5.5 Hz, 1H), 7.82 (s, 2H), 8.07 (s, 1H), 8.33 (s, 1H), 8.52 (s, 1H), 10.15 (s, 1H).
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][CH2:7][C:6]2=[O:13].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:19]=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:19][C:15]1[S:14][CH:18]=[CH:17][N:16]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: O=Cc1nccs1
Product: COc1ccc2c(c1)C(=O)C(=Cc1nccs1)CO2

Procedure:
By the method of Example 1, 6-methoxy-4-chromanone (3.97 g, 0.0223 mol) and 2-thiazolecarbaldehyde (3.00 g, 0.0265 mol) were converted to present title product which was recrystallized from methanol, 1.20 g (20%), m.p. 130°-132° C., tlc (1:19 CH3OH:CH2Cl2) Rf 0.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][O:16][CH:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:18]1.Br[CH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[C:42]#[N:43]>>[C:42]([C:41]1[CH:40]=[C:39]([CH:46]=[CH:45][CH:44]=1)[CH2:38][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:22]2[CH2:21][CH2:20][N:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:18][CH:17]2[O:16][CH2:15][C:4]2[CH:5]=[C:6]([O:13][CH3:14])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[O:2][CH3:1])=[CH:28][CH:27]=1)#[N:43]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(O)cc2)c(OC)c2ccccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCc3cccc(C#N)c3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 44 e), by alkylating tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate with 3-bromomethyl-benzonitrile there was obtained tert-butyl (3RS,4RS)-4-[4-(3-cyano-benzyloxy)-phenyl]-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a beige solid; MS: 609 (M+H)+.
Reaction SMILES: [C@@H:1]1([C:8]([O:10]C)=[O:9])[CH2:3][C@@H:2]1[C:4]([O:6][CH3:7])=[O:5].[OH-].[K+]>CO>[CH3:7][O:6][C:4]([C@H:2]1[CH2:3][C@H:1]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)[C@H]1C[C@H]1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
To 150 ml of a methanol solution of 14.68 g (92.8 mmol) of dimethyl cis-1,2-cyclopropanedicarboxylate was added 67 ml of an aqueous solution of 7.52 g (113.9 mmol) of potassium hydroxide under cooling with ice, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, and to the residue was added water. The reaction mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 12.38 g (92.5%) of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[N:3]=1.[CH3:28][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25]([OH:27])([CH3:28])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[N:3]=1
Reactant: COc1ncc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
A suspension of 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (140 mg, 0.38 mmol) in THF (2 mL) at 0° C. was treated with methylmagnesium bromide (1.9 mL of 1.4 M in toluene/THF=75/25, 2.65 mmol). The reaction mixture was stirred at 0° C. for 5 min followed by RT for 30 min and then quenched with sat. NH4Cl solution and extracted with EtOAc. The organic layer was concentrated and purified on a silica gel column eluting with 5-10% MeOH in DCM to give 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)propan-2-ol (50 mg, 34%) as a yellow crystalline solid. m/z (ESI, +ve ion) 386.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.91 (br., 1H); 8.95 (d, J=2.6 Hz, 1H); 8.43-8.37 (m, 3H); 7.89 (s, 1H); 7.73 (s, 1H); 5.15 (s, 1H); 3.93 (s, 3H); 2.45 (s, 3H); 1.47 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1>>[Br:7][C:8]1[N:13]=[C:12]([NH:14][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1cccc(Br)n1

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 6-bromo-2-pyridinamine: ESMS m/e: 242.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].S([O-])([O-])=O.[Na+].[Na+].[C:20](=O)(O)[O-].[Na+].BrCC(O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([CH3:20])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: O=C(O)CBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(F)c(F)cc1Cl
Temperature: 150 °C
Yield: 48 %

Procedure:
2-Chloro-4,5-difluorobenzenesulfonyl chloride (300 mg) was added to a solution of sodium sulfite (306 mg) and sodium bicarbonate (153 mg) in water (4 mL). The mixture was heated to 150° C. in a sealed microwave vial for 400 seconds and allowed to cool. The mixture was treated with bromoacetic acid (253 mg) in water (1 mL), and heated to 150° C. for 300 seconds then allowed to cool, following which the precipitate was removed by filtration and dried in vacuo to give the desired compound (132 mg). The material was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[CH2:33][C:32]([CH2:34]Br)=[CH:31][CH2:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[CH2:33][C:32]([CH2:34][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:31][CH2:30]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2=CCC(CO)C2)c(=O)[nH]c1=O
Yield: 21.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled compound. (52 mg)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([NH:20][CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([N:20]([C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C=C(C)CNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C)CN(CC)c1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 41.3 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.29 mmol), N-ethyl-2-methylallylamine (Aldrich Chemical Company) (0.19 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by preparative TLC on silica gel with 1:1 EtOAc:hexanes as eluant to give 36.7 mg (42%) of the title compound as off-white solid. An analytical sample was obtained by recrystallization from EtOAc. Mp: 148-150° C. 1H NMR (CDCl3; 500 MHz): δ 1.32 (t, 3, J=7.1), 1.95 (s, 3), 2.59 (s, 3), 3.78 (q, 2, J=7.1), 4.20 (s, 2), 5.18 (s, 1), 5.24 (s, 1), 6.74 (s, 1), 7.35-7.48 (m, 3), 7.55 (d, 2, J=7.4), 8.47 (br s, 1). MS m/z: 307 (M+1), 305 (M−1). Anal. Calcd for C19 H22N4: C, 74.48; H, 7.24; N, 18.28. Found: C, 74.36; H, 7.27; N, 18.19.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8](/[C:10](=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])/[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH:13][S@@:14]([C:16]([CH3:17])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](N[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Reaction time: 2 h

Procedure:
To a chilled (−78° C.) solution of (R)-2-methyl-propane-2-sulfinic acid[1-(5-methanesulfonyl-furan-2-yl)-prop-(E)-ylidene]-amide (0.360 g, 1.18 mmol) in THF (15 mL) was added a 1 M solution of L-Selectride (2.4 mL, 2.4 mmol) in THF in several portions. After stifling for 2 hours, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(5-methanesulfonyl-furan-2-yl)-propyl]-amide.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:14][C@H:13]([NH2:15])[CH2:12]3)[S:9][C:5]=2[CH:4]=1.Cl[C:19]1[C:24]([N:25]([CH3:30])[C:26](=O)[O:27]C)=[CH:23][CH:22]=[CH:21][N:20]=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:12][C@H:13]([N:15]4[C:19]5=[N:20][CH:21]=[CH:22][CH:23]=[C:24]5[N:25]([CH3:30])[C:26]4=[O:27])[CH2:14]3)[S:9][C:5]=2[CH:4]=1
Reactant: COC(=O)N(C)c1cccnc1Cl
Reactant: N[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccc(F)cc4s3)C2)c2ncccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.099 g, 0.533 mmol), 2-chloro-6-fluoro-1,3-benzothiazole (0.100 g, 0.533 mmol) and diisopropylethylamine (0.185 ml, 1.066 mmol) in DMSO (0.5 mL) contained in a microwave vial was capped and heated to 120° C. for 2 hrs. The mixture was diluted with water and extracted with EtOAc. EtOAc extract was concentrated to give crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate. To the crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate was added hydrogen chloride, 4N in 1,4-dioxane (10 ml, 40.0 mmol) and the resulting solution stirred at room temperature for 2 h and concentrated to afford crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride. The crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride was added to mixture of methyl (2-chloropyridin-3-yl)(methyl)carbamate, INTERMEDIATE 40, (0.107 g, 0.533 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl)]2-(2-aminoethyl)Ph)Pd(II) (0.021 g, 0.027 mmol), and sodium tert-butoxide (0.261 ml, 2.132 mmol) in dioxane (10 mL). The mixture was stirred at 100° C. for 2 h and concentrated. The residue was diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO on silica gel column eluting with 0-80% EtOAc/hexanes to give the title compound 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.092 g, 0.249 mmol, 46.7% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 8.07 (dd, J=5.18, 1.27 Hz, 1 H), 7.49 (dd, J=8.90, 4.79 Hz, 1 H), 7.32 (dd, J=8.12, 2.64 Hz, 1 H), 7.17 (dd, J=7.73, 1.27 Hz, 1 H), 6.97-7.07 (m, 2 H), 5.90 (br. s., 1 H), 5.33-5.50 (m, 1 H), 4.48-4.74 (m, 1 H), 3.48-3.67 (m, 2 H), 3.43 (s, 3 H), 2.34-2.63 (m, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[NH:22]=[C:23]=N.CN>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:22][CH3:23])=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: N=C=N
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Agent: CN
Solvent: ClCCl
Product: CNC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 23.1 %

Procedure:
A mixture of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropyl-methyl)glycine (0.148 g, 0.5 mmol), and resin bounded carbodiimide (PS-Carbodiimide) (1.0 g, 1.26 mmol/g) was shaken in CH2Cl2 (15 mL) for 30 min, then methylamine (33% solution in water, 0.1 mL, 1 mmol) was added, and the mixture was shaken for another 12 h. The resin was filtered and washed with CH2Cl2 (2×10 mL). The resulting filtrate was concentrated under vacuum. The residue was purified via preparative HPLC to obtain 0.036 g (23%) of the title compound as a white foam: 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=8.5 Hz, 1H), 6.99 (bs, 1H), 6.89 (dd, J=8.8, 2.6 Hz, 1H), 6.28 (bs, 1H), 4.08 (s, 2H), 3.34 (d, J=6.6 Hz, 2H), 2.80 (d, J=4.7 Hz, 3H), 1.06 (m, 1H), 0.65 (m, 2H), 0.31 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[C:24](=[O:28])[N:25]([CH3:27])[CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:24](=[O:28])[N:25]([CH3:26])[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)c1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-(N,N-dimethylcarbamoyl)nitrobenzene (3.1 g) in methanol (30 ml) was added palladium on carbon (0.3 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol 19/1 as an eluant to give the desired compound (2.8 g, yield 99%) as a yellow amorphous solid.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[P:37](Cl)([O:42][CH2:43][CH3:44])([O:39][CH2:40][CH3:41])=[O:38]>C(Cl)Cl>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:37]([O:42][CH2:43][CH3:44])([O:39][CH2:40][CH3:41])=[O:38])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CCOP(=O)(OCC)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reaction time: 0.17 h

Procedure:
A suspension of 2.816 g (8.5 mmol) of ciprofloxacin base in 100 ml of dry CH2Cl2 was stirred under argon as 3.46 g (17 mmol) of N,O-bis(trimethylsilyl)acetamide was added. After the solid had dissolved (2-3 hours), 1.47 g (8.5 mmol) of diethyl chlorophosphate was added. After 24 hours at approximately 23° the solution was evaporated, finally at 0.03 mm for 15 hours. Washing of the solid residue with water gave a white solid which was dried and then recrystallized from CH2Cl2 -toluene, boiling out the CH2Cl2 within 10 minutes to avoid thermal degradation. The product was 3.74 g (94%) of cream-colored solid, m.p. 192°-193° C.; NMR (CDCl3, 80 MHz) δ 1.36 (t, CH3), 3.30 (s, CH2N), 4.06 (5 peaks, OCH2); IR (KBr) 1028(P=O), 1630 (--COOH), 1724 cm- (C=O).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[H][H]>[Pd]>[CH3:10][CH:4]1[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: [H][H]
Agent: [Pd]
Product: CC1CC(=O)CC(C)(C)C1
Temperature: 50 °C

Procedure:
2.2 kg of isophorone and 5 g of 5% palladium-on-carbon catalyst are added to a 3 liter autoclave which is fitted with heating means, cooling means and a stirrer. A hydrogen pressure of 8-10 atmospheres is now generated and the mixture is slowly warmed to 30°-35° C. Since the hydrogenation is exothermic, provision is made by cooling that a temperature of 50° C. is not exceeded. After completion of the hydrogen uptake (temperature drop), the catalyst is filtered off. There are thus obtained 2.2 kg of crude dihydroisophorone, which is uniform according to gas chromatography and which is used directly.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]([O:16][CH3:17])=[C:6]([C:12](OC)=[O:13])[C:7]=1[C:8](OC)=[O:9].O.[NH2:20][NH2:21]>CO>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:21][NH:20][C:12](=[O:13])[C:6]=2[C:5]([O:16][CH3:17])=[N:4][C:3]=1[CH3:18]
Reactant: NN
Reactant: COC(=O)c1c(OC)nc(C)c(N)c1C(=O)OC
Solvent: CO
Solvent: O
Product: COc1nc(C)c(N)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 8 ml of methanol was dissolved 280 mg of 3-amino-4,5-dimethoxycarbonyl-6-methoxy-2-methylpyridine, and then 0.54 ml (10 eq.) of hydrazine monohydrate was added to the solution. The mixture was refluxed. The resulting crystals were collected by filtration and washed with methanol. The crystals were suspended in water, and the suspension was acidified with hydrochloric acid. The crystals were collected by filtration and washed with water.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15](O)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH:25]([C:29]1[CH:37]=[CH:36][C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)[CH2:26][CH2:27][OH:28]>>[O:33]1[C:32]2[CH:36]=[CH:37][C:29]([CH:25]([NH:24][C:15]([CH:11]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:2][CH:3]=4)(=[O:8])=[O:9])[CH2:14][CH2:13][S:12]3)=[O:16])[CH2:26][CH2:27][OH:28])=[CH:30][C:31]=2[O:35][CH2:34]1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: NC(CCO)c1ccc2c(c1)OCO2
Product: O=C(NC(CCO)c1ccc2c(c1)OCO2)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3-amino-3-(1,3-benzodioxol-5-yl)-1-propanol (Intermediate 2), the title compound was obtained in 92% purity by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](O)=[O:6].C([N:16](CC)CC)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:16])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cccc(OC)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
5.0 of 2,6-dimethoxybenzoic acid suspended in 200 ml of anhydrous methylene chloride are added with 7.65 ml of triethylamine and then with 3.6 ml of oxalyl chloride. The mixture after being stirred at room temperature for three hours is concentrated under reduced pressure, cooled with ice, added with 10 ml of concentrated ammonia, then stirred for half an hour, then again evaporated under reduced pressure, taken with water and filtered. The solid so obtained, after crystallization from methanol, gives 2,6-dimethoxybenzamide with melting point 208°-209° C.; yield is 54%.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[N:7]=3.CO[C:21](OC)([N:23]([CH3:25])[CH3:24])[CH3:22]>C1(C)C=CC=CC=1>[CH3:24][N:23]([CH3:25])/[C:21](=[N:16]/[C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:15])/[CH3:22]
Reactant: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (0.280 g, 0.000909 mol) in toluene (5 mL) was added dimethylacetamide-dimethylacetal (0.405 mL, 0.00273 mol). The solution was stirred at 95° C. for 4 h. The toluene was removed in vacuo to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide. MS(ESI+) 377.1/379.1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[CH3:19][N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1>>[Cl:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@H:3]([CH3:4])[CH2:2][NH:1][C:25]([C:23]3[N:22]=[CH:21][N:20]([CH3:19])[CH:24]=3)=[O:26])[N:6]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cnc(C(=O)O)c1
Product: C[C@H](CNC(=O)c1cn(C)cn1)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Yield: 14.4 %

Procedure:
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg, 1.15 mmol) was coupled with 1-methyl-1H-imidazole-4-carboxylic acid (174 mg, 1.38 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 61 mg (14%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.45 (d, 3H), 3.52-3.72 (m, 4H), 3.67 (s, 3H), 4.63-4.75 (m, 1H), 6.95 (d, 1H), 7.62 (dd, 1H), 7.89 (d, 1H), 7.99 (s, 1H), 8.00 (s, 1H), 8.10 (t, 1H), 8.18 (t, 1H).