Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-]=[N+]=[N-].[N:4]([C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[O:10][CH2:9][CH2:8]1)=[N+]=[N-].CP(C)C.O>C1COCC1>[I:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH2:8][C:7]2([CH3:18])[NH2:4]
Reactant: CC1(N=[N+]=[N-])CCOc2ccc(I)cc21
Agent: CP(C)C
Agent: [N-]=[N+]=[N-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(N)CCOc2ccc(I)cc21
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a mixture of 6-iodo-4-methylchroman-4-ol (1.0 g, 3.4 mmol) and NaN3 (0.7 g, 10.3 mmol) in CHCl3 (15 ml), at 0° C., was added TFA (1.3 ml, 17.2 mmol) as a solution in 10 ml of CHCl3 dropwise via addition funnel. The addition was carried out over 2 h and stirring continued for an additional 2 h at 0° C. The mixture was warmed to r.t. and stirred over night. The mixture was diluted with 30 ml of water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 4-azido-6-iodo-4-methylchroman as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=2.07 Hz, 1H), 7.50 (dd, J=8.71, 2.07 Hz, 1H), 6.66 (d, J=8.71 Hz, 1H), 4.27 (m, 2H), 2.06 (m, 2H), 1.68 (s, 3H). MS (ESI+) for C10H10IN3O m/z 273.0 (M+H)+ loss of azide. The crude azide was dissolved in THF (15 ml) followed by the addition of trimethylphosphine (4 ml, 1.0 M in THF) at r.t. After 15 min. 3 ml of water was added and stirring continued at r.t. for 2 h until complete as indicated by LC/MS. The solvent was removed in vacuo and the residue diluted with water (75 ml) and extracted with CH2Cl2 (3×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacou to yield 6-iodo-4-methylchroman-4-amine (0.900 g, 91%) as a yellow oil. This material was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.07 Hz, 1H), 7.40 (dd, J=8.60, 2.18 Hz, 1H), 6.59 (d, J=8.50 Hz, 1H), 4.25 (m, 2H), 2.01 (m, 2H), 1.53 (s, 3H). MS (ESI+) for C10H12INO m/z 273.2 (M+H)+ loss of NH3.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([CH2:31][NH2:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:32][CH2:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCc2cccc3ccccc23)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and C-naphthalen-1-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H23NO5 [M+H]+: 394.
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[O:37]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)[C@H](Cc1ccc(SCCN(C)C(=O)C2CCCCC2)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(CCSc1ccc(C[C@H](NC2=NS(=O)(=O)c3ccccc32)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
The crude product from Step A was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2/ethyl acetate/hexane). The yield was 40%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:35]([F:36])=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]O)=[CH:27][C:26]=3[F:37])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:38][CH3:39].[C:40]([O:44][C:45]([NH:47][C:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[NH:49])=[O:46])([CH3:43])([CH3:42])[CH3:41].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:54]([O:53][C:51](=[O:52])[N:50]=[C:48]([NH:47][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[NH:49][CH2:32][CH2:31][CH2:30][O:29][C:28]1[CH:34]=[C:35]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:38][CH3:39])[CH:4]=3)([CH3:9])[CH3:10])=[CH:12][N:13]=2)=[C:26]([F:37])[CH:27]=1)([CH3:57])([CH3:56])[CH3:55]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl

Procedure:
In a manner described previously, a mixture of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)propan-1-ol (330 mg, 0.57 mmol), 1,3-bis(tert-butoxycarbonyl)guanidine (266 mg, 1.02 mmol), PPh3 (225 mg, 0.85 mmol) and DIAD (177 μL, 0.85 mmol) was reacted in THF, processed and purified by flash chromatography (80% EtOAc/Hex) to give tert-butyl(tert-butoxycarbonylamino)(3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)propylamino)methylenecarbamate. MS (EI) m/z 818.6 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][NH:18][C:17](=O)[CH:16]2[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.B.CSC.Cl.[NH4+].[OH-]>O1CCCC1.O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)CC1C(=O)NCCN1Cc1ccccc1-c1ccc(Cl)cc1
Agent: B
Agent: Cl
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC1CNCCN1Cc1ccccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of EXAMPLE 27D in tetrahydrofuran (3.6 mL) was added borane-methyl sulfide complex (10M in tetrahydrofuran) (0.24 mL). The reaction was heated under reflux for 16 hours, then cooled in an ice/water bath. Methanol (5 mL) was added carefully, and the mixture was stirred cold for 75 minutes. Then 4N HCl in dioxane (0.65 mL) was added and the reaction heated under reflux for 60 minutes. After cooling to room temperature, 1N NH4OH (2.6 mL) was added and the reaction was stirred for 15 minutes. Then the reaction was concentrated, redissolved in methanol, concentrated, redissolved in toluene and concentrated. The crude solids were slurried in CHCl3/methanol, the solids were filtered off, and the filtrate concentrated to afford the title compound.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[O:7][C:6]1=[O:13])[CH3:3].Cl.[C:15]([C:17]1[CH:24]=[CH:23][C:20](CN)=[CH:19][CH:18]=1)#[N:16].CC(C)([O-])C.[Na+].Cl>C(O)C>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:3][N:2]2[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:6]([OH:7])=[O:13])=[CH:4]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1

Procedure:
A solution of 3-dimethylaminomethylene-6-methyl-pyran-2,4-dione (preparation 1a, 2.00 g, 9.38 mmol based on 85% purity), 4-cyanobenzylamine hydrochloride (4.00 mL, 23.7 mmol) and sodium tert-butoxide (2.74 g, 28.5 mmol) in ethanol (11 mL) is heated for 48 h at 90° C. The reaction mixture is acidified with 4N aqueous HCl and extracted several times with dichloromethane. The combined organic layer is dried over Na2SO4, evaporated under reduced pressure and purified by preparative reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 0.94 g (37% of theory); ESI mass spectrum: [M+H]+=269; Retention time HPLC: 0.86 min (Z002—005).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[N:3]=[N:2]1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH3:12][N:13]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:16][CH2:15]1)[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[N:2][NH:1][CH:5]=1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: CNC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)CCCc1c[nH]nn1)C1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 216 h

Procedure:
4-(1H-1,2,3-Triazol-4-yl)butanoic acid (Example 17, step 4) (200 mg, 1.289 mmol) and 3,5-dichlorobenzyl 4-(methylamino)piperidine-1-carboxylate (Step 2) (456 mg, 1.289 mmol) were dissolved in DMF (6 ml) and treated with DIPEA (1.126 ml, 6.45 mmol) followed by 50% T3P® in DMF (1.505 ml, 2.58 mmol). After stirring at RT for 9 days, the mixture was evaporated under reduced pressure. The crude product was solubilised in DCM and washed with 10% citric acid. The organic portion was passed through a phase separating cartridge and the filtrate was evaporated under reduced pressure. The crude residue was purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound;
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2CC2CCN(C(=O)OC(C)(C)C)CC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.42 (m, 1 H), 7.21-7.14 (m, 1 H), 7.12-7.08 (m, 1 H), 6.95 (dd, J=4.9, 8.4 Hz, 1 H), 6.33 (dd, 1 H), 5.53 (d, J=3.7 Hz, 1 H), 4.30 (t, J=5.2 Hz, 2 H), 4.13 (dd, J=7.0, 14.2 Hz, 3 H), 3.50 (s, 1 H), 2.98-2.77 (m, 5 H), 2.67 (br. s., 2 H), 2.25-2.14 (m, 1 H), 2.14-2.02 (m, 2 H), 1.64 (d, J=12.7 Hz, 1 H), 1.56 (br. s., 1 H), 1.50-1.42 (m, 10 H), 1.31-1.13 (m, 2 H), 0.99-0.89 (s, 9 H); LC/MS (m/z) ES+=592.32 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:22]3[CH2:23][CH2:24][CH:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:8]=1
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Clc1ccc2scc(CN3CCC(c4ccccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene (150 mg 0.9 mmol) and 4-(2-pyridyl)piperidine (181 mg, 1.0 mmol) were processed as described in Example 2 to provide the title compound. 1H NMR (300 MHz, d6-DMSO) δ 2.73 (t, J=1.86 Hz, 4H)) 3.18 (m, 4H) 3.55 (s, 1H) 4.63 (s, 2H) 7.29 (m, 2H) 7.50 (dd, J=8.31, 1.86 Hz, 1H) 7.78 (m, 1H) 8.15 (m, 2H) 8.32 (m, 1H) 8.53 (s, 1H); (ESI) m/z 343 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([F:24])[C:21]([Cl:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:25][C:21]1[CH:20]=[CH:19][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[N:23][C:22]=1[F:24]
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: Fc1nc(Br)ccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(F)n2)n1
Temperature: 105 °C
Yield: 48.1 %

Procedure:
To a mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (1.325 mmol; 279.9 mg) and 6-bromo-3-chloro-2-fluoro-pyridine (1.988 mmol; 418.3 mg) in 1,4-Dioxane (10 mL) under Argon was added cesium carbonate (3.975 mmol; 1295 mg), Xantphos (0.2253 mmol; 130.4 mg), and tris(dibenzylideneacetone)dipalladium(0) (0.1325 mmol; 121.3 mg). The resulting mixture was sealed in a pressure tube and heated at 105° C. overnight. The reaction mixture cooled to room temperature, and filtered through Celite. The filter cake was washed with DCM. The filtrate was concentrated. The residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford 1-(5-chloro-6-fluoro-2-pyridyl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (217.1 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[Br:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(Br)c(C=CC(=O)O)cc1OC
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3Br)nc2n(CCC)c1=O
Yield: 56.3 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.0 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.80 g (9.75 mmol) of 2-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.38 g (yield 56%) of Compound 58 as pale yellow needles.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])=[N:13][C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[C:11]2[S:20][N:21]=[C:22]([CH3:23])[C:10]=12
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(-c2cnccn2)c2snc(C)c2c1O
Product: Cc1nsc2c(-c3cnccn3)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-pyrazin-2-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 346.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[S:15][C:14]=1Br)=[O:12].C[O-].[Na+].O.Cl>CN(C)C=O>[CH3:18][C:16]1[S:15][C:14]2[O:1][C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=3[NH:10][C:11](=[O:12])[C:13]=2[CH:17]=1
Reactant: COc1cccc(NC(=O)c2cc(C)sc2Br)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1Oc1sc(C)cc1C(=O)N2
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of N-(2-hydroxy-3-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.30 g) and sodium methoxide (549 mg) in N,N-dimethylformamide (12 ml) was stirred under reflux with heating for 19 hours. The reaction system was cooled to room temperature, and the reaction mixture was poured into water (50 ml). The mixture was neutralized with hydrochloric acid, extracted twice with chloroform and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent hexane:ethyl acetate=1:1) to give 2-methyl-9-methoxythieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.87 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:16])[NH2:15])=O)(C)(C)C.[ClH:17]>C(OCC)(=O)C>[ClH:17].[C:14]([C@@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]1)(=[O:16])[NH2:15]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1C[C@@H](O)CN1
Reaction time: 0.5 h

Procedure:
4.50 g of the product obtained in step (1) above were suspended in 45 ml of ethyl acetate and then 14.9 ml of 4.84M hydrogen chloride in ethyl acetate were added under ice-cooling. The mixture was stirred at 25°-30° C. for 30 minutes, after which the reaction mixture was worked up in the same manner as in Preparation 4(2) to give 3.21 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: O=C(CCCCCOc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCCCCC(=O)Oc2ccc(N)cc2)cc1
Reaction time: 1 h
Yield: 65.5 %

Procedure:
6-(4-nitrophenoxy)-hexanoic acid 4-nitrophenyl ester (20 g) was dissolved in ethyl acetate (150 ml) in a pressure vessel. Palladium on carbon (50% wet, 3 grams) was added as a catalyst and the mixture was stirred under an atmosphere of hydrogen (5 Kg) for 1 hour. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure, and the residue was triturated with cold hexane, filtered, and dried to give pure 6-(4-aminophenoxy)-hexanoic acid 4-amino-phenyl ester (11 grams) as off-white powder with a melting point of 99-101° C. The product was characterized by 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.85 (m, 6H, CH2X2), 2.55 (t, 2H, CH2), 3.50 (bs, 4H, NH2), 3.90 (t, 2H, CH2), 6.60 to 6.90 (m, 8H, Ar).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(#N)C.[CH3:12][S:13][CH2:14]Cl>C(N(CC)CC)C>[C:1]([O:8][CH2:12][S:13][CH3:14])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CSCCl
Reactant: CCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC(=O)OCSC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three-necked 1000 ml. round-bottomed flask fitted with a mechanical stirrer, thermometer and reflux condenser is placed 63.8 g. of hexanoic acid in 200 ml. of acetonitrile. To the stirred mixture is added, at 20°-30° C., 55 g. of triethylamine over a period of 30 minutes. The reaction mixture is stirred at room temperature for an additional 60 minutes. Then is added, at 20°-24° C., 53 g. of chloromethyl methyl sulfide in a few minutes. The reaction mixture is warmed and allowed to reflux for 24 hours. The reaction mixture is cooled to 5°-0° C. and filtered. The solvent is stripped off under vacuum at 12 mm Hg pressure. The residue is taken up in diethyl ether and washed successively with a 10% solution of sodium bicarbonate and with water. The organic layer is dried over anhydrous sodium sulfate. Distillation gives the title ester; b.p. 57°-58° C./2 mm Hg, n20 1.4545.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18]O>>[C:1]([O:12][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:20])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 4-dimethylamino-1-butanol as starting materials to give the aimed compound.
Reaction SMILES: N1CCOCC1.C(=O)([O-])[O-].[K+].[K+].C(=O)CC.[CH2:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:18]=[CH2:19]>CS(C)=O>[O:23]1[CH2:24][CH2:25][N:20]([CH:17]=[CH:18][CH3:19])[CH2:21][CH2:22]1
Reactant: C=CCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC=O
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: CC=CN1CCOCC1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A 500 ml 4-neck flask was equipped with a stirrer, thermometer, addition funnel and condenser. To the flask was charged 191.7 g (2.2 m) of morpholine and 138.2 g (1 m) of potassium carbonate (anhydrous) and the mixture was stirred and cooled to -5° C. with an ice-salt bath. To the flask was added 58 g (1 m) of propionaldehyde over a period of 55 minutes at a pot temperature of -5° C. The temperature was then allowed to rise to 25° to 27° C. and the reaction was continued for 2 hours at 25° C. The product was filtered and the filter cake washed with four 15 ml washes of toluene. The fitrate was heated under vacuum while morpholine was stripped using a 1 foot Vigreux column. This treatment was carried out at an oil bath temperature of 85° to 112° C., a pot temperature of 70° to 90° C., a vapor temperature of 41° to 58° C. and at a pressure of approximately 35 to 40 mm of Hg. The vacuum stripping was carried out until 133.3 g of product was obtained as a residue. GLC and GC/MS established that the predominant product was 4-(2-propenyl)morpholine. 13C NMR in d6 -DMSO (in δ units): 15.2 (CH3); 95.1 (CH3 --CH)=; 140.8 (--CH=CH--); 49.4 (--N(--CH2 --)2); and 66.1 (O(--CH2 --)2).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([O:22]COC)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl>CO>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC(F)F
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Temperature: 50 °C
Yield: 69 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one (1 g, 2.7 mmol) in methanol (75 mL) was added concentrated hydrochloride (5 mL) and the reaction mixture was heated to 50° C. for 1 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The obtained residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (600 mg, 68%).