Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11]([O-])([O-])OCC>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:3]=1[N:10]=[CH:11][NH:9]2
Reactant: Cc1nc(N)c(N)c(Cl)n1
Reactant: CCOC([O-])[O-]
Product: Cc1nc(Cl)c2nc[nH]c2n1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
6-Chloro-2-methylpyrimidine-4,5-diamine (8.89 g, 56.1 mmol, the material from Step 1) was suspended in ethyl orthoformate (100 mL, 601 mmol) in a flask fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred for 75 minutes. Then, the reaction was cooled to room temperature, concentrated, treated with hexanes and filtered. The solid washed with hexanes, collected, and taken on to Step 3. MS (ESI pos. ion) m/z: 169. Calculated exact mass for C6H5ClN4: 168.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[SH2:17]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)(=[S:17])[NH2:2]
Reactant: CCOC(=O)c1cc2cc(C#N)cnc2o1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(C(N)=S)cnc2o1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 5-cyanofuro[2,3-b]pyridine-2-carboxylate (773 mg, 4.14 mmol) was dissolved in a mixed solvent of pyridine (40 ml) and triethylamine (8 ml), and a hydrogen sulfide gas was blown in for 10 minutes. The mixture was stirred at room temperature for 14 hours. The solvent was distilled away from the reaction mixture under reduced pressure to give ethyl 5-thiocarbamoylfuro[2,3-b]pyridine-2-carboxylate as a yellow solid. Acetone (80 ml) and methyl iodide (8.0 ml) were added and the mixture was refluxed under heating for one hour. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 5-[(1-methylthio)-iminomethyl]furo[2,3-b]pyridine-2-carboxylate. Methanol (80 ml) and ammonium acetate (694 mg, 9.00 mmol) were added and the mixture was refluxed under heating for 3.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=97/3-4/1) to give 2.05 g of ethyl 5-amidinofuro[2,3-b]pyridine-2-carboxylate hydrochloride as a yellow solid (69% in 3 steps).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].C(N(CC)CC)C>C1COCC1>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][C:15](=[O:16])[NH:14][N:13]=3)=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccn3c(I)cnc3c2)o1
Reaction time: 3 h
Yield: 115.2 %

Procedure:
To a solution of 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (196 mg, 0.5 mmol) (prepared as described in Example 329 steps a-c) in THF (10 ml) was added carbonyldiimidazole (243 mg, 1.5 mmol) and triethylamine (0.35 ml, 2.5 mmol) and the reaction mixture left to stir for 3 h. The precipitate formed in the reaction was filtered off, washed with Et2O and dried to afford the desired product (189 mg). MS: [M+H]+=329.
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCCCC1.NC1SC=NC=1.C([O:53][C:54](=[O:58])C(S)C)C>>[CH:24]1([N:16]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH3:23])[CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:54]([OH:58])=[O:53])=[CH:9][N:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CCOC(=O)C(C)S
Agent: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][C:32]([O:34]CC)=[O:33])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[NH:24])=[CH:21][CH:20]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[ClH:1].[C:2]1([N:8]([CH2:31][C:32]([OH:34])=[O:33])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[NH:24])=[CH:21][CH:20]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(Cc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 13 from 4-[(5-(N-phenyl-N-ethoxycarbonylmethyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Reaction SMILES: [CH2:1]([O:11][C:12]([CH:14]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:21])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[Cl:33]Cl>C(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([C:14]([C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])([Cl:33])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CCCCCCCOC(=O)C(C(=O)OCCCCCCCC(C)C)n1cncn1
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CC(C)CCCCCCCOC(=O)C(Cl)(C(=O)OCCCCCCCC(C)C)n1cncn1

Procedure:
1-[bis(isodecyloxycarbonyl)methyl]-1,2,4-triazole, which is the product of Example 12 (15.6 g), was dissolved in carbon tetrachloride (20 ml). Phosphorus trichloride (3 drops) was added and the solution was stirred and heated at 60° whilst a slow stream of chlorine was bubbled through it for 1 hour. The solution was then cooled, washed with aqueous sodium sulphite solution and with water, and the solvent was distilled under reduced pressure yielding 1-[bis(isodecyloxycarbonyl)chloromethyl]-1,2,4-triazole (12.9 g), which had a purity of 82.4% as measured by non-aqueous titration with perchloric acid. This compound was evaluated as an extractant for copper by the procedure of Example 1 and the results are presented in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].Cl.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])[CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][CH2:25][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:32]1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCSC2=Nc3ccc(Cl)cc3C(c3ccccc3Cl)=NC2)CC1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 11.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 100 ml of anhydrous dimethylformamide is added under ice cooling with stirring 2.1 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at 30° C. for 1 hour. To the mixture is added dropwise a solution of 12.5 g of 1-chloro-3-[4-(2-methoxyphenyl)-1-piperazinyl]propane hydrochloride in 50 ml of dimethylformamide over a period of 15 minutes, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into iced water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 10.5 g of 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 189°-191° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)=[O:25]
Reactant: COC(=O)C1CCN(c2ncc(N)cc2C)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cnc(N2CCC(C(=O)OC)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To an ice-water cooled solution of methyl 1-(5-amino-3-methylpyridin-2-yl)piperidine-4-carboxylate (2.14 g; 8.59 mmol) in DCM (43 mL) was added methyl chloro(oxo)acetate (1.03 mL; 11.17 mmol) followed by pyridine (834 μL; 10.31 mmol) and the reaction mixture was allowed to stir at ˜0° C. for 30 mins, then allowed to warm to room temperature. The reaction solution was washed with water (40 mL) then saturated brine (40 mL). The organics were dried over MgSO4, filtered and evaporated under vacuum to yield a pale tan solid (2.01 g, 70% yield). This was used for the next stage without further purification. 1H NMR δ 1.60-1.80 (m, 2H), 1.85-1.99 (m, 2H), 2.18 (s, 3H), 2.54-2.62 (m, 1H), 2.69-2.88 (m, 2H), 3.26-3.40 (m, 2H), 3.56 (s, 3H), 3.82 (s, 3H), 7.87 (d, 1H), 8.40 (d, 1H), 10.75 (s, 1H). MS m/e MH+ 336.20.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Br[CH:12]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[C:13]2=[O:18])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CN1CCC(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OC2CCN(C)C2=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (100 mg) in N,N-dimethylformamide (2 mL) is added 3-bromo-1-methylpyrrolidin-2-one (100 mg) and K2CO3 (105 mg). The mixture is stirred for 12 hours at room temperature. Then the mixture is partitioned between water and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. Yield: 65 mg; LC (method 7): tR=1.0 min; Mass spectrum (ESI+): m/z=298 [M+H]+.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][CH:12]1[N:15](/[C:16](=[C:20](/[O:22][CH3:23])\[CH3:21])/[C:17](Cl)=[O:18])[C:14](=[O:24])[CH:13]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.S1C2C=CC=CC=2N=C1SSC1N(/C(=C(\OC)/C)/C(Cl)=O)C(=O)C1NC(=O)COC1C=CC=CC=1.C(N(CC)CC)C.[C:78]([OH:82])([CH3:81])([CH3:80])[CH3:79]>C(Cl)Cl>[C:78]([O:82][C:17]([CH:16]1[N:15]2[C:14](=[O:24])[C@@H:13]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:12]2[S:11][CH:21]=[C:20]1[O:22][CH3:23])=[O:18])([CH3:81])([CH3:80])[CH3:79]
Reactant: CO/C(C)=C(\C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: CC(C)(C)O
Agent: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 266 mg (0.5 mM) of a crude mixture consisting of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl ]-3-methoxy-crotonic acid chloride and 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride is added dropwise over the course of 15 minutes at 0° C., whilst stirring, to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml of methylene chloride. After a further 15 minutes stirring, the reaction mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric acid and again with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate (4:1) as the running agent. 7β-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid tert.butyl ester is obtained. IR spectrum (in CH2CL2): characteristic bands at 5.60, 5.77, 5.90 and 8.29 μ.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH:5]1[C:4]2[N:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:23])=[O:22]
Reactant: OC1CCCc2ccc(Br)nc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCc2ccc(Br)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a cold (0° C.) stirred solution of 2-bromo-5,6,7,8-tetrahydroquinolin-8-ol (500 mg, 2.36 mmol) in dry CH2Cl2 (10 mL) was added triethylamine (0.72 mL, 5.2 mmol) followed by methanesulfonyl chloride (0.35 mL, 3.6 mmol). The resulting mixture was stirred at 0° C. for 1 h, then warmed slowly to room temperature and stirred a further 1 h. Saturated aqueous NaHCO3 (30 mL) was added and the phases were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic extracts were dried (MgSO4) and concentrated to give 605 mg (88%) of 2-bromo-5,6,7,8-tetrahydroquinolin-8-yl methanesulfonate as an orange solid.
Reaction SMILES: Cl.[C:2]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)N)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]1[C:23](=O)[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])([C:25]([OH:27])=[O:26])[CH2:19]1.C(O)(=O)C>O>[C:2]([N:10]1[C:23]2[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])([C:25]([OH:27])=[O:26])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN(C(=O)c1ccccc1)c1ccccc1
Reactant: O=C1CCC(C(=O)O)(C(=O)O)CC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)n1c2c(c3ccccc31)CC(C(=O)O)(C(=O)O)CC2

Procedure:
1-Benzoyl-1-phenylhydrazine hydrochloride (5 g.) and 4 g. of cyclohexanone-4,4-dicarboxylic acid in 10 ml. of glacial acetic acid were heated at 60°-70°C. for thirty minutes. The mixture was diluted with water and the resulting solid was collected by filtration and washed with water to give 7.1 g. of the title compound; m.p. 160°C. (acetone and hexane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:44][N:43]=[CH:42][CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.5 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.5 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C26H34FN5O5S, 548. found, 548.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30](N(OC)C)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]
Reactant: CCOc1ccc(-c2nc(CCC(=O)N(C)OC)cs2)cc1OCC
Reactant: c1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(CCC(=O)c3nccs3)cs2)cc1OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution (2 ml) of thiazole (129 mg, 1.5 mmol) in THF was cooled to −70° C., and n-butyllithium (a 2.44M hexane solution) (0.62 ml, 1.5 mmol) was added, and the resulting mixture was stirred at −70° C. for 30 minutes. A solution (4 ml) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamide (500 mg, 1.4 mmol) in THF was added to the reaction mixture, followed by stirring at −70° C. for 3 hours. After heating to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol, to thereby obtain 350 mg (yield: 66%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-thiazole-2-yl-1-propanone as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[Cl:28][CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>ClCCl>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1)(=[O:34])=[O:33]
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOc1ccc(NS(=O)(=O)CCCCl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
368 mg (1.0 mmol) of the compound from example 44A are reacted with 266 mg (1.5 mmol) of 3-chloropropanesulfonyl chloride and 0.81 ml (10.0 mmol) of pyridine in 12 ml of dichloromethane for 3 hours.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=O)=[O:11])[CH2:3][CH2:2]1.[NH2:28][C@@H:29]([CH2:50][C:51]1[N:52]=[CH:53][NH:54][CH:55]=1)[C:30]([NH:32][C@@H:33]([CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[C@@H:34]([OH:42])[CH2:35][C@@H:36]([CH:39]([CH3:41])[CH3:40])[CH:37]=[CH2:38])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:44]1([CH2:43][C@H:33]([NH:32][C:30](=[O:31])[CH:29]([NH:28][C:14](=[O:16])[CH:13]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:12][C:10](=[O:11])[NH:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:50][C:51]2[N:52]=[CH:53][NH:54][CH:55]=2)[C@@H:34]([OH:42])[CH2:35][C@@H:36]([CH:39]([CH3:41])[CH3:40])[CH:37]=[CH2:38])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCN1CCOCC1)Cc1cccc2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
A mixture of 95 mg of (RS)-α-[(2-morpholinoethyl)carbamoylmethyl]-1-naphthalenepropionic acid, 100 mg of (S)-α-amino-N-[(1S,2S.4S)-1-(cyclohexylmethyl) 2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and 97 mg of HBTU in acetonitrile was stirred at room temperature for 3.5 hours and then worked-up in the usual manner. The residue was chromatographed on silica gel with a 4: mixture of methylene chloride and methanol as the eluting agent, to obtain 60 mg of N-[(1S,2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[3-[(2-morpholinoethyl)carbamoyl]-2-(1-naphthylmethyl)propionamido]imidazole-4-propionamide as a foam. MS: 743 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=2)[N:16]=1.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([C:32]([F:31])([F:40])[F:41])[CH:34]=3)=[O:26])=[CH:23][CH:22]=2)[N:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1
Yield: 7.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-5-(cyclopropane carboxamidomethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate (Intermediate-42, 0.100 g, 0.24 mmol), 3-(trifluoromethyl)aniline (0.050 g, 0.36 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (8.0 mL). The reaction mass was quenched in water, extracted with DCM and the organic layer was concentrated to afford 0.010 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.70 (s, 4H), 1.62 (m, 1H), 4.33 (d, J=6.3 Hz, 2H), 7.44-7.67 (m, 4H), 8.10-8.26 (m, 6H), 8.68 (m, 1H), 10.53 (s, 1H), 12.68 (br s, 1H); MS (m/z): 554.30 (M−H)−.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:3][CH2:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH:11][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:1][CH2:2][CH2:3]3)[O:13][CH2:14][C:15]=2[CH:21]=1)=[O:26]
Reactant: Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Yield: 83.1 %

Procedure:
Prepared from rac-N2-chroman-4-yl-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 75) (591 mg, 2.0 mmol) and chloroacetyl chloride (167 ul, 2.1 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as an off-white solid (618 mg, 83%), MS (ISP) m/e=372.1 [(M+H)+] and 374 [(M+2+H)+].