Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.C[Si]([N:26]=[C:27]=[O:28])(C)C>C(Cl)Cl.C(O)(C)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:13]([C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:27]([NH2:26])=[O:28])=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccc(Cl)cc2)C1
Solvent: CC(C)O
Solvent: ClCCl
Product: NC(=O)N(Cc1ccc(Cl)cc1)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(R)-3-(4-Chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butylester (0.690 g, 2.2 mmol) was dissolved in CH2Cl2 with a few drops of isopropanol and trimethylsilylisocyanate (0.365 mL, 2.6 mmol) were added. The solution was allowed to stir at room temperature for 12 h, the reaction was concentrated down and used directly in the next reaction. ESI-MS m/z: 354 (M+1), retention time 2.15.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)([O-:5])=[O:4].CS(O[CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:18][CH2:19][CH2:20][CH3:21])(=O)=O.O>CO>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:9]1[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[N:7]=[CH:8]1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CCCCC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(Cn1cnc([N+](=O)[O-])c1)c1ccc(Cl)cc1Cl
Yield: 106.6 %

Procedure:
To 1.3g (0.0307 mole) of sodium hydroxide in 150 ml of methanol is added 3.5g (0.0307 mole) of 4-nitroimidazole, and the solution is heated and the methanol distilled off. To the concentrate is added 100 ml of dimethyl formamide and the solution is heated up to 120° to remove the excess methanol and water. This dimethyl formamide solution is then cooled to less than 90° and 10.0g (of 0.0307 mole) of 2-(2,4-dichlorophenyl)hexyl methane sulfonate is added. The reaction mixture is heated up to 145° for 2 hours and then cooled and poured into water. The organic material is extracted out with ether and after drying, the extract is stripped to give 11.2g of residue. The concentrate is triturated with hexane and then dissolved in 25 ml of methanol. The methanol solution is poured slowly into water and a gummy solid forms. This solid is separated by filtration, dried and recrystallized from acetone-hexane to give 4.2g (41%) of the product, m.p. 67°-9°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][CH2:8]O.[Cl:10]S(Cl)=O.N#N>>[Cl:10][CH2:8][CH2:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1
Reactant: O=S(Cl)Cl
Reactant: OCCCC1CCCO1
Agent: N#N
Product: ClCCCC1CCCO1
Temperature: 25 °C

Procedure:
To 3-(tetrahydrofuran-2-yl)propan-1-ol (3.90 g, 30.0 mmol) was added dichlorosulfoxide (15 mL) dropwise under N2 and the mixture was refluxed for 3.5 h. It was then cooled to rt and concentrated in vacuo. To the residue was added water (30 mL) and the resulting mixture was extracted with DCM (30 mL×4). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as yellow liquid, which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(Cl)nc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(4-trifluoromethylphenyl)-1H-pyridin-2-one (23.7 g, 77 mmol) and phosphoryl chloride (35.2 mL, 386 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (16.5 g, 66%). MS (ISP) 326.1 [(M+H)+] and 328 [(M+2+H)+].
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:7](=[CH:11][C:12](=[S:23](=[O:25])=[O:24])[CH:13]([CH3:22])[C:14]=1[C:15]1[CH2:19][CH:18]([CH2:20][Cl:21])[O:17][N:16]=1)[C:8](O)=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:5][C:6]1[C:7](=[CH:11][C:12](=[S:23](=[O:25])=[O:24])[CH:13]([CH3:22])[C:14]=1[C:15]1[CH2:19][CH:18]([CH2:20][Cl:21])[O:17][N:16]=1)[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)Cl

Procedure:
3.23 g (27.2 mmol) of thionyl chloride were added dropwise to a mixture of 4.5 g (13.6 mmol) of 2-methyl-3-(5-chloromethyl-4,5-dihydroisoxazol-3-yl)-4-methyl-sulfonylbenzoic acid, 100 ml of toluene and three drops of N,N-dimethylformamide. The mixture was refluxed for 4 hours and then cooled, and the solvent was removed. The residue was then taken up in methylene chloride and once more concentrated to dryness. This gave 4.74 g (100% of theory) of the title compound in the form of a pale powder.
Reaction SMILES: O[NH:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[NH:23]O)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[NH:4].[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C.[Pd]>[C:26]([OH:29])(=[O:28])[CH3:27].[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:7]3[O:6][C:5]([C:3]([NH2:4])=[NH:2])=[CH:9][CH:8]=3)=[CH:11][CH:12]=2)=[CH:21][CH:20]=1)(=[NH:23])[NH2:25]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(NO)c1ccc(-c2ccc(-c3ccc(C(=N)NO)o3)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)o3)cc2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 3 (1 mmol) in glacial acetic acid (10 mL) was slowly added acetic anhydride (0.35 mL). After stirring for overnight TLC indicated complete acylation of the starting material, then was added 10% palladium on carbon (80 mg). The mixture was placed on Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered through hyflo and the filter pad washed with water. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 5 in 71% yield, mp 236-238° C. 1H NMR (D2O/DMSO-d6); δ 1.78 (s, 2×CH3), 7.31 (d, J=3.6 Hz, 1H), 7.61 (d, J=3.6 Hz, 1H), 7.85-8.11 (m, 8H). EIMS m/e (rel. int.); 304 (M+, 20), 287 (100), 270 (50), 216 (30), 190 (10). High resolution Calc. for C18H16N4O ms 304.13241. Observed 304.13201. Anal. Calc. for C16H14N4O2-2.0AcOH-1.75H2O-0.25EtOH: C %, 57.81; H %, 6.25; N %, 11.98. Found C %, 58.18; H %, 5.90; N %, 11.56.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:8]1([CH3:31])[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[CH2:30][CH2:29][CH2:28][NH:27][C:17]3=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([N:27]1[C:17]2=[N:18][C:19]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH3:31])=[CH:9][CH:10]=3)[N:15]=[C:16]2[CH2:30][CH2:29][CH2:28]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: C=CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hex-5-enal (step 1) (solution in DCM, 25 mmol) was treated with 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate B) (3.94 g, 12.5 mmol). After stirring at room temp under nitrogen for 30 mins, sodium triacetoxyborohydride (3.18 g, 15.00 mmol) was added and stirring continued at room temperature overnight. Water (100 ml) was added to the reaction mixture. Once effervescence had ceased the organic portion was separated and dried by passing through a phase separating column. The solvent was removed under reduced pressure and the resulting brown oil was purified by flash column chromatography on silica eluting with 0-100% EtOAc in iso-hexane on a 80 g silca cartridge. The combined fractions were allowed to stand at room temperature for 2 days. The resulting suspension was collected by filtration and dried in a vacuum oven. The crude material was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[CH2:21]1[CH2:26][CH2:25][CH:24]([CH2:27][N:28]=[C:29]=[O:30])[CH2:23][CH2:22]1.CCCCCC>C1(C)C=CC=CC=1>[CH:24]1([CH2:27][NH:28][C:29]([NH:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)=[O:30])[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]1
Reactant: O=C=NCC1CCCCC1
Reactant: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCC(=O)NNC(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 (0.30 g, 1.07 mmol) in anhydrous toluene (5 mL), cyclohexanemethyl isocyanate (0.16 g, 0.165 mL, 1.16 mmol) was added and the mixture was heated at reflux until all solid dissolved. The solution was allowed to cool slowly to room temperature. Hexane was added and the resulting oil was extracted with ethyl acetate, the organic phase was washed with water, dried over MgSO4 and evaporated under reduced pressure to afford 0.40 mg (87%) N-(cyclohexylmethyl)-2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-1-hydrazinecarboxamide D4 as a pale yellow oil.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][OH:9])[CH2:3][S:4]([NH2:7])(=[O:6])=[O:5].[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1.Cl>CN(C=O)C>[CH3:1][C@@H:2]([CH2:3][S:4](=[O:6])(=[O:5])[NH2:7])[CH2:8][O:9][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1
Reactant: Clc1ccc2nccn2n1
Reactant: C[C@H](CO)CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](COc1ccc2nccn2n1)CS(N)(=O)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 0.93 g of 2-(R)-methyl-3-hydroxy-1-propylsulfonamide in 50 ml of DMF was added by portions 0.48 g of sodium hydride, followed by stirring for 30 minutes at 70° C. The mixture to which 0.93 g of 6-chloroimidazo[1,2-b]pyridazine was added was refluxed for 5 hours. After cooling, the reaction mixture was adjusted to pH 6.0 with 1N-hydrochloric acid and concentrated to dryness under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with chloroform-methanol (10:1). The corresponding fractions were collected and concentrated to obtain 1.06 g of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6](OC)=[O:7]>C(O)C>[NH:2]([C:6](=[O:7])[C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4])[NH2:3]
Reactant: NN
Reactant: COC(=O)C(=O)NCCCOc1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)C(=O)NCCCOc1ccccc1
Temperature: 85 °C

Procedure:
Hydrazine monohydrate (6.3 mL) was added to a stirred suspension of methyl oxo[(3-phenoxypropyl)amino]acetate (3080 mg) in ethanol (50 mL). The reaction mixture was heated to 85° C. for 3 hours then allowed to cool. The precipitate was filtered off, washed with Et2O and dried under vacuum, to give the title compound (Intermediate 46, 2.269 g) as a solid; 1H NMR δ 9.95 (1H, s), 8.77 (1H, s), 7.28 (2H, m), 6.92 (3H, m), 4.50 (2H, s), 3.99 (2H, t), 3.30 (2H+H2O, m), 1.94 (2H, t); MS m/e MNa+ 260.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].Cl>O1CCOCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([NH:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(N)CCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(CCC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A stirred solution containing 4-amino-4-methylpentanoic acid (0.90 g, 6.86 mmol, Chembridge), Na2CO3 (2.9 g, 27. mmol), and 1,4-dioxane (10 mL) was cooled in an ice bath and Fmoc-Cl (2.1 mg, 8.2 mmol) dissolved in 1,4-dioxane (10 mL) was added in over about 2 min. The mixture was stirred at about 0° C. for about 1 h and then allowed to warm to rt. The mixture was neutralized with aqueous 6 N HCl and extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatograph (40 g silica gel column, 10-60% EtOAc/Heptane) to give 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-methylpentanoic acid the title compound (1.2 g, 49%): LC/MS (Table 2, Method b) Rt=2.31 min.; MS m/z: 352 (M−H)+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:12][CH:13]([CH2:15][C:16](Cl)=[S:17])[F:14]>ClCCl>[F:12][CH:13]([CH2:15][C:16]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[S:17])[F:14]
Reactant: FC(F)CC(=S)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=S)CC(F)F
Yield: 48.6 %

Procedure:
To a stirred and ice cooled solution of t-butanol (1.2 equivalents) and pyridine (1.3 equivalents) in dichloromethane (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride, and the mixture is stirred for 4 hours. The mixture is washed with water, dried and concentrated in vacuum. The residual liquid is distilled to give t-butyl difluoromethylthioacetate as an oil. Yield: 48.6%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][C:9](=[O:16])[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H][H]>[Rh].C(O)C>[CH2:1]([N:3]1[C:7]2[NH:8][C:9](=[O:16])[CH2:10][CH:11]([C:12]([F:13])([F:15])[F:14])[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCn1ncc2c(C(F)(F)F)cc(=O)[nH]c21
Agent: [Rh]
Solvent: CCO
Product: CCn1ncc2c1NC(=O)CC2C(F)(F)F

Procedure:
16.2 G. of 1-ethyl-1,7-dihydro-4-(trifluoromethyl)-6H-pyrazolo[3,4-b]pyridin-6-one, dissolved in 250 ml. of absolute ethanol, are catalytically hydrogenated by means of rhodium on charcoal catalyst (5%) at a temperature of 90°-100°. The reaction is performed in an autoclave at a hydrogen pressure of 10 atm. for 14 hours. After cooling, the catalyst is filtered off and the solution evaporated to dryness. The residual 1-ethyl-1,4,5,7-tetrahydro-4-(trifluoromethyl)-6H-pyrazolo[3,4-b]pyridin-6-one is treated with hot hexane providing 13.3 g. (81.5%) of the compound, m.p. 129°-130°. Recrystallization from a mixture of benzene/petroleum ether (1:2) raises the melting point at 130°-132°.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[C:4](F)=[C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[N:7][C:6]2=[C:13]([C:16]#[N:17])[C:14]=1[CH3:15].C(N(CC)CC)C.[CH3:27][N:28]([CH3:34])[C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CSC>[CH:10]1([C:8]2[O:9][C:5]3[C:6](=[C:13]([C:16]#[N:17])[C:14]([CH3:15])=[C:3]([N:2]([CH3:19])[CH3:1])[C:4]=3[N:31]3[CH2:32][CH2:33][C@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]3)[N:7]=2)[CH2:12][CH2:11]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(N(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CSC
Product: Cc1c(N(C)C)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
6-Dimethylamino-2-Cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-321) (34 mg, 0.10 mmol) was dissolved in dimethyl sulfide (4 ml), then triethylamine (29 μl, 0.20 mmol) and (3S)-3-(dimethylamino)pyrrolidine (27 μl, 0.21 mmol) were added, followed by stirring under nitrogen atmosphere at 100° C. for 24 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (20 mg, 64%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=3)=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:26][CH2:27][CH2:28][OH:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[S:19][C:20]([C:23]([NH:26][CH2:27][CH2:28][OH:29])=[O:24])=[CH:21][N:22]=3)=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ncc(C(=O)O)s1)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc(C(=O)NCCO)s1)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Temperature: 40 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
A mixture of 2-[({1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylic acid (Intermediate 14) (0.18 g, 0.45 mmol), 2-aminoethanol (32 μL, 1.2 eq), HATU (0.22 g, 1.3 eq) and DIPEA (100 μL, 1.3 eq) in DMF (20 mL) was stirred at 40° C. for 48 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The insoluble compound was filtered and washed with a mixture of acetonitrile/methanol 80/20 and then purified by flash chromatography eluting with DCM/MeOH (95/5) to give the title compound as a white solid (60 mg, 30%). HRMS calculated for C16H14Cl2N6O3S (M+H)+441.0303, found: 441.0339, Rt: 2.39 min. MP: 274.8° C.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:30][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 1-bromo-3,3-dimethylbutan-2-one (0.52 mL) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.76 g, 61%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(CC(N)CO)cc23)CC1

Procedure:
The product from step (e) (0.08 g) was dissolved in ethanol (25 ml) and 10% w/w Pd/C (0.23 g) added. The mixture was stirred under 1 atmos. pressure of hydrogen for 7 hours when uptake was complete. The mixture was filtered through celite and the filtrate evaporated in vacuo to give the desired product as colourless oil which was eluted through a silica column using DCM/EtOH/NH4OH (50:8:1) as eluant.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:18][C:19](=[S:20])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(NNC=O)cc1
Reactant: S=C=NC1CCCCC1
Product: O=CNNc1ccc(NC(=S)NC2CCCCC2)cc1

Procedure:
Procedure (12.) was employed with 1-formyl-2-(4-aminophenyl)hydrazine (7.5 g, 0.05 mole) and cyclohexyl isothiocyanate (7.1 g, 0.05 mole). Yield 9.6 g (66%), m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C@@H:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:24]([O:31][C:32]([NH:34][C:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][C:38](O)=[O:39])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:16])[C@H:6]([NH:7][C:38](=[O:39])[CH2:37][CH2:36][C:35]([NH:34][C:32]([O:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])([CH3:42])[CH3:41])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: C=CCOC(=O)[C@H](N)CCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
D-Homophenylalanine allyl ester (175 mg; 0.80 mmol) (see Example 9, Step B), triethylamine (222 μl; 1.59 mmol) were dissolved in dry methylene chloride (2 ml) and 4-(benzyloxycarbonylamino)-4-methyl-pentanoic acid (211 mg; 0.80 mmol) added. The solution was stirred at room temperature and BOP (353 mg; 0.80 mmol) was added over 5 minutes, and this reaction mixture stirred at room temperature for 17 h. The reaction was quenched by adding brine and then the products of the reaction isolated by extraction with methylene chloride (3×15 ml). The methylene chloride layers were combined and dried with anhydrous magnesium sulfate powder, filtered and evaporated under reduced pressure. A thick golden yellow gum was obtained which was purified by column chromatography on silica gel using ethyl acetate and hexanes 1:2 v/v. The product (182 mg; 48.9%) was isolated as a pale yellow gum. FAB-MS:- calculated for C27H34 N2O5 466.3; found 467.7 (M+1).