Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:11][C:12]([C@H:14]1[CH2:16][C@@H:15]1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:22]([CH:24]([CH2:27][CH3:28])[CH2:25]Br)[CH3:23].C([O-])([O-])=[O:30].[K+].[K+]>CN(C=O)C.CCOCC>[OH:1][CH:2]([OH:30])[C@H:3]([NH:11][C:12]([C@H:14]1[CH2:16][C@@H:15]1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:25][CH:24]([CH2:27][CH3:28])[CH2:22][CH3:23])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(CC)CBr
Reactant: O=C(N[C@@H](CO)c1ccc(O)cc1)[C@H]1C[C@@H]1c1cccs1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)COc1ccc([C@@H](NC(=O)[C@H]2C[C@@H]2c2cccs2)C(O)O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-[4-hydroxy-phenyl)-ethyl]-amide (35 mg, 0.105 mmol) dissolved in 0.8 mL DMF was added the 2-ethylbutyl bromide (38 mg, 0.231 mmol) followed by K2CO3 (32 mg, 0.231 mmol). It was heated to 60° C. with stirring overnight. On the next day it was cooled to rt, diluted with ether and quenched with water. The organic layer was washed with water and brine, dried over MgSO4, and concentrated. It was then purified by flash column (20-40% EtOAc in DCM) to afford the titled compound (26 mg, 58%). 1H NMR (400 MHz, MeOD) δ ppm 5.8 (d, J=8.6 Hz, 2 H), 5.7 (dd, J=5.2, 1.1 Hz, 1H), 5.4 (d, J=8.6 Hz, 3H), 5.3 (d, J=3.5 Hz, 1H), 3.4-3.5 (m, 1H), 2.4 (d, J=5.6 Hz, 2H), 2.2 (dd, J=6.6, 3.0 Hz, 2H), 1.0 (dd, J=6.3, 2.5 Hz, 1H), 0.5 (ddd, J=8.6, 4.7, 4.4 Hz, 1H), 0.1-0.2 (m, 1H), −0.1-0.1 (m, J=15.1, 7.7, 7.6, 7.6 Hz, 5H), −0.2 (ddd, J=8.5, 6.2, 4.3 Hz, 1H), −0.5 (t, J=7.5 Hz, 6H). LRMS (ESI)=388, [(M+1)+ calcd for C22H30NO3S 387.5].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:10])=[CH:6][C:7]=1[CH2:8][CH3:9].O.[NH2:12][NH2:13]>O1CCOCC1>[Cl:10][C:5]1[N:4]=[N:3][C:2]([NH:12][NH2:13])=[C:7]([CH2:8][CH3:9])[CH:6]=1.[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cc(Cl)nnc1Cl
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Cl)nnc1NN
Product: CCc1cc(NN)nnc1Cl
Reaction time: 1 h

Procedure:
3,6-Dichloro-4-ethylpyridazine (W4.003, 2×2.4 g) was divided between 2 microwave vessels and each was admixed with a mixture of hydrazine monohydrate (6 ml) and dioxane (7 ml). The reaction mixture was kept in the microwave at 130° C. for 1 h. Subsequently, the contents of the two vessels were combined in a round-bottom flask and dried. The residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The workup process was repeated twice more. The residue thus obtained was separated by means of preparative HPLC (method A, except gradient of 100% water+0.05% TFA→15% acetonitrile/85% water+0.05% TFA in 25 min). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 1.35 g of (6-chloro-4-ethylpyridazin-3-yl)hydrazine as the trifluoroacetate and 3.96 g of (6-chloro-5-ethylpyridazin-3-yl)hydrazine as the trifluoroacetate were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.O[CH:48](S([O-])(=O)=O)[CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.[Na+].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][CH2:48][CH2:49][N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Reactant: O=S(=O)([O-])C(O)CN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2nc3cc(NCCN4CCOCC4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 24 h
Yield: 12.5 %

Procedure:
To a slurry of 4 Å molecular sieves (0.9 g), 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.187 g, 0.475 mmol), sodium 1-hydroxy-2-morpholin-4-yl-ethanesulfonate (0.122 g, 0.523 mmol) and THF (2.5 mL) was added triethylamine (0.300 mL, 2.15 mmol). The slurry was stirred at 23° C. for 24 h, and sodium triacetoxyborohydride (0.282 g, 1.33 mmol) was added. The reaction mixture was stirred for an additional 24 h. Additional sodium 1-hydroxy-2-morpholin-4-yl-ethanesulfonate (62.0 mg, 0.270 mmol) was added and the reaction was allowed to continue for another 24 h at 23° C. The reaction mixture was diluted with EtOAc, filtered, and washed with saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (EtOAc/hexanes) to yield the titled compound (30 mg, 12% crude yield). This compound was used without further purification in subsequent reactions. MS (ESI/CI): mass calcd. for C23H31ClN6O5, 506.2; m/z found, 507.2 [M+H]+.
Reaction SMILES: [OH2:1].[OH-].[Na+].[C:4]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[O:21])[CH:12]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:33]1[CH2:38][CH2:37]OCC1>>[C:38]([CH2:37][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][CH:12]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C:13]1=[O:21])([OH:33])=[O:1]
Reactant: C1COCCO1
Reactant: O
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 95 %

Procedure:
Crude product 27 of Example 6 (6 g, 12.73 mmol) was dissolved in dioxane (15 mL) and water (15 mL) and cooled in an ice bath. 2N sodium hydroxide was added to this solution till pH of the solution reached 10. The heterogenous mixture was stirred at room temperature until it became homogenous. The homogenous layer was extracted with ether, and the aqueous layer acidified to pH 2 using 4N HCl. This was extracted with dichloromethane (150×3 mL), and dried over magnesium sulphate to give 5.52 g of 29 (95% yield from compound 26) as a pure white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:8]=[C:7]([N:18]2[CH2:23][C@@H:22]3[CH2:24][C@H:19]2[CH2:20][O:21]3)[N:6]=1)(=O)=O.Cl.[NH:26]1[CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:26]1([C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=3)[CH:8]=[C:7]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][O:21]4)[N:6]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)c1nc(-c2cnc(N)nc2)cc(N2C[C@@H]3C[C@H]2CO3)n1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CO4)nc(N3CCC3)n2)cn1
Temperature: 130 °C

Procedure:
5-[2-methylsulfonyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine (30.0 mg, 0.861 mmol), azetidine hydrochloride (24.7 mg, 0.258 mmol), potassium carbonate (71.4 mg, 0.517 mmol), and 1-methyl-2-pyrrolidinone (0.861 mL) were combined in a reaction flask and heated to 130° C. for 16 hrs. The reaction was filtered and purified by reverse phase column chromatography using a gradient of 20% to 60% acetonitrile in 0.1% ammonium hydroxide in water. The combined fractions containing product were concentrated under reduced pressure to provide 2-(azetidin-1-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.99 (t, J=7.5 Hz, 4H), 3.77 (dd, J=7.3, 1.5 Hz, 1H), 3.64 (d, J=7.3 Hz, 1H), 3.43 (dd, J=10.5, 1.5 Hz, 1H), 3.40-3.32 (m, 1H), 3.17 (s, 1H), 2.24 (p, J=7.5 Hz, 2H), 1.85 (s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CO>[C:33]([NH:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Solvent: CO
Product: CC(=O)N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C)Cc1ccccc1

Procedure:
A solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (25 mg, 0.058 mmol) and acetic anhydride (200 ml)-in methanol (2 ml) was kept at room temperature for 1 h. Evaporation followed by chromatography of the resultant product on a column of silica gel (10% methanol/dichloromethane) provided the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]1([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=2)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>CN(C=O)C>[N:1]([CH2:17][C:16]1[CH:19]=[CH:20][C:13]([C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:12])=[CH:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: O=C(c1ccc(CBr)cc1)C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
Add sodium azide (441 mg, 6.785 mmol) to a stirred solution of 4-(cyclohexanecarbonyl)-benzyl bromide (954 mg, 3.393 mmol) in anhydrous DMF (20 mL) and heat the mixture to 90° C. for 2 h. Cool the mixture to room temperature, add water and extract the aqueous solution with diethyl ether. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as oil (310 mg, 38%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[S:28][CH:29]=[CH:30][N:31]=1)CCC>CN(C=O)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nccs2)CC1
Temperature: 90 °C
Yield: 94.3 %

Procedure:
A solution of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.205 g, 0.58 mmol) and 2-(tri-n-butylstannyl)thiazole (0.239 g, 0.64 mmol) in 6 mL of dry DMF was degassed with a stream of Ar bubbles for 10 min. To this solution was added (Ph3P)4Pd (0.067 g, 10 mol %) and CuI (0.011 g, 10 mol %), and then the reaction vessel was sealed and heated at 90° C. for 18 h. The cooled mixture was concentrated and then it was partitioned with EtOAc-water. The organic phase was washed (brine), dried (MgSO4) and evaporated. Flash chromatography of the residue (SiO2/hexane-EtOAc, 3:2) afforded the title compound (0.195 g, 94%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14]C)=[O:13])[CH:8]=2)[N:3]=1.C1C[O:19]CC1>>[O:19]=[C:2]1[CH:11]=[CH:10][CH:9]2[CH:4]([CH:5]=[CH:6][C:7]([C:12]([OH:14])=[O:13])=[CH:8]2)[NH:3]1
Reactant: COC(=O)c1ccc2nc(Cl)ccc2c1
Reactant: C1CCOC1
Product: O=C1C=CC2C=C(C(=O)O)C=CC2N1

Procedure:
A solution of methyl 2-chloroquinoline-6-carboxylate (60 mg, 0.271 mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to 60° C. in a heating block. LCMS shows major product 86% peak area corresponding to title compound with hydrolysis of methyl ester (m/z=189.9). The reaction was concentrated and used in the subsequent amide coupling steps without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC=O
Reactant: CC(=O)O[C@@H]1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC[C@@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBR) in DCE (7 ml) was added ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) followed by sodium triacetoxyborohydride (236 mg, 1.112 mmol). The reaction mixture was left to stir at room temperature overnight under an atmosphere of nitrogen. A further portion of ethyl 7-oxoheptanoate (6 equivalents) was added and the reaction mixture was left to stir at RT for 4 days. The mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH2:10])=[S:9])[CH2:3][CH2:2]1.Br[CH:12]([CH2:18][CH3:19])[C:13](OCC)=[O:14]>>[CH:4]1([NH:7][C:8]2[S:9][CH:12]([CH2:18][CH3:19])[C:13](=[O:14])[N:10]=2)[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: NC(=S)NC1CCCCC1
Reactant: CCOC(=O)C(Br)CC
Product: CCC1SC(NC2CCCCC2)=NC1=O

Procedure:
Synthesis was performed from n-cyclohexylthiourea and ethyl 2-bromobutyrate according to Method C. Gave 201 mg (75%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].[Li+].[OH-].C(O)(=O)C>C1COCC1.O>[CH3:17][S:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2)(=[O:16])=[O:15]
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To a solution of the 5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester (0.49 g) in THF (12 mL) and water (4 ml) was added LiOH (0.098 g). The reaction mixture was left to stir for 2 hours. Acetic acid was added and the product extracted with dichloromethane. The organic extracts were combined, dried with magnesium sulfate, filtered and the filtrate evaporated to give the title compound as a solid (0.110 g).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([NH:45][C@H:46]([C:48]([NH:50][C@H:51]([C@H:56]([CH2:58][C:59]([O:61][CH3:62])=[O:60])[OH:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:49])[CH3:47])=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([NH:45][C@H:46]([C:48]([NH:50][C@H:51]([C@H:56]([CH2:58][C:59]([O:61][CH3:62])=[O:60])[OH:57])[CH2:52][CH:53]([CH3:54])[CH3:55])=[O:49])[CH3:47])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 52 mg of BOC-Phe-His-OH, 60 mg of H-Leu-Val-Ala-Sta-OCH3.HCl, 18 mg of HOBT, 0.24 ml of ethyldiisopropylamine and 34 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (30 g of silica gel 60, 40-63 μm, system N8). Rf(N9)=0.38.
Reaction SMILES: [S:1]1[C:5]([SH:6])=[N:4][N:3]=[C:2]1[SH:7].[H-].[Na+].Br[CH2:11][CH2:12][CH3:13].Cl[C:15]1[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:11]([S:6][C:5]1[S:1][C:2]([S:7][C:15]2[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=2)=[N:3][N:4]=1)[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: Sc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,3,4-thiadiazole-2,5-dithiol (601 mg, 4.00 mmol) in DMF and benzene (6 ml, 1/1) was added NaH (60% dispersion in mineral oil, 176 mg, 4.40 mmol) slowly at 0° C. under nitrogen atmosphere. The resulting suspension was stirred at 0° C. for 15 minutes and then to the mixture was added bromopropane (492 mg, 2.00 mmol). The reaction was stirred at rt for 1 hr. To the reaction was added NaH (60% dispersion in mineral oil, 176 mg, 4.40 mmol) slowly at 0° C. and stirred for 15 minutes after addition. Then, 3-chloropyrazine-2-carbonitrile (557 mg, 4.00 mmol) was added to the mixture and the reaction was stirred at 50° C. under N2 overnight. The reaction was then cooled to room temperature and quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4. Removal of solvent gave the crude product which was purified by chromatography to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]4[CH2:20][O:19]4)=[CH:17][C:12]=3[C:11]3=[N:21][CH:22]=[N:23][N:10]3[C:9]2=[O:24])=[CH:5][CH:4]=1.ClC1C=CC=[C:30]([C:34]([O:36]O)=O)C=1.COC1C=C[C:43]([CH2:44][N:45]2C3N=CC(C=C)=CC=3C3=NC=NN3C2=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:19][CH:18]([C:16]1[CH:15]=[N:14][C:13]2[N:8]([CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9](=[O:24])[N:10]3[N:23]=[CH:22][N:21]=[C:11]3[C:12]=2[CH:17]=1)[CH2:20][N:45]1[CH2:30][CH2:34][O:36][CH2:43][CH2:44]1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C4CO4)cnc32)cc1
Reactant: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(O)CN4CCOCC4)cnc32)cc1
Reaction time: 18 h
Yield: 82 %

Procedure:
6-(4-Methoxybenzyl)-9-(oxiran-2-yl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one. 3-Chloroperbenzoic acid (139 mg, 0.62 mmol) was added to a stirred solution of 6-(4-methoxybenzyl)-9-vinylpyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 30, 138 mg, 0.41 mmol) in DCM (1.3 mL) and the mixture was stirred for 18 h. Saturated sodium bicarbonate (3 mL) was added to the reaction mixture and the mixture was stirred for 2 h. The reaction mixture was diluted with DCM (5 mL), and the organic layer was separated, dried (MgSO4), and concentrated under vacuum to afford the title compound (118 mg, 82%) as a yellow semi-solid, which was used without further purification in the next step.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:9](O)([CH3:12])([CH3:11])[CH3:10].[CH2:14]=[C:15]([CH3:17])[CH3:16].S(=O)(=O)(O)O.[OH-].[Na+]>>[C:1]([O:8][C:15]([CH3:17])([CH3:16])[CH3:14])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5]
Reactant: O=C(O)CCC(=O)O
Reactant: C=C(C)C
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)CCC(=O)OC(C)(C)C
Temperature: 3.3500000000000227 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
An autoclave is charged with 212.5 g (1.80 mol) of succinic acid and 166.8 g (2.25 mol) of tert-butanol and then 808 g (14.40 mol) of isobutene are forced in at 263 K jacket temperature. After the addition is complete, 108.1 g (1.08 mol) of 98% sulfuric acid are pumped in over 70 minutes at a temperature of 268 to 275 K in the vessel. The reaction mixture is then stirred for 30 minutes at a temperature of 275 to 278 K in the vessel and, after increasing the temperature to 293 to 295 K, it is stirred for another 14 hours at that temperature and at a pressure from (4×105) to (5×105) Pa. The reaction mixture is then forced into an agitated mixture consisting of 1000 g of ice and 300 ml (3 mol) of 30% sodium hydroxide solution and the autoclave is then flushed with 200-300 ml of petroleum ether which is also added to the mixture of ice/sodium hydroxide solution. The mixture is warmed to room temperature and the organic phase is separated. The aqueous phase is extracted 3 times with 100-150 ml of petroleum ether each and the organic phases are then combined. The organic phases are concentrated in a rotary evaporator at a bath temperature of 323 K and (3×103) Pa (final value). To purify the crude product it is fractionally distilled, with addition of about 0.5 g of magnesium oxide, via a 30 cm packed column (Raschig rings 5×5 mm) under vacuum. The ester content of the individual fractions is determined by gas chromatography. Fractions having ester contents of <97% by weight are distilled again. After a total of 3 distillations, 329.3 g (79.4% of theory) of di-tert-butyl succinate are obtained having a 97.2% purity (percent per area), determined by gas chromatography, corresponding to 7.2% of theory a 100%.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)C.O.[NH2:15][NH2:16]>C(O)(=O)C>[C:1]1(=[N:15][NH2:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NN=C1CCc2ccccc21
Temperature: 20 °C

Procedure:
A mixture of indan-1-one (10.0 g), ethanol (35 ml), hydrazine hydrate (10.0 ml) and glacial acetic acid (2.0 ml) was boiled under reflux under nitrogen for 1 hour. The mixture was cooled to 20° C. and the mixture concentrated under reduced pressure to give a solid which was collected by filtration to give indan-1-one hydrazone, m.p. 84-86° C.