Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=2)[CH2:4]1)=O.COC(OC)OC.[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32]>CO>[CH3:32][CH:31]([CH3:33])[CH2:30][CH2:29][NH:34][CH2:1][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=2)[CH2:4]1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CC(C=O)C3)nc1
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)CCNCC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 25 %

Procedure:
Combine 6-(2-Formyl-indan-5-yloxy)-nicotinamide (Intermediate 32, 25.3 mg, 0.09 mmol), MeOH (2.4 mL), trimethylorthoformate (1.6 mL), and isopentyl amine (9 uL, 0.08 mmol). After the reaction stirs at room temperature under a nitrogen atmosphere for 4.5 hours, add NaBH (4.1 mg, 0.11 mmol), then stir at room temperature for another 12 hours. After that time, concentrate under reduced pressure then add ethyl acetate. Wash the organic phase with water, brine, and dry over Na2SO4. After concentration under reduced pressure the mixture, add to a 2 g SCX column, wash with MeOH and elute with 1N NH3-MeOH. After concentration, flash chromatograph using 2% 1N NH3-MeOH, 20% THF, 38% DCM to afford 7.0 mg, 0.02 mmol (25% yield) of the title compound: 1H NMR (500 MHz, d-Methanol); 0.9 (6H, d), 1.4-1.5 (2H, m), 1.6-1.7 (1H, m), 2.6-2.8 (6H, m), 3.1-3.2 (2H, m), 3.3-3.4 (1H, m), 6.8 (1H, d), 6.9 (1H, s), 7.1 (1H, d), 7.2 (1H, d), 8.1 (1H, d), 8.5 (1H, s); TLC 2% 1N NH3-MeOH:20% THF:78% CH2Cl2:Rf:=0.27.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:12]Br>O>[Br:12][C:9]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][NH:7][CH:8]=1
Reactant: BrBr
Reactant: CC(C)(C)c1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 7 h

Procedure:
2.48 g of 3-t-butyl-1H-pyrazole was suspended in 35 ml of water, and 2.5 g of 50% aqueous solution of sodium hydroxide was added to it. The mixture was cooled to 0° C., and then 3.50 g of bromine was added to the mixture, followed by stirring at room temperature for 7 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.14 of 4-bromo-3-t-butyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH:19][C:20](=O)[C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].O>O1CCCC1>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[S:33][C:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[N:19][N:18]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(CCC(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOc1ccc(CCc2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 126.7 %

Procedure:
A suspension of 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.0 g) and diphosphorus pentasulfide (730 mg) in tetrahydrofuran (20 ml) was stirred for 1 hour at 60° C. To a reaction mixture was added water and the mixture was stirred for 1 hour at room temperature. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give methyl 4-[5-[2-(4-n-hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoate (883 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31]Cl)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH3:35][NH:36][CH3:37]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31][N:36]([CH3:37])[CH3:35])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: CS(=O)(=NC(=O)CCl)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-chloroacetyl sulfoximide (100 mg, 0.185 mmol, Example 6) in DMF (0.2 mL) was added 50% aqueous dimethylamine solution (164 mg, 0.162 mmol) followed by catalytic amount of KI. The reaction mixture was stirred at 25-30° C. for 12 hr and then diluted with water (5 mL). Filtration and drying afforded 50 mg of titled compound in 49% yield.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[C:11]([C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[N:12].C(N(CC)CC)C>C(O)C>[CH2:7]([N:9]1[C:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])=[CH:20][C:21](=[O:22])[NH:10]1)[CH3:8]
Reactant: CCNN
Reactant: CCOC(=O)C#Cc1cccc(C#N)c1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1[nH]c(=O)cc1-c1cccc(C#N)c1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
Ethyl hydrazine oxalate (4.01 g, 26.7 mmol, 1.50 equiv) was added to a solution of ethyl 3-(3-cyanophenyl)prop-2-ynoate (3.55 g, 17.8 mmol, 1 equiv) and triethylamine (3.73 mL, 26.7 mmol, 1.50 equiv) in ethanol (180 mL). The reaction mixture was heated to 80° C. for 3.5 hours, then cooled to 22° C. The cooled reaction mixture was concentrated by rotary evaporation, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (3.5 g, 3:1 mixture of regioisomers in favor of desired product). The mixture of regioisomers was used without separating in the next step. Calcd (M+1)+: 214.1. Found: 214.1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=2)=[N:10]1
Reactant: FC(F)(F)c1ccc(-c2n[nH]cc2-c2cnccn2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Reaction time: 24 h
Yield: 59 %

Procedure:
To a solution of 2-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (200 mg, 0.69 mmol) and epichlorohydrin (0.540 mL, 6.9 mmol) in DMF (2 mL) was added cesium carbonate (450 mg, 1.38 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc, and washed with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 5% acetone/CH2Cl2) to afford 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (141 mg, 59%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.38. MS (electrospray) m/z 347.1 (347.1, calculated for C17H13F3N4O, M++H). 1H NMR (400 MHz, CDCl3): 8.51 (dd, J=2.8, 1.8 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.38 (d, J=12.8 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 4.57 (dd, J=14.7, 3.1 Hz, 1H), 4.21 (dd, J=14.7, 6.1 Hz, 1H), 3.44 (m, 1H), 2.91 (t, J=4.5 Hz, 1H), 2.62 (dd, J=4.0, 2.5 Hz, 1H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([NH2:11])[CH3:10].C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:32]3[N:33]=[C:34]4[C:40]([C:41](O)=[O:42])=[CH:39][N:38]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:35]4=[N:36][CH:37]=3)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([NH:11][C:41]([C:40]1[C:34]2[C:35](=[N:36][CH:37]=[C:32]([C:26]3[C:25]4[C:29](=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[N:28]([CH3:31])[N:27]=3)[N:33]=2)[N:38]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:39]=1)=[O:42])[CH3:10]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of (R)-1-pyridin-2-yl-ethylamine dihydrochloride (66 mg, 0.34 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.13 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to give 117 mg (95%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:34]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH:33]=[CH2:34])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(NC1CCC2(CC1CS(=O)(=O)c1ccc(Br)cc1)OCCO2)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(S(=O)(=O)C[C@@H]2CC3(CC[C@@H]2NC(=O)OCc2ccccc2)OCCO3)cc1

Procedure:
[7-(4-Bromo-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester from example (3e) (1.0 g), was dissolved in toluene (15 ml) prior to the addition of PdCl2(PPh3)2 (66 mg) and Sn(vinyl)Bu3 (0.61 ml), and a few crystals of 2,6-di-tert-butyl-4-methylphenol. The resulting solution was heated to reflux for 4 h. After cooling, the solution was concentrated. Flash chromatography of the resulting residue gave (7R,8S) [7-(4-vinyl-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (668 mg). MS found: (M+H)+=460.3.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].C(N(CC)CC)C.[Cl-].[CH3:24][O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>C(OCC)C>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[N:5]([CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])[C:28](=[O:29])[CH2:27][C:26]([O:25][CH3:24])=[O:31]
Reactant: COC(=O)CC(=O)O
Reactant: COC(CNc1c(C)cccc1C)OC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CC(=O)N(CC(OC)OC)c1c(C)cccc1C
Yield: 33.9 %

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-2,6-dimethyl aniline (4.45 g, 0.02 mol), triethylamine (2.76 ml, 0.02 mol) in ethyl-ether (25 ml.), malonic acid methyl ester monochloride (2.1 ml, 0.02 mol) was added dropwise in 15' at 0°-5° C. under stirring. The reaction mixture was then stirred 1 hour at 0° C. and 10 minutes at room temperature, then it was filtered, washed twice with 10 ml of a hydrogen chloride solution (5%), then with water till a neutral pH (3×10 ml). The organic phase was anhydrified on anhydrous Na2SO4 and the solvent was evaporated. The residue (yellow oil) was purified by chromatography on a silica gel column using hexane-ethyl acetate (7:3) as eluent. Thereby 2.1 g of the desired product (oil) were obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:25][NH2:26]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:4]2[N:3]=[C:2]([NH:25][NH2:26])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[CH:18][CH:19]=1
Reactant: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from [2-chloro-9-(2-ethoxy-ethyl)-9H-purin-6-yl]-(4-chloro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][OH:12])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.O[C:14]1[CH:36]=[CH:35][C:17]2[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:22][C:16]=2[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N:1]1[C:2]([CH2:10][CH2:11][O:12][C:14]2[CH:36]=[CH:35][C:17]3[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:26])([F:27])[F:25])[CH2:22][C:16]=3[CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2CN(CC(F)(F)F)C1=O
Reactant: OCCc1cn2cccnc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1Cc2ccc(OCCc3cn4cccnc4n3)cc2CN(CC(F)(F)F)C1=O

Procedure:
To 55 mL of a tetrahydrofuran solution containing 0.39 g (2.40 mmol) of 2-(imidazo[1,2-a]pyrimidin-2-yl)ethanol obtained in Example 1-(b) were added 0.69 g (2.00 mmol) of ethyl 8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate (see WO 98/14192 A) and 0.74 g (2.80 mmol) of triphenyl-phosphine, and the mixture was stirred under ice-cooling. Then, 2.6 mL of a tetra-hydrofuran solution containing 0.53 g (2.60 mmol) of diisopropyl azodicarboxylate was added dropwise to the mixture over 3 minutes, the mixture was gradually elevated to room temperature, and stirred for 14 hours.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].CCN(CC)CC.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C(Cl)Cl>[C:21]1([CH3:22])[CH:23]=[CH:24][C:18]([S:15]([N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[CH:6]=[O:7])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccnc2C=O)cc1
Yield: 58.2 %

Procedure:
To a suspension of 2-imidazolecarboxaldehyde (1.01 g, 10.51 mmol) in CH2Cl2 (25 mL) was added Et3N (2.9 mL, 21.02 mmol) and tosyl chloride (3.01 g, 15.77 mmol) and the reaction mixture was heated to reflux overnight. Then the mixture was cooled and washed with saturated NH4Cl (4×30 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a dark brown oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded 1-(toluene-4-sulfonyl)-1H-imidazole-2-carbaldehyde as a yellow oil (1.53 g, 58%). 1H NMR (CDCl3) δ 2.45 (s, 3H), 7.31 (s, 1H), 7.49 (d, 2H, J=6.0 Hz), 7.83 (s, 1H), 8.00 (d, 2H, J=7.5 hz), 9.78 (s, 1H).
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:16])=[CH:13][CH:12]=1
Reactant: N=C(N)NN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N=C(N)NNC(=O)c1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
To a solution of hydrazinecarboximidamide bicarbonate salt (2.3 g, 31.05 mmol) in pyridine (70 ml) was added dropwise 4-chlorobenzoyl chloride (4.5 g, crude) in DCM (20 ml). After stirring overnight at 15° C., the resulting mixture was concentrated under vacuum, quenched by the addition of water (20 ml) and adjusted to pH 13 with sodium hydroxide solution (10N). The product was collected by filtration and dried to give 2-(4-chlorobenzoyl)hydrazinecarboximidamide as a white solid (2.1 g, crude).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:24])[O:9][C:10]3[CH:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:12][CH2:13][CH2:14][C:15]=3[C:16]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][CH:27]([CH3:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:1]1([C:7]2[C:8](=[O:24])[O:9][C:10]3[CH:11]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:13][CH2:14][C:15]=3[C:16]=2[O:17][CH2:26][CH:27]([CH3:35])[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2c1ccccc1
Reactant: CC(CCl)CN1CCOCC1
Product: CC(COc1c2c(oc(=O)c1-c1ccccc1)C(c1ccccc1)CCC2)CN1CCOCC1
Yield: 35 %

Procedure:
Prepared according to the method of Example 9 from 3,8-diphenyl-4-hydroxy-5,6,7,8-tetrahydrocoumarin and 1-chloro-2-methyl-3-morpholino-propane. A thick, brown oil is obtained which cannot be crystallised. Yield 35%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O-:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[N:18]1([C:15]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)[O-])CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N2CCCC2)CCCCC1

Procedure:
1-[(tert-Butoxycarbonyl)amino]cyclohexancarboxylate, pyrrolidine, 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide hydrochloride and 1-hydroxybenzotriazole were allowed to undergo the reaction at room temperature in methylene chloride. By post-treating the reaction liquid, tert-butyl [1-(pyrrolidin-1-ylcarbonyl)cyclohexyl]carbamate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:13]=[C:12]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH2:23]([NH:26][CH2:27][C:28]#[CH:29])[C:24]#[CH:25].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:22][C:12]1[CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:15]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:11])[N:26]([CH2:27][C:28]#[CH:29])[CH2:23][C:24]#[CH:25]
Reactant: O=C(O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: C#CCNCC#C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C#CCN(CC#C)C(=O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 0.20 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)valeric acid and 0.05 g of dipropargylamine dissolved in 10 ml of chloroform was added 0.11 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.21 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(N,N-dipropargylcarbamoyl)butyl-oxy)benzene (92% yield), nD25.0 1.5481.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:17](=[O:19])[CH3:18])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1ncc(Br)cn1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(=O)Nc1ncc(Br)cn1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 5-bromo2-aminopyrimidine (2.0 g, 11.5 mmole) in CH2Cl2 (75 mL) at RT was added 2,6-lutidine (2.7 mL, 23.0 mmole) followed by acetyl chloride (0.99 g, 12.6 mmole). After stirring for 8 hours, the reaction solution was concentrated under vacuum. The remaining residue was dissolved EtOAc (200 mL), washed with H2O (100 mL) and brine, and dried over Na2SO4. Flash chromatography on silica gel (95:5 CHCl3/MeOH) and drying under high vacuum gave the title compound (1.74 g, 70%) as a yellow solid: MS (ES) m/e 217 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]([NH2:19])=[N:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1C[C@@H](C#N)N(C(=O)OCc2ccccc2)C1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@@H]1C[C@@H](C(N)=NO)N(C(=O)OCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To benzyl-(2S,4R)-2-cyano-4-methoxypyrrolidine-1-carboxylate, dissolved in ethanol (0.4 M), hydroxylamine hydrochloride (1.3 eq.) and triethylamine (1.5 eq.) were added. The mixture was stirred at 40° C. for 4 hours then at room temperature overnight. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate washed with brine, dried over Na2SO4, filtered and concentrated to give title compound.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26]([C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])#[CH:27]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:25][C:4]1[C:3]([C:27]#[C:26][C:28]2[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=2)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Reactant: C#Cc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4cccc(CNC(=O)OC(C)(C)C)c4)c3N)cc2C)cn1
Yield: 78.6 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 3-ethynylbenzylcarbamate (247 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (376 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).