Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCC[CH2:2]1.[CH2:6]([N:10]1[C:18]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1)=[N:14][C:15]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]1[CH3:31])[CH:7]([CH3:9])[CH3:8].N1(C=O)C2C=CC=CC=2N=N1.[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:18]([N:19]4[CH2:24][CH2:23][N:22]([CH:2]=[O:1])[CH2:21][CH2:20]4)[N:10]3[CH2:6][CH:7]([CH3:9])[CH3:8])=[C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[CH3:31])[N:14]=2)=[CH:33][N:34]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Reactant: C1CCOC1
Agent: O=Cn1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)Cn1c(N2CCN(C=O)CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 79 %

Procedure:
A tetrahydrofuran (3 ml) solution of 5-{9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-8-piperazin-1-yl-9H-purin-2-yl}pyrimidin-2-amine (103 mg, 0.23 mmol) and 1H-benzotriazole-1-carboaldehyde (37 mg, 0.25 mmol) was stirred at room temperature for 16 hours. Chloroform and 2 N aqueous sodium hydroxide solution were added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=95:5) to give a solid. Ether was added to the resulting solid and the solid was collected by filtration and dried to give the title compound (86 mg, 79%) as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:25]OS(C)(=O)=O)([CH2:19]OS(C)(=O)=O)[C:7](=[O:18])[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2:40].[Na+].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:19][S:40][CH2:25]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(COS(C)(=O)=O)(COS(C)(=O)=O)c2ccc(Br)cc21
Reactant: [S-2]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cc(Br)ccc2C12CSC2
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 6-bromo-3,3-bis((methylsulfonyloxy)methyl)-2-oxoindoline-1-carboxylate (3.70 g, 7.0 mmol) in anhydrous DMF (33 mL, deoxygenated with argon for 10 min) was added sodium sulfide nonahydrate (1.01 g, 4.20 mmol) under an argon atmosphere. The solution was stirred at 110° C. for 3 h, poured into saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (eluting with a gradient of 10-50% EtOAc in hexanes) gave 6-bromospiro[indoline-3,3′-thietan]-2-one as a yellow solid. Mass Spectrum (ESI) m/e=270.0 [(M+1) (79Br)] and 271.9 [(M+1) (81Br)].
Reaction SMILES: N(CCO)(CCO)CCO.[CH2:11]([O:21][C:22]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:25](C(O)=O)[NH:24][C:23]=1C(O)=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)=O>O>[CH2:11]([O:21][C:22]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][NH:24][CH:23]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCOc1c(C(=O)O)[nH]c(C(=O)O)c1OCCCCCCCCCC
Agent: O=C=O
Solvent: O
Solvent: OCCN(CCO)CCO
Product: CCCCCCCCCCOc1c[nH]cc1OCCCCCCCCCC
Temperature: 180 °C
Yield: 90.6 %

Procedure:
Into a 300-ml three-necked flask, 100 ml of triethanolamine was put, and was heated to 180° C. and stirred. Then, 23.4 g (50.0 mmoles) of the 3,4-didecyloxypyrrole-2,5-dicarboxylic acid was added thereto at one time. The mixture was vigorously stirred until carbon dioxide stopped being generated. The reaction product formed was cooled (for about 5 minutes) to room temperature, and 200 ml of water was added thereto, followed by extraction with chloroform. The organic layer formed was dried with magnesium sulfate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: chloroform/hexane=2/1) to obtain 17.2 g of 3,4-didecyloxypyrrole (yield: 90.7%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][C:25](=[O:34])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].CC1C=CC=C(C)C=1NC(=O)CN1CCNCC1>>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[C:18]=1[NH:24][C:25](=[O:34])[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:29][C:28]1=[O:33]
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1=O
Agent: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Product: Cc1nc2cc(OCC(O)CN3CCN(CC(=O)Nc4c(C)cccc4C)C(=O)C3)ccc2s1

Procedure:
Compound 64 was prepared in the manner of compound 7 substituting compound 33 for compound 6 and compound 32 for compound 5 in part D of compound 7: Mass Spectrum (MH+)=483.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[C:14]1(N)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.Cl>[Cl:1][C:2]1[C:7]([C:8]2[NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:9]=2)=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Reactant: Nc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nc3ccccc3[nH]2)c(Cl)n1
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
A mixture, homogenised in a mortar, of 19.5 g (100 mmol) of 2-chloro-3-cyano-6-tert-butylpyridine (S28), 36.2 g (200 mmol) of o-phenylenediamine and 38.0 g (200 mmol) of p-toluenesulfonic acid monohydrate is heated at 220° C. (oil-bath temperature) for 3 h. After cooling, the black, glassy sinter cake is taken up in a mixture of 100 ml of ethanol and 100 ml of 1N hydrochloric acid with vigorous stirring. After stirring for 30 min., the grey-green solid is filtered off with suction, washed three times with 50 ml of water each time and dried in vacuo. The solid is taken up in 200 ml of ethyl acetate, chromatographed on silica gel (ethyl acetate/heptane 1:1, Rf about 0.7) in order to remove 2-tert-butyl-6,11-dihydrobenzo[b]pyrido[2,3-e]-1,4-diazepin-5-one and brown by-products. The crude product obtained in this way is dissolved in ethyl acetate at the boiling temperature, and four times the amount of cyclohexane is added dropwise. After stirring at room temperature for 18 h, the crystals formed are filtered off with suction, washed with n-heptane and dried in vacuo. Yield: 7.5 g (26 mmol), 26%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.Cl.FC1C=C(N[C:60](=[O:72])[CH2:61][C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)=[O:63])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:60](=[O:72])[CH2:61][C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)=[O:63])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of 3-fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (15 mg, 0.037 mmol) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (8 mg, 0.04 mmol, Compound A of Example 25) in DMF (1 mL) were added DIEA (0.1 mL, 0.57 mmol) and TBTU (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature overnight and then purified using preparative HPLC. The fraction containing the desired product was collected and concentrated in vacuo. The residue was neutralized with 1 N NH4OH and concentrated again. The solid that formed was filtered, washed with 1 N NH4OH, dissolved in MeOH/H2O, and lyophilized to give the title compound (8 mg, 37%). 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.23 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 7.70 (m, 1H), 7.50 (m, 2H), 7.30-7.45 (m, 3H), 7.04-7.17 (m, 3H), 6.85-6.92 (m, 2H), 3.36 (s, 4H), 3.44 (s, 6H); MS(ESI) m/z 586.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[C:45]1(C)C=CC=CC=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH3:45])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Agent: Cl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 3 h

Procedure:
To 30 mg of 4-((S)-4-Carboxy-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester, 2 ml of methanolic hydrochloric acid was added at RT and stirred for 3 h. Then, 10 ml of toluene was added and the solvents were removed under reduced pressure and the product was lyophilized to yield a white solid. Yield: 25 mg MS (ES+): m/e=614.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:27][CH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][CH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:31][CH:30]=1
Reactant: OCc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(-c2ccc(CO)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 66 using 5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 67.1) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.0 min, m/z=459.2 [M+H]+, m/z=456.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.84 (m, 4H) 3.05-3.21 (m, 4H) 4.62 (br. s, 2H) 5.50 (br. s, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.54 (d, J=8.03 Hz, 1H) 7.81 (dd, J=8.03, 2.26 Hz, 1H) 7.83-7.89 (m, 2H) 8.01 (d, J=2.38 Hz, 1H) 8.51-8.55 (m, 1H) 8.76 (d, J=2.38 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:12]=[C:13]([Cl:17])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O.C(O)C.[Cu]>[Cl:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Clc1cccc(Br)c1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc(Oc2cccc(Cl)c2)cn1

Procedure:
3 g of a potassium salt of 5-hydroxy-2-methylpyridine, 3.83 g of m-bromochlorobenzene and 200 mg of a copper powder were suspended in 8 ml of dimethylformamide, followed by allowing the mixture to react in a nitrogen gas stream at 130° C. for 13 hours while stirring. The reaction mixture was diluted with 40 ml of ethanol and filtered. The filtrate was immediately concentrated, and 80 ml of chloroform was added to the residue. The mixture was washed with a 0.01 N aqueous sodium hydroxide solution. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and dried to solidify to obtain 2.96 g of oily 5-(m-chlorophenoxy)-2-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[NH:4][C@@H:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:24](O)(=O)C.C(N)=N>C(OCCO)C>[N+:21]([C:19]1[CH:18]=[CH:17][C:3]2[N:4]([C@@H:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH:24]=[N:1][C:2]=2[CH:20]=1)([O-:23])=[O:22]
Reactant: COC(=O)C[C@@H](Nc1ccc([N+](=O)[O-])cc1N)c1ccccc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCOCCO
Product: COC(=O)C[C@H](c1ccccc1)n1cnc2cc([N+](=O)[O-])ccc21
Temperature: 85 °C

Procedure:
To a solution of methyl (3R)-3-(2-amino-4-nitroanilino)-3-phenylpropanoate (2.10 g, 6.7 mmol) in 2-ethoxyethanol (65 mL) was added formamidine acetate (2.8 g, 26.6 mmol), and the mixture heated to 85° C. for 5 hours. The mixture was then cooled to room temperature, evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5) to afford a mixture of the title compound and the corresponding 2-ethoxyethanol ester, which was used directly without any additional purification. [LCMS (Method C, Mobile Phase I) RT=2.86 mins (broad), MH+ 326 (Me-ester) and 384 (EtOCH2CH2-ester)].
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:11].Cl[C:13]1[C:14](I)=[C:15]([OH:20])C=C(Cl)C=1>>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:14]([CH2:15][OH:20])=[CH:13][C:2]=2[CH:7]=1)[CH2:9][CH3:10]
Reactant: Oc1cc(Cl)cc(Cl)c1I
Reactant: CCCc1ccc(O)c(I)c1
Product: CCCc1ccc2oc(CO)cc2c1

Procedure:
When the product of Step A was substituted for 3,5-dichloro-2-iodophenol in Example 8, Step E, the similar process afforded the title compound in 31%, as off-white oil. 1H-NMR (CDCl3) 0.93 (m, 3H); 1.58-1.73 (m, 2H); 1.9 (tr, 1H, J=6 Hz); 2.65 (tr, 2H, J=6 Hz); 4.76 (d, 2H, J=6 Hz); 6.58 (s, 1H); 7.08 (dd, 1H, J=3, 9 Hz); 7.3-7.37 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-])(O)=O.[Na+].CI>CC(N(C)C)=O>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([O:14][CH3:23])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCOCc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](CCOCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of (R)-2-(2-(benzyloxy)ethyl)-4-tert-butoxy-4-oxobutanoic acid (120 g, 388 mmol) in DMA (750 mL) was added NaHCO3 (65.2 g, 776 mmol) followed by MeI (36.4 mL, 582 mmol) and stirred overnight at room temperature. Additional NaHCO3 (130 g, 1.55 mol), and MeI (72.8 mL, 1.16 mol) were added and stirring was continuted for an additional 20 h. The mixture was filtered and the filtrate partitioned between MTBE (1.5 L) and H2O (1.5 L). The aqueous phase was separated and back-extracted with MTBE (1.0 L). The combined organics were washed with H2O (2×1.5 L), brine (1 L), dried over MgSO4, and filtered. The filtrate was concentrated to give a pale yellow oil containing (R)-4-tert-butyl 1-methyl 2-(2-(benzyloxy)ethyl)succinate (140 g, 379 mmol, 98% yield). Exact mass calculated for C18H26O5: 322.2, found: LCMS m/z=323.3, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9 H), 1.82 (m, 1 H), 1.97 (m, 1 H), 2.42 (dd, J1=16.3, J2=5.3 Hz, 1 H), 2.63 (dd, J1=16.5, J2=9.0 Hz, 1 H), 2.96 (m, 1 H), 3.50 (t, J=6.2 Hz, 2 H), 3.65 (s, 3 H), 4.48 (s, 2 H), 7.32 (m, 5 H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:9][CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Acryloyl chloride (86.9 g) was added dropwise with stirring to a solution of 4-chlorobenzylamine (135.8 g) and triethylamine (133.5 ml) in dichloromethane (500 ml) at -15 to -20° C., under nitrogen. After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture was washed with dilute aqueous sodium hydroxide solution and then with water. The dichloromethane solution was dried and evaporated under reduced pressure. The solid residue was recrystallised from ethyl acetate to give N-(4-chlorobenzyl)acrylamide, m.p. 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.CN(C)C=O.C1C(=O)N([Br:27])C(=O)C1>CC(=O)OCC>[Br:27][C:11]1[S:10][C:9]([CH2:13][OH:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: OCc1sccc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1sc(Br)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-chlorophenyl)thiophen-2-yl]methanol (3.6 g, 16.02 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL). This was followed by the addition of NBS (2.85 g, 16.01 mmol, 1.00 equiv) portions at −5° C. The resulting solution was stirred for 2 h at room temperature (20 degree C.). The resulting solution was diluted with 100 mL of EA. The resulting mixture was washed with 3×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 4.8 g (99%) of [5-bromo-3-(4-chlorophenyl)thiophen-2-yl]methanol as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)CN
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCC(C)C)c([N+](=O)[O-])c1
Yield: 81.2 %

Procedure:
4-Isobutylamino-3-nitro-benzoic acid methyl ester (950.0 mg) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (1.0 g) and isobutyl amine (402.0 mg) in DMF (10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C1(C#C)C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C#N>C(#N)C1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:22]=[C:23]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:24]=1
Reactant: C#CC(C)(C)C
Reactant: COc1cccc(C#N)c1
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: COc1cccc(C#CC(C)(C)C)c1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
The procedure was identical to Example 1, with the exception that 3,3-dimethyl-1-butyne (0.488 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-methoxybenzonitrile (0.245 ml; 0.266 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 16 h at 65° C. showed the presence of 1.85 mmol (92% yield) of 1-methoxy-3-(3,3-dimethyl-1-butynyl)benzene and no remaining 3-methoxybenzonitrile in the reaction mixture.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:12]1[N:13]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[N:14]=[C:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[N:23][C:24]([CH3:28])([CH3:27])[CH2:25]O)[NH:16]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([C:12]1[N:13]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[N:14]=[C:15]2[N:16]3[CH2:25][C:24]([CH3:28])([CH3:27])[N:23]=[C:17]3[N:18]([CH3:22])[C:19](=[O:21])[C:20]=12)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cn1c(=NC(C)(C)CO)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1C(=O)c2c(nn(Cc3ccc(-c4ccccc4)cc3)c2Cc2ccccc2)N2CC(C)(C)N=C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A 2.0 M solution of thionyl chloride (25 μL, 0.050 mmol) in CH2Cl2 is added into a solution of 3-benzyl-2-(biphenyl-4-ylmethyl)-6-(1-hydroxy-2-methylpropan-2-ylimino)-5-methyl-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (5.0 mg, 0.010 mmol) in methylene chloride (1 mL). The reaction mixture is stirred at r.t. overnight, and then quenched with 5% NaHCO3. The resulting mixture is purified by chromatography to give 3.2 mg of the final product (Yield: 67%). MS (FAB) m/z 476.4 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18].C([Li])CCC>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve (R)-4-Benzyl-2-oxazolidinone (5.906 g, 33.33 mmoles) and 4-Pentenoyl chloride (4.54 g, 38.33 mmoles) in THF (50 mL). Cool the mixture in a dry ice acetone bath, and add n-Butyl Lithium (36.66 mmoles; 14.66 mL; 10.12 g) dropwise at −78° C. Stir the mixture at −78° C. for 30 min and then warm to ambient temperature. Quench the solution with 60 ml of sat. ammonium chloride, and then extract with 60 ml MTBE. Separate the organics and dry over magnesium sulfate. Filter the drying agent and concentrate under vacuum to an oil (6.96 g). LCMS=100% 260 amu (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>CO.C(#N)C>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N
Reactant: N#CCCCCn1cnc(NC(=S)NCC(F)(F)F)n1
Solvent: CC#N
Solvent: CO
Product: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
This nitrile (3.6 g.) in MeOH (80 ml.) and acetonitrile (5 ml.) was treated with mercuric oxide (3.06 g.) and methanolic ammonia (15 ml.). After stirring for 1.5 hours the black suspension was filtered through diatomaceous earth and the filtrates evaporated to give a white solid. The solid was washed with ether and filtered to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (2.87 g.) as a white solid, m.p. 200°-201° after recrystallisation from EtOH.