Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5](Br)=[C:6]([OH:8])[CH:7]=1.Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].NC1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]2[C:6]([OH:8])=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: C/C=C/C=O
Reactant: Nc1cc(O)c(Br)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Product: Cc1ccc2c(O)cccc2n1

Procedure:
To a stirred mixture of the 5-amino-2,4-dibromophenol prepared in example 3 (13 g, 49 mmol), acetic acid (65 mL) and HCl (65 mL) was added crotonaldehyde and the resultant mixture was heated at reflux for 1.5 h under argon. HBr (65 mL) and aniline (13 mL) were added and the mixture was refluxed for 5 h. After cooling, the reaction mixture was neutralized by adding of NaHCO3 (˜180 g) and then extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacuo to give a black solid (22 g). The crude product was purified by column chromatography (eluents: CH2Cl2-MeOH 98:2). Yield 5 g (49%) brown-white solid. Rf=0.43 (CH2Cl2-MeOH 9:1).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH3:9][C:10](O)([CH3:12])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:7])[CH2:3]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask was placed a solution of 3-oxocyclobutane-1-carboxylic acid (114 g, 999.13 mmol, 1.00 equiv) in dichloromethane (400 mL), 2-methylpropan-2-ol (102 g, 1.38 mol, 1.37 equiv), N,N-dimethylpyridin-4-amine (67.2 g, 550.06 mmol, 0.55 equiv), followed by the addition of a solution of N—(N-cyclohexylcarboximidoyl)cyclohexanamine (226.6 g, 1.10 mol, 1.10 equiv) in dichloromethane (300 mL) dropwise with stirring at room temperature over 25 min. The resulting solution was stifled overnight at room temperature. The solids were filtered out and the filtrate was washed with 2×500 mL of HCl (1 M) and 1×500 mL of saturated aqueous NaHCO3, and concentrated under vacuum. The residue was diluted with 500 mL of hexane. The mixture was decolorized by 50 g of active carbon and stirring for 3 minutes. The solids were filtered out and the filtrate was concentrated under vacuum to afford 102 g (60%) of tert-butyl 3-oxocyclobutane-1-carboxylate as a light yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)CCNCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and β-alanine (43.2 mg; 0.48 mmol) to give Example 127 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.5, 1.6 Hz), 7.97 (2H, d, J=8.1 Hz), 7.91 (1H, td, J=7.6, 1.7 Hz), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.58 (2H, d, J=8.1 Hz), 7.55-7.45 (2H, m), 3.87 (2H, s), 2.81-2.68 (2H, m), 2.39 (2H, t, J=6.7 Hz). LC/MS (Method C): 484 (M+H)+. HPLC (Method F) Rt 2.83 min (Purity: 99.2%).
Reaction SMILES: [CH:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][CH:8]=[C:2]12.[CH3:12]O>Cl>[CH:1]1([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][CH:8]=[C:2]12
Reactant: CO
Reactant: O=C(O)C1CCn2cccc21
Agent: Cl
Product: COC(=O)C1CCn2cccc21

Procedure:
2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is dissolved in methanol containing a small amount of concentrated hydrochloric acid. The resulting solution is heated to reflux, and then cooled. The title compound is isolated by rotary evaporation of the solvent under reduced pressure, and may be purified by chromatography on silica gel with hexane/ethyl acetate as eluent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[CH:6]1([Mg]Cl)[CH:10]=[CH:9][CH:8]=[CH:7]1>>[CH2:2]([C:10]1[CH2:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: CCCCBr
Product: CCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-bromobutane (105 g, 0.766 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 20 minutes. After stirring for an additional 2 hours at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (85 g, crude butylcyclopentadiene). To the crude butylcyclopentadiene (75 g) dissolved in methanol (500 mL) was added acetone (54 mL) followed by pyrrolidine (63 mL) at 0° C. The mixture was warmed up to room temperature and stirred for 24 hours. The reaction was quenched with a mixture of ice and acetic acid. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave the desired product (89 g) as a brown liquid.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:14]=[C:13](C(O)=O)[CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[ClH:43]>CCOC(C)=O.CCCCCC.CCN(CC)CC.C(O)CCC>[ClH:43].[C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:14]=[C:13]([NH2:21])[CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C=Cc2cccc(C(=O)O)n2)cc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCCCO
Product: Cc1ccc(C=Cc2cccc(N)n2)cc1

Procedure:
In a variation to the procedure referred to in example 1, 6-(2-p-tolyl-vinyl)-pyridine-2-carboxylic acid (2.81 g, 11.7 mmol) was brought to reaction with triethylamine (1.21 g, 12.0 mmol), diphenyl phosphoryl azide (3.56 g, 12.9 mmol) and butanol (33 ml). After extractive workup the residue was refluxed (4 hr) with 3N HCl. Extractive workup and chromatography (SiO2 with AcOEt/hexane/NEt3=10:20:1) afforded the title compound as an oil which was crystallized as the yellow hydrochloride salt (0.95 g, 33%). Mp.>250° C. (MeOH/Et2O), MS: m/e=210 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:7].[H-].[Na+].C(OC(=O)C)C>CN(C=O)C.C1COCC1>[CH3:15][C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:8]1[CH2:2][CH2:3][CH2:4][NH:5][C:6]1=[O:7]
Reactant: Cc1ccncc1NC(=O)NCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccncc1N1CCCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
1-(3-Chloro-propyl)-3-(4-methyl-pyridin-3-yl)-urea (I-130a: 2 g, 9.25 mmol) in dry DMF (15 mL) was added to a stirred mixture of sodium hydride (330 mg, 13.87 mmol) in THF (30 mL) at 0° C. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with MeOH at 0° C., concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 1.7 g (96.5% yield) of 1-(4-methyl-pyridin-3-yl)-tetrahydro-pyrimidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[C:12](Cl)(=O)C>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Bromo-2-chlorobenzoic acid (1.00 g, 4.25 mmol) was added to a solution of acetyl chloride (1.70 mL, 23.9 mmol) in methanol (30 mL). The mixture was allowed to stir at rt for 3 days, and was then concentrated in vacuo. This gave 0.84 g (80%) of the title compound. 1H NMR (400 MHz, CD2Cl2) δ 3.85 (s, 3H), 7.51 (d, 1H), 7.45 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+].C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
2-(S)-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester was (4.83 g, 18.2 mmol) was taken up in THF (11 mL), cooled to 0° C. under N2, treated drop-wise with a lithium triethylborohydride (1.0 M in THF, 73 mL), stirred at ambient temperature for 6 hours, treated with ethyl acetate (500 mL), washed with water, washed with 0.25 M HCl, washed with NaHCO3 solution, washed with brine (2×), dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with a gradient of 10:1 and then 5:1 hexane:ethyl acetate to provide 0.95 g (30%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 1.37 (d, J=6.10 Hz, 3 H) 1.44 (s, 9 H) 1.76 (m, 1 H) 2.27 (m, 1 H) 3.81 (t, J=7.46 Hz, 2 H) 4.28 (m, 1 H).
Reaction SMILES: [NH2:1]C(N)=O.[N:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16](F)(F)F)=[C:6]=[S:7]>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:5][C:6]([NH2:1])=[S:7])=[C:9]([CH3:16])[CH:10]=1
Reactant: COc1ccc(N=C=S)c(C(F)(F)F)c1
Reactant: NC(N)=O
Product: COc1ccc(NC(N)=S)c(C)c1

Procedure:
The title compound is prepared as described in Example 1 for [4-2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using 1-isothiocyanato-4-methoxy-2-trifluoromethyl-benzene. Title compound: ES-MS: 251.0 [M+H]+; single peak at tR=3.13 min (System 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([OH:12])=[N:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[CH2:23]([N:10]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]1=[O:12])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ncc(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2)cnc(C(=O)OCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
2-Ethyloxycarbonyl-3-hydroxy-5-phenylpyrazine (214.4 mg, 0.88 mmol) was dissolved in dimethylformamide (2.1 ml), and sodium hydride (60% in oil, 42.1 g, 1.05 mmol) was added to it under cooling on ice and stirred for 30 minutes. After allyl bromide (0.11 ml, 1.32 mmol was added, the mixture was stirred at room temperature for 1 hour and then at 80° C. for 1 hour. The reaction solution was left to be cooled to room temperature, thereafter the reaction was terminated by adding distilled water, and the product was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) whereby the title compound was obtained (24 mg, 9.6% yield).
Reaction SMILES: C([Li])CCC.O1CCCC1.[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH:43]([C:45]1[CH:46]=[C:47]([C:50]([O:52][CH3:53])=[O:51])[NH:48][CH:49]=1)=O>CCCCCC.O>[CH:43](/[C:45]1[CH:46]=[C:47]([C:50]([O:52][CH3:53])=[O:51])[NH:48][CH:49]=1)=[CH:23]/[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: COC(=O)c1cc(C=O)c[nH]1
Reactant: CCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC/C=C\c1c[nH]c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A ca. 15% solution (18.5 ml) of n-butyllithium in hexane was added dropwise at -50° C. to a tetrahydrofuran suspension (95 ml) of 16.0 g (31.4 mmol) of dodecyltriphenylphosphonium bromide described in Chemistry and Industry (London) p. 1086, 1958. The temperature was raised to room temperature and the mixture was stirred for 30 minutes. The temperature was again lowered to -50° C. To the mixture was added dropwise a tetrahydrofuran solution (50 ml) of 2.4 g (15.7 mmol) of methyl 4-formylpyrrole-2-carboxylate described in Bulletin de la Societe Chimique de France, p. 283, 1972. The mixture was stirred for 1 hour, diluted with water, extracted with ethyl acetate, washed with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/7) to obtain 3.11 g (65% yield) of methyl 4-(1-cis tridecenyl)pyrrole-2-carboxylate, m.p. 51°-52° C.
Reaction SMILES: [CH3:1][C:2]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[CH:13][N:12]=1)([NH:4]C(=O)C(F)(F)F)[CH3:3].[OH-].[Na+]>CO.C(OCC)(=O)C>[NH2:4][C:2]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[CH:13][N:12]=1)([CH3:3])[CH3:1]
Reactant: CC(C)(NC(=O)C(F)(F)F)c1ncc2sccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(N)c1ncc2sccn12
Temperature: 50 °C
Reaction time: 10 h
Yield: 0.1 %

Procedure:
To the solution of 1 g (3.6 mole) of 5-[1-methyl-1-[(trifluoroacetyl)amino]-ethyl]imidazo[5,1-b]thiazole in 3 ml of methanol was added 0.72 g (0.018 mole) of sodium hydroxide, and the mixture was stirred at 50° C. for 10 hours. The reaction mixture was concentrated, and the residue thus obtained was dissolved in 100 ml of ethyl acetate and washed twice with 100 ml of a saturated aqueous potassium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.74 g of crude 5-(1-amino-1-methylethyl)imidazo[5,1-b]thiazole. The mixture of 0.74 g of the crude product, 3 ml of formic acid and 1.5 ml of acetic anhydride was stirred in the absence of solvents for 3 hours and treated in the same manner as in Preparation 15 (c) to give 0.63 g of the title compound. Yield 83%. NMR (CDCl3) δ: 1.74 (6H, s), 6.95 (1H, s), 7.11 (1H, d, J=4.8 Hz), 7.71 (1H, d, J=4.8 Hz), 8.01 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[N:10]1([C:16]([S:18][CH3:19])=[S:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:13]1[CH2:14][CH2:15][N:10]([C:16]([S:18][CH3:19])=[S:17])[CH2:11][CH2:12]1
Reactant: Cc1ccccc1CCl
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2C)CC1
Yield: 28.2 %

Procedure:
1.405 g (10 mmol.) of 2-methylbenzyl chloride, 1.76 g (10 mmol.) of methyl 1-piperazinecarbodithioate, 1.06 g (10 mmol.) of anhydrous sodium carbonate and 14 ml of ethanol. The mixtrue was refluxed under heating for2.5 hours. Ethanol was distilled off under reduced pressure. The residue was mixed with water and ether. The organic solvent portion was taken out,and to the portion was added 15 ml of 8-N hydrochloric acid. The aqueous portion was neutralized with 1-N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill offthe solvent. The residue was purified over a silica gel column to give 790 mg of methyl 4-(2-methylbenzyl)-1-piperazinecarbodithioate as a white crystalline product, yield 28.2%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH2:6]1)=[O:4]>CCO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2cccc([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CN(Cc2cccc(N)c2)C1
Reaction time: 1 h

Procedure:
To a solution of INT 2 (250 mg, 0.99 mmol) in EtOH (10 mL) was added Pd—C 10% (25 mg). The mixture was stirred under 1 atm of H2 for 1 hour. The mixture was quenched with CH2Cl2 and filtered through a pad of Celite. The filtrate was concentrated to give INT 3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][O:9][C:10]([N:12]([C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[NH2:23])(=[O:15])=[O:14])=[O:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:8][O:9][C:10]([N:12]([C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[NH:23][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])(=[O:14])=[O:15])=[O:11]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2N)ccc2c1OCC1CC21
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2NC(=O)CCCCl)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
4-Chlorobutyryl chloride (3.0 g) was added to a stirred, cooled solution of methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(2-amino-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 110, 0.135 g) and triethylamine (1.0 g) in THF (10 mL) at 0° C. On completion of the addition, the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether, with a gradient of 20-25% to give methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-(4-chlorobutyrylamino)-4-fluoro-benzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.15 g) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12](=[O:24])[CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=3[CH3:23])[CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:35]2[NH:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[NH:31][CH2:30][C:29]=2[CH:28]=[N:27]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]1([CH2:5][N:6]2[CH2:7][CH2:8][N:9]([C:12](=[O:24])[CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:31]4[CH2:30][C:29]5[CH:28]=[N:27][N:26]([CH3:25])[C:35]=5[NH:34][C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]4=5)=[O:19])=[CH:16][C:15]=3[CH3:23])[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)O)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Yield: 32 %

Procedure:
WSCD (76 mg, 0.39 mmol) and DMAP (7 mg, 0.06 mmol) were added to a solution of 4-[2-(4-cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid from Example E85.2 (100 mg, 0.30 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (61 mg, 0.30 mmol) in dichloromethane (20 ml) and DIEA (0.16 ml, 0.91 mmol). The mixture was heated at reflux for 20 h and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 6% methanol:94% dichloromethane to 1% 35% ammonia:7% methanol:92% dichloromethane) to give an off-white solid identified as the title compound (50 mg, 32%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[I-].[K+].C[CH:30]=[CH:31][CH2:32][NH2:33].O1CCC[CH2:35]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:33]([CH2:32][CH:31]=[CH2:30])[CH3:35])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: CC=CCN
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Product: C=CCN(C)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 32, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-nitro-1-[(allyl-methylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:37])[CH:20]4[CH2:36][CH2:35][C:23]5([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:37])[CH:20]4[CH2:36][CH2:35][C:23]5([CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)n3)cc2nn1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CCNC5)CC4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of tert-butyl 8-((2-((2,3-dimethyl-2H-indazol-6-yl)amino)pyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (657 mg, 1.3 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (0.30 g, 56.9%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:33]3[CH2:38][CH2:37][CH2:36][C@H:34]3[N:35]=[C:3]12.[OH:39]OS([O-])=O.[K+]>CC#N.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:39])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:33]3[CH2:38][CH2:37][CH2:36][C@H:34]3[N:35]=[C:3]12
Reactant: CN1C(=O)c2c(nn(Cc3ccc(-c4cccc(F)n4)cc3)c2Sc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CN1C(=O)c2c(nn(Cc3ccc(-c4cccc(F)n4)cc3)c2S(=O)c2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylthio)-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (12 mg, 0.023 mmol) is dissolved in CH3CN (2 mL) and CH3OH (2 mL), and then an aqueous solution of oxone is added. The reaction mixture is stirred at room temperature for a week, and then purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 541.2 [M+H]+.