Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>C(#N)C>[Br:30][C:8]1[N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)cnc2c1Br)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
A mixture of N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (134 mg described in Example 180) and N-bromosuccinimide (68 mg) in acetonitrile (3.5 mL) was heated to 60° C. overnight. The mixture was concentrated under reduced pressure to yield a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (125 mg, 80%). MS (ES): M/Z [M+H]=502. 1H NMR: (400 MHz, DMSO-d6): 1.78 (s, 3H), 5.10-5.22 (m, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.58 (d, J=1.9 Hz, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][OH:39])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>C(#N)C>[OH:39][CH2:38][CH2:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Reaction time: 2 h

Procedure:
A mixture of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.85 g) and 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.432 g) in acetonitrile (10 mL) at 20° C. was treated with triethylamine (0.616 mL) and then stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 1% triethylamine and 3% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.71 g.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([CH3:33])([CH3:32])[C:30]#[CH:31].[Cl-].[NH4+]>CN(C=O)C.[Cu](I)I>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]3[O:19][C:29]([CH3:33])([CH3:32])[CH:30]=[CH:31][C:16]=3[CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)Cl
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(O)cc21
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2cc3c(cc2O1)C(=O)C(=O)N3Cc1ccccc1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
Under nitrogen stream, a solution of N-benzyl-5-hydroxyisatin (4.74 g, 18.7 mmol), potassium iodide (5.09 g, 31.8 mmol), potassium carbonate (5.17 g, 37.4 mmol), copper iodide (71 mg, 0.37 mmol) and 3-chloro-3-methyl-1-butyne (4.83 mL, 43.0 mmol) in DMF (47 mL) was stirred at 70° C. for 2 hours. Upon the completion of the reaction, saturated ammonium chloride aqueous solution was added thereto, the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and purified by silica gel short column (chloroform). 1,2-Dichlorobenzene (9 mL) was added and the resulting mixture was stirred at 200° C. for 30 minutes. After concentrating the reaction solution, the residue was purified by silica gel column (hexane/ethyl acetate=5/1) to obtain the aimed product (yield: 8%).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([C:13]2[C:18]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([O:22]C)=[O:21])=[C:17]([CH3:27])[N:16]=[C:15]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[N:14]=2)=[CH:5][CH:4]=[C:3]3[CH2:2]1.[OH-].[Na+]>CO>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([C:13]2[C:18]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([OH:22])=[O:21])=[C:17]([CH3:27])[N:16]=[C:15]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)[N:14]=2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c3c(cccc13)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c3c(cccc13)CC2
Yield: 108.6 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(1,2-dihydroacenaphthylen-5-yl)-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.040 g; 0.090 mmol), sodium hydroxide 10N (0.150 mL; 1.50 mmol) in methanol (1.5 mL) at 60° C. for 18 h. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane, followed by a purification by preparative HPLC (HPLC method 1) furnished 0.042 g (100%) of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].O.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1>[OH-].[K+].C(O)C.C(=O)C>[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:2][CH:1]=[O:4])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(=O)O
Agent: CC=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=CC=Cc1ccc2c(c1)OCCO2
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
To a solution which is 5 molar in 2,3-dihydro-1,4-benzodioxin-6-carboxaldehyde of formula XXVII ##STR19## and 0.58 molar in potassium hydroxide in ethanol as the solvent is added acetaldehyde in an amount sufficient to make the solution nominally 4 molar in acetaldehyde, over a period of 20 minutes and while stirring at 10° C. After the mixture is stirred at 10° C. for an additional 10 minutes, it is acidified by the addition of glacial acetic acid. Water is then added and the insoluble oil formed is extracted with ether. The ether solution is washed with water, dried and distilled to yield 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-propenal of formula XXVIII ##STR20##
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:12][CH2:11][N:10]2[C:13](=[O:30])[C:14]3[C:19]4[CH2:20][CH2:21][C:22]([CH:28]=[O:29])=[C:23]([S:24][CH2:25][CH2:26][CH3:27])[C:18]=4[S:17][C:15]=3[N:16]=[C:9]2[CH2:8][CH2:7]1)=[O:5])C.O>C1COCC1.O[K].O.CO>[CH:28]([C:22]1[CH2:21][CH2:20][C:19]2[C:14]3[C:13](=[O:30])[N:10]4[CH2:11][CH2:12][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][C:9]4=[N:16][C:15]=3[S:17][C:18]=2[C:23]=1[S:24][CH2:25][CH2:26][CH3:27])=[O:29]
Reactant: CCCSC1=C(C=O)CCc2c1sc1nc3n(c(=O)c21)CCC(C(=O)OCC)CC3
Agent: O[K]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCSC1=C(C=O)CCc2c1sc1nc3n(c(=O)c21)CCC(C(=O)O)CC3

Procedure:
Compound 22 (130 mg) in THF (2 ml) and 0.7 ml 10% KOH H2O/MeOH (2:1) were stirred over night in room temperature. The reaction mixture was poured into water and washed with ether. The water phase was acidified with HCl and extracted with EtOAc. Organic phase was washed with brine and dried with Na2SO4. After filtration the solvent was evaporated and the product recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].CC#N.O.C(O)(C(F)(F)F)=O>O.C1(C)C=CC=CC=1.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>[Br:13][C:14]1[CH:19]=[C:18]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=2[C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: OB(O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 500 mg of 5-amino-2-bromobenzotrifluoride (Dakwood Products, Inc.), 6.2 mMol 3-bromophenylboronic acid (Aldrich), 70 mg of Pd(PPh3)4 and 5 ml of Na2CO3, 2 M solution in H2O, in 14 ml of toluene is stirred at reflux for 1 our. The mixture obtained is allowed to cool to rt and filtered through a pad of celite. The layers obtained are separated and the aqueous phase obtained is extracted with CH2Cl2. The organic phase obtained is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The concentration residue obtained is subjected to MPLC(CH3CN/H2O/TFA). 3′-Bromo-2-trifluoromethyl-biphenyl-4-amine is obtained. MS: 315.9 [M−1]−; HPLCDtRet=4.9; Rf=0.16 (Hexane/EtOAc, 4:1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:17]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>>[N+:1]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:24]=1[NH:23][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C:28]([O:30][CH3:31])=[O:29])([O-:4])=[O:2]
Reactant: CCCCC(=O)Nc1ccc(C(=O)OC)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Fuming nitric acid (1.4 ml) was added dropwise to acetic anhydride (12 ml) under ice-cooling and then was added conc. sulfuric acid (0.1 ml). To the stirred mixture was added methyl 4-valerylaminobenzoate (2.3 g) under ice-cooling, followed by stirring for one hour. To the resultant mixture was added ice water, and the crystals separated out were recrystallized from ethyl acetate-hexane to give yellow prisms (2.14 g, 76%), m.p. 106-107° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OCC)(OCC)(OCC)[CH3:14]>>[CH3:13][C:14]1[NH:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1N
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nc2cnc3ccccc3c2[nH]1

Procedure:
Using the method of Example 147, 3,4-diaminoquinoline (from Example 39) was reacted with triethyl orthoacetate to provide 2-methyl-1H-imidazo[4,5-c]quinoline as a tan solid, m.p. 242°-245° C.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([C:24]([F:27])=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8].[CH3:29]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[F:28][C:3]1[C:2]([CH3:29])=[CH:26][CH:25]=[C:24]([F:27])[C:4]=1[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(C)c1F
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl) ester (226 mg), tetrakis(triphenylphosphine)palladium (56 mg), trimethylboroxine (122 mg) and potassium carbonate (200 mg) in dioxane (5 mL) was heated to reflux with stirring for 6 h. The cooled was mixture was partitioned between water and ethylacetate. The water phase was extracted once with ethylacetate, organic phases were pooled and dried with Na2SO4 to yield after evaporation a dark oil (259 mg). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate gradient) to yield 160 mg (82%) of a yellow oil. MS (ISP): 416.4 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C@H:9]1[C:17]2[C:16]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:8][C@H:9]1[C:17]2[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11][CH2:10]1
Reactant: C[C@@H]1CCc2ncnc(C3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCc2ncnc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (193 μL, 2.50 mmol) was added to a solution of (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate (32 mg, 0.10 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated to give (R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine as an oil, which was used further without purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:18]2[S:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])=[CH:2]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 102.4 %

Procedure:
The suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (example 1b, 1.2 g, 8.22 mmol), rhodanine (1.09 g, 8.22 mmol) and sodium acetate (2.69 g, 32.8 mmol) in acetic acid (12 mL) was stirred under reflux for 12 h. After cooling to room temperature, water (150 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxo-thiazolidin-4-one (2.2 g, 100%) as a brawn solid. LC-MS m/e 262 (MH+).
Reaction SMILES: [Br:1][C:2]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH2:3].[OH-].[K+].[CH:14]([Br:17])(Br)[Br:15]>C(Cl)Cl>[Br:15][C:14]1([Br:17])[CH2:3][C:2]1([Br:1])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: BrC(Br)Br
Reactant: C=C(Br)COCCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCOCC1(Br)CC1(Br)Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.9 %

Procedure:
A mixture of 5.9 g of 2-bromo-3-hexyloxypropene(26.7 mmol), 2.05 g of N,N′-dibenzyl-ethane-1,2-bis-(diethylammonium bromide), 10.5 g of 45% potassium hydroxide (84 mmol), 23.3 g of bromoform (92 mmol) and 70 g of methylene chloride were rapidly stirred at room temperature for two days. When the reaction stalled, the reaction mixture was transferred to a separatory funnel and washed with water. The methylene chloride phase was transferred to a flask and treated with the same amount of the phase transfer catalyst and 45% potassium hydroxide, then stirred at room temperature for an additional 3 days. The workup-recharge sequence was repeated once more, and the reaction was stirred one more day at room temperature. The reaction mixture was washed with water, the methylene chloride phase was dried with magnesium sulfate, and then stripped. The product was chromatographed on silica gel with 20% ethyl acetate 80% hexane to give 1.35 g of 87% pure 1,1,2-tribromo-2-(hexyloxymethyl)cyclopropane.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([NH:19][CH2:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:19]2[C:16]3([CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20]3)[CH2:17][CH2:18]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN2)C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CCN2S(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 177.9 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-1,6-diaza-spiro[3.3]heptane oxalate (350 mg, 719 μmol) in dichloromethane (6 mL) was added at 0° C. triethylamine (221 μl, 1.58 mmol) followed by 4-fluorobenzene-1-sulfonyl chloride (294 mg, 1.51 mmol). The reaction mixture was stirred at ambient temperature for 15 h. Further 4-fluorobenzene-1-sulfonyl chloride (100 mg, 0.51 mmol) and triethylamine (200 μl, 1.4 mmol) were added, the reaction mixture was stirred at ambient temperature for another 3 h. The reaction mixture was then diluted with dichloromethane 10 mL) and quenched with water (10 mL). The aqueous phase was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; heptane:ethyl acetate 2:1) to give the title compound (456 mg, 89%) as a colorless oil. MS (EI) m/e: 357.1 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:18][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:19][CH3:20])[CH2:9][NH:8][CH2:16]2
Reactant: COc1cc2c(cc1OC)CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1OC)CNC2
Reaction time: 4 h
Yield: 77.3 %

Procedure:
1.20 g (4.46 mmol) of 2-benzyl-5,6-dimethoxyisoindoline was dissolved in 40 ml of methanol at 40° C., and 84 mg of 10% palladium carbon was added thereto. Under a hydrogen stream, catalytic reduction was conducted at the same temperature for 4 hours. The solvent was distilled off under reduced pressure, and a small amount of ethyl acetate and diethylether was added to the residue and stirred. The precipitates were collected to obtain 617 mg (yield: 77.3%) of the above identified compound.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.[CH3:18][NH:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1.CCOCC>[CH3:18][NH:19][S:20]([N:4]1[CH2:5][CH2:6][N:7]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][C:3]21[CH2:1][CH2:2]2)(=[O:22])=[O:21]
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reactant: CNS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CNS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(4,7-Diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (2 g, 8.7 mmol) (intermediate 21) in dry pyridine (100 mL) was cooled to 0° C. and dropwise added a solution of commercial available methylsulfamoyl chloride (419 mg, 8.7 mmol) in dry Et2O (5 mL). After complete addition, the reaction mixture was allowed to warm up to rt and was afterwards stirred at rt for 1 h. An additional equivalent of methylsulfamoyl chloride (419 mg, 8.7 mmol) in dry Et2O (5 mL) was added and after additional 1 h at rt a third equivalent of methylsulfamoyl chloride (419 mg, 8.7 mmol) in dry Et2O (5 mL) was added. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Recrystallised in EtOH:CH2Cl2 affording the title compound as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[F:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:11]4([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCCOC3)Oc3ccc(-c4cccc(F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3-fluorophenylboronic acid (29.3 mg, 0.2 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure product 6-(3-fluorophenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (5 mg, 10%). 1H-NMR (MeOD): 1.70 (m, 3H), 2.01 (m, 3H), 2.49 (m, 0.5H), 2.71 (m, 1H), 3.32 (d, 3H), 3.43 (m, 1H), 3.53 (m, 1H), 3.91 (dd, 2H), 4.19 (m, 2H), 7.03 (m, 2H), 7.32 (d, 1H), 7.43 (m, 2H), 7.66 (t, 1H), 7.89 (s, 1H).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:13][C:14]1[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([OH:24])=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O1CCCC1>[NH2:13][C:14]1[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)=[O:24]
Reactant: CN1CCNCC1
Reactant: Nc1ccccc1Cn1cccc1C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cccn2Cc2ccccc2N)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 3.40 g. of carbonyl diimidazole and 25 ml. of tetrahydrofuran is cooled and 4.32 g. of 1-o-aminobenzyl-2-pyrrolecarboxylic acid is added. The mixture is allowed to stand at 25°-30° C. for 30 minutes and 2.6 ml. of N-methylpiperazine is added. The mixture is allowed to stand 48 hours, then concentrated to about 1/2 volume and treated with ether. The mixture is filtered. The filtrate is evaporated to remove the solvent. The residue is treated with water and methylene chloride. The methylene chloride layer is separated and concentrated and further purified by partition chromatography giving 1-[1-(o-aminobenzyl)-2-pyrrolecarbonyl]-4-methylpiperazine as a viscous oil.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][CH2:8][N:9]([N:13]1[C:17](=[O:18])[C@H:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([NH2:25])=[NH:24])[NH:15][C:14]1=[O:26])[C:10](=[O:12])[CH3:11])(C)(C)C>FC(F)(F)C(O)=O>[NH:22]([CH2:21][CH2:20][CH2:19][C@@H:16]1[NH:15][C:14](=[O:26])[N:13]([N:9]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:7][C:6]([OH:27])=[O:5])[C:17]1=[O:18])[C:23]([NH2:25])=[NH:24]
Reactant: CC(=O)N(CCC(=O)OC(C)(C)C)N1C(=O)N[C@@H](CCCNC(=N)N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(CCC(=O)O)N1C(=O)N[C@@H](CCCNC(=N)N)C1=O
Reaction time: 1 h

Procedure:
1.3 g of [5-(S)-(3-guanidinopropyl)-2,4-dioxoimidazolidin-3-yl]-acetyl-β-alanine tert-butyl ester are dissolved in 15 ml of 90% strength aqueous trifluoroacetic acid. The mixture is left to stand at room temperature for one hour and concentrated. The residue is dissolved in water and extracted by shaking 3 times with diethyl ether. The aqueous solution is filtered off to remove the insoluble material and freeze-dried.