Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7]1=[O:20])[CH3:4].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>>[ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8][C:7]1([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[OH:20])[CH3:4]
Reactant: CN(C)CC1CC(CCc2ccccc2)CCC1=O
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: COc1cccc(C2(O)CCC(CCc3ccccc3)CC2CN(C)C)c1
Yield: 40 %

Procedure:
The base of compound (48) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified firstly with 7:1 ether/methanol via a silica gel column and subsequently via HPLC. It was taken up in 2-butanone and trimethylchlorosilane/water was added, with the addition of ether if necessary. Compound (45) was obtained in a yield of 40% theoretical.
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[Cl:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[C:28]([F:29])([F:30])[F:31])[O:27][CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 167 mg, 0.47 mmol) in dimethylsulfoxide (2 mL) was added 2-chloro-4-hydroxybenzotrifluoride (92 mg, 0.47 mmol) followed by addition of potassium carbonate (129 mg, 0.94 mmol). The reaction was left to stir at room temperature for 18 hours. The reaction was diluted with dichloromethane (20 mL) and washed with aqueous potassium hydrogen sulfate (5 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (30 mL) and filtered through a phase separation cartridge. The solvent was removed under reduced pressure and the crude product purified by reverse phase preparative HPLC. The correct fractions were combined and reduced to dryness to afford the title compound as white solid (23 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:1][C:2]1[C:14]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][S:24]([C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[O:25])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)cc21
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[C:32]([Cl:38])[CH:31]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][CH:11]([NH:10][C:4]3[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:12]2)=[O:19])=[C:32]([Cl:38])[CH:31]=1
Reactant: NCc1ccc(Br)cc1Cl
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nc(C)nc(NC2CCCC(C(=O)NCc3ccc(Br)cc3Cl)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.324 g, 0.855 mmol) in N,N-Dimethylformamide (DMF) (25 ml) was added diisopropylethylamine (0.329 ml, 1.881 mmol) followed by 1-(4-bromo-2-chlorophenyl)methanamine (0.286 g, 0.855 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.416 g, 0.940 mmol). The reaction was stirred at room temperature for 3 hours. Saturated NaHCO3 was added to the reaction, at which time white solids precipitated from solution. The solids were filtered, washed with acetonitrile, and dried to provide N-[(4-bromo-2-chlorophenyl)methyl]-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (160 mg, 0.34 mmol, 40%). MS (ES+): m/e 467, 469 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[N:29]1[CH:30]=[CH:31][N:32]=[CH:33][C:28]=1[NH:27][C:11](=[O:13])[C@@H:10]([N:8]1[CH2:9][C:5]([O:4][C:3]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])[C:2]=2[F:1])=[CH:6][C:7]1=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Reactant: Nc1cnccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Yield: 52.6 %

Procedure:
A solution of (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (prepared as in Example 143, 400 mg, 1.10 mmol), 2-aminopyrazine (208 mg, 2.18 mmol) and carbonyldiimidazole (186 mg, 1.15 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 12 h. At this time the mixture was transferred to an Emrys Optimizer microwave tube and microwaved at 120° C. for 5 h. The mixture was concentrated in vacuo and the residue partioned between ethyl acetate and 0.1N aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, aqueous sodium bicarbonate solution, and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by ISCO flash chromatography (RediSep silica 40 g, 70% to 100% ethyl acetate/hexanes) to afford (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (256 mg, 53%) as an off-white fluffy powder: HR-ES-MS (m/z) calculated for C23H27FN4O4 [M+H]+ 443.2089, observed 443.2088. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=6.8 Hz, 6H), 1.41-1.54 (m, 1H), 1.49 (s, 6H), 1.56-1.73 (m, 1H), 1.73-1.91 (m, 1H), 4.25 (d, J=18.4 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.04 (dd, J=11.0, 4.4 Hz, 1H), 5.42 (br. s., 1H), 7.24 (t, J=7.7 Hz, 1H), 7.32-7.40 (td, J=7.7, 1.5 Hz, 1H), 7.56 (td, J=7.7, 1.5 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.42 (s, 1H), 9.28 (s, 1H), 11.19 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([NH:19]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[S:18])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CNC(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-[({[(fluoren-9-ylmethoxy)carbonylamino]thioxomethyl}amino)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester (1896 mg, 3.69 mmol) in DMF (15 ml), piperidine (1.8 ml, 18.5 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, water (100 ml) was added and extraction was performed with ethyl acetate (100 ml×3 times). The extracted organic layer was washed with water (300 ml×2 times) and then with saturated brine; dried over anhydrous sodium sulfate, and then filtered and concentrated. It was subsequently purified by silica gel column chromatography (hexane/ethyl acetate=1/1, ethyl acetate) to obtain 4-{[(aminothioxomethyl)amino]methyl}-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by LC-MS. Yield: 900 mg (84%), M+1=292.1
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:36])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([C:16]3[N:21]=[C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]5[CH2:34][CH2:33][O:32]C5=O)[CH2:24][CH2:23]4)[CH:19]=[CH:18][CH:17]=3)[CH:7]=[CH:6][C:5]1=2>CO>[CH3:3][C:4]1([CH3:36])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([C:16]3[N:21]=[C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][CH2:34][CH2:33][OH:32])[CH2:24][CH2:23]4)[CH:19]=[CH:18][CH:17]=3)[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCN(CCN5CCOC5=O)CC4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCN(CCNCCO)CC4)n3)ccc21

Procedure:
450 μl of 1 N NaOH were added to 70 mg (0.15 mmol) of 3-(2-{4-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazin-1-yl}ethyl)oxazolidin-2-one in 2 ml of methanol, and the mixture was refluxed for 3 days. The reaction mixture was evaporated, extracted with ethyl acetate, dried and evaporated. The crude product was purified by means of pep. HPLC.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:26](OCCC(C)C)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[N:9]([C:10](=[O:12])[CH3:11])[N:26]=[CH:13]2
Reactant: CC(=O)Nc1cc(F)c(Br)cc1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2cc(Br)c(F)cc21
Reaction time: 3 h

Procedure:
To a solution of 77.0 g of N-(4-bromo-5-fluoro-2-methylphenyl)acetamide in 930 mL of toluene were added 93.0 mL of acetic anhydride and 37.0 g of potassium acetate at room temperature, and the resultant solution was heated at 90° C., slowly added dropwise with 67.0 mL of isoamyl nitrite, and stirred at this temperature for 3 hours. After diluting with ethyl acetate, washing successively with water and saturated brine, and drying over anhydrous magnesium sulfate, the solvent was evaporated. The precipitated crystals were washed with diethyl ether:n-hexane=1:10, the filtrate concentrated and purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=0:100-1:5) and finally combined with the previous crystals, to afford 22.5 g of the title compound as pale brown crystals.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17].CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[C:19]1([C:16](=[O:18])[CH2:17][C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2ccccc2c1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cnc2ccccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethyl-3-quinolinate (0.50 gm, 0.0025 mole) and acetophenone (0.30 gm, 0.0025 mole) was added to an ice-cold suspension of potassium tertiary butoxide in THF (5.0 ml). The reaction mixture was stirred at room temp. for 2 hours, acidified with a dilute acetic acid (10%). The resulting solid was filtered, air dried and recrystallised from boiling ethyl acetate to yield the desired product as a pale yellow colour solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Cl[CH2:10][CH2:11][N:12]([CH2:20][CH2:21]Cl)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:12]1[CH2:20][CH2:21][C:6]([C:7]#[N:8])([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CCc1cccs1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccs2)CC1

Procedure:
Prepare by the method of example 30.2 using 2-thiopheneacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol). Purify to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([Br:28])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(S(=O)(=O)C2CCOCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Yield: 37.1 %

Procedure:
[4-(Tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (1.60 gm, 5.36 mmol), NBS (1.04 g, 5.90 mmol) and benzoyl peroxide (0.130 g, 0.53 mmol) in carbon tetrachloride (50 ml) was refluxed for 7 hrs. Reaction mixture was diluted with DCM (50 ml), washed with water and brine (100 ml each), dried over anhydrous sodium sulfate, fliltered and concentrated. Crude compound was purified by column chromatography over silica gel using 30% ethyl acetate hexane as eluent to give the pure bromo-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.75 gm).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([Cl:22])[N:8]=1.CN(CCN(C)C)C.[CH3:31][C:32]([CH3:34])=[O:33]>C1COCC1>[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([C:32]([OH:33])([CH3:34])[CH3:31])[N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([Cl:22])[N:8]=1
Reactant: CC(C)=O
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 61.8 %

Procedure:
BuLi (20 mL, 40.0 mmol, 2 M in pentane) was added dropwise to a solution of 2,6-dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine (8.0 g, 29.3 mmol) and TMEDA (6.4 mL, 42.4 mmol) in anhydrous THF (100 mL) at −78° C. The resulting dark solution was stirred at −78° C. for 45 min, then acetone (4 mL, 54.5 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min, then at RT for 30 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 20% ethyl acetate in cyclohexane) affording 2-[2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-propan-2-ol as a dark solid (6.0 g, 62%). 1H NMR (400 MHz, CDCl3); δ 6.19 (1H, dd, J=11.2, 2.8 Hz), 4.26 (1H, m), 3.77 (1H, m), 2.87 (1H, m), 2.09 (1H, m), 1.90-1.71 (11H, m).
Reaction SMILES: Cl.CN(C=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:8]=1)C>>[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:8]=1
Reactant: CN(C)C=Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Agent: Cl
Product: Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
To a solution of 10% 1N HCl in doxane (3 mL) was added benzenesulfonic acid 4-(dimethylamino-methyleneamino)-5-fluoropyrimidin-2-yl ester (0.090, 0.3 mmol) and the mixture was agitated on an orbital shaker at room temperature for 1.5 h. The solvent was removed by evaporation and the residue was dissolved in a 1:1 solution of dioxane and water (2.5 mL) and treated with saturated aq NaHCO3 (0.5 mL). After 16 h, the reaction mixture was partitioned between EtOAc and water and the organic phase was dried over Na2SO4, filtered, and the solvent evaporated to yield the title compound (0.059 g, 79% yield) as a white solid: mp 139-141° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.05-8.00 (m, 3H), 7.90-7.75 (m, 3H), 7.70-7.63 (m, 2H); HPLC-MS (ESI) m/z 268 (M−H)−, 270 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@@H:13]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:14]([NH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)=[O:15]>>[CH2:22]([N:19]1[CH2:20][CH2:21][C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10]([NH:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[O:11])[C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)[C@H](N)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C=Nc1cc(F)ccc1F
Product: CC(C)(C)[C@H](NC(=O)Nc1cc(F)ccc1F)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
Compound 3d was prepared from 2,5-difluorophenyl isocyanate and compound 2a using the method described in Example 9. MS (EI)=444 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[S:27][C:26](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:30](=[O:31])[CH:29]=[CH:28][C:26]4[S:27][C:23]([Cl:22])=[CH:24][CH:25]=4)[C@@H:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C(O)/C=C/c1ccc(Cl)s1
Product: CC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C=Cc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-ethyl-piperazine-2-one, EXAMPLE 77 and 3-(5-chloro-thiophen-2-yl)-(E)-acrylic acid, EXAMPLE 25. 1H NMR(d6-DMSO+1 drop TFA, 300 MHz) δ9.78 (bs, 2H), 8.79 (s, 1H), 8.37 (d, 1H), 7.65 (m, 2H), 7.50 (s, 1H), 7.41 (m, 1H), 7.11 (d, 1H), 6.98 (d, 1H), 4.88 (m, 2H), 4.60 (m, 1H), 4.31 (m, 1H), 3.52 (m, 1H), 3.30 (m, 2H), 1.96 (m, 2H), 0.88 (m, 3H). MS (ion spray), m/z, (M+H)=456, 458 (Cl pattern). Elemental analysis, cal C22H22ClN5O2S.1.5C2HF3O2% C=47.89, % H=3.78, % N=11.17; found % C=47.34, % H=4.00, % N=11.12.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([O:25]C)[N:15]3[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:11]([NH2:27])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:27][C:11]1[N:10]=[C:9]([O:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:17]=[C:16]2[C:12]=1[NH:13][C:14](=[O:25])[N:15]2[CH2:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(OCC2CCCCC2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (RS105369-181A2) (0.1657 g) was dissolved in methanol (5 mL) and then added 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then evaporated under reduced pressure to give a solid that was then suspended in water (1 mL) and methanol (˜2-3 mL) before being neutralised (to pH 7) by the addition of 2N sodium hydroxide. The resultant mixture was evaporated to near dryness before being suspended in water (3 mL) and the solid is filtered off under suction. This solid was then washed with a few drops of methanol and then air-dried under suction before finally being dried to constant weight under vacuo at 50° C. This gave the title compound as a white solid (134 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([F:20])[CH2:19][O:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH2:28][O:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([C:4]3[S:3][C:2]([NH:1][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([CH2:28][O:29][CH2:30][C:31]([OH:33])([CH3:32])[CH3:34])[N:27]=4)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=3)=[CH:11][CH:12]=2)[CH2:17][O:18][CH2:19]1
Reactant: NC(=O)c1cc(-c2ccc(C3(F)COC3)cc2)sc1N
Reactant: CC(C)(O)COCc1cccc(Br)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)COCc1cccc(Nc2sc(-c3ccc(C4(F)COC4)cc3)cc2C(N)=O)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Amino-5-[4-(3-fluorooxetan-3-yl)phenyl]thiophene-3-carboxamide (88 mg, 0.301 mmol), 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (Example 217 Step 1) (78 mg, 0.301 mmol), Pd2dba3 (27.6 mg, 0.030 mmol), K2CO3 (45.8 mg, 0.331 mmol) and X-Phos (71.8 mg, 0.151 mmol) were added to a 5 mL microwave vial. Degassed tert-amyl alcohol (0.6 mL) was added and the vial evacuated and back-filled with N2 (3×). The resulting mixture was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with methanol, silica gel was added, and the solvent was removed in vacuo. Purification of the residue by flash chromatography (silica, 0-10% MeOH-DCM) followed by flash chromatography (silica, 12-100% EtOAc-hexanes) gave the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:58]=[CH:57][C:5]([CH2:6][CH:7]2[CH2:16][N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11][CH2:10][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[N:8]2S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1.[BrH:59].[C:60](O)(=O)[CH3:61]>C(OCC)C>[BrH:59].[BrH:59].[BrH:59].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:61][CH2:60][NH:8]2)=[CH:57][CH:58]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC(Cc3ccc(O)cc3)N(S(=O)(=O)c3ccc(C)cc3)N(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CCOCC
Product: Oc1ccc(CC2CNCCNCCNCCN2)cc1

Procedure:
12.0 g (12.7 mmol) of 2-(4-hydroxybenzyl)-1,4,7,10-tetra-tosyl-1,4,7,10-tetraazacyclodecane is heated in 50 ml of glacial acetic acid with 33% of hydrogen bromide for four hours to 100° C. It is poured into 300 ml of diethyl ether, suctioned off and resuspended twice in 300 ml of diethyl ether each. All operations are performed under nitrogen protective atmosphere. After drying in a vacuum, 5.16 g (78% of theory) is present of colorless crystals, which melt with decomposition at 115°-117° C.