Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:29][N:30]([CH3:40])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])(C(C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[OH:26][CH2:27][CH:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:29][N:30]([CH3:40])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]
Reactant: CN(CC(CO[Si](C)(C)C(C)(C)C)c1ccccc1)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CC(CO)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A THF solution of tetrabutylammonium fluoride (1.0 M, 3.9 mL, 3.9 mmol) was added to dropwise to a solution of N-(3-(tert-butyldimethylsilyloxy)-2-phenylpropyl)-N-methylbenzenesulfonamide (570 mg, 1.31 mmol) in 5.0 mL of THF. After stirring for 30 min at room temperature, the mixture was diluted with 50 mL of ethyl acetate and washed in sucession with 30 mL of 2.0 N aqueous HCl, 30 mL of saturated aqueous sodium bicarbonate, and 30 mL of brine. The organic layer was dried over sodium sulfate, decanted and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 20-30% of ethyl acetate in hexanes to give 393 mg of the title compound as a colorless syrup. 1NMR (400 MHz, CD3OD): δ 7.74 (d, 2H, J=7 Hz), 7.64 (tt, 1H, J=7, 1 Hz), 7.56 (t, 2H, J=7 Hz), 7.33-7.20 (m, 5H), 3.79-3.71 (m, 2H), 3.41 (dd, 1H, J=13, 7 Hz), 3.24 (dd, 1H, J=13, 8 Hz), 3.13-3.04 (m, 1H), 2.58 (s, 3H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:40]([O:42][C:43]([C:45]1([NH2:54])[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH3:41].CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C(Cl)Cl>[CH2:40]([O:42][C:43]([C:45]1([NH:54][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH3:41]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 133.6 %

Procedure:
A 25 mL vial containing a stirring bar is charged with 2-cyclobutoxy-3-methyl-benzoic acid (1.01 g, 4.87 mmol) and dry DCM (14 mL). Stirring is initiated. HBTU (1.84 g, 4.86 mmol) is added. After 5 min, the 2-aminoindane-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) is added followed by the DIPEA (1.9 mL, 10.92 mmol). The reaction is allowed to stir for 12 days. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (70 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous HCl (3%, 35 mL), saturated aqueous NaHCO3 (35 mL) and brine (35 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 2.56 g of an off-white solid. This material is dissolved in 15 mL of DCM. This is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% over 10 column volumes and then 100% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 7 through 22 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 1.73 g.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15]([OH:23])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.C(=O)([O-])[O:25][CH2:26][CH2:27]Cl>N1C=CC=CC=1>[C:26]([NH:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1)(=[O:25])[C:27]1[CH:3]=[CH:4][CH:7]=[N:8][CH:9]=1
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Reactant: O=C(O)c1cccnc1
Reactant: O=C([O-])OCCCl
Solvent: c1ccncc1
Product: O=C(Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1)c1cccnc1
Temperature: 60 °C
Yield: 64.5 %

Procedure:
1.9 g of benzoguanamine and 2.6 g of nicotinic acid are dissolved in 50 ml of pyridine and mixed with 2.2 g of chloroethyl carbonate. After heating the mixture at 60° C with agitation for 3 hours, it is processed as described in Example 4 to yield 1.3 g of 2,4-bis(nicotinamido)-6-phenyl-s-triazine [dinicotinoylbenzoguanamine].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([C:39]2[CH:40]=[N:41][C:42]([O:45][CH:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:43][CH:44]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([C:39]2[CH:40]=[N:41][C:42]([O:45][CH:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[CH:43][CH:44]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCOCC3)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCOCC3)nc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogen carbonate (0.4 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-6-oxo-4-propyl-1-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.25 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL) N,N′-carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.18 g, 64%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:27][C:28]1[N:29]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[S:31][C:32]=1[CH:33]=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>O1CCCC1.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH:16]=[CH:33][C:32]2[S:31][C:30]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)=[N:29][C:28]=2[CH3:27])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[4-(benzyloxy)-3-methylphenyl]ethanone (intermediate 8, 1.15 g) in dry tetrahydrofuran (15 ml) at −78° C. was treated dropwise with lithium diisopropylamide (2.6 ml of 2M solution in heptane/tetrahydrofuran/ethylbenzene) under nitrogen. The reaction mixture was warmed to 0° C. for 30 minutes. The mixture was cooled to −78° C. and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (intermediate 2, 1.08 g) in dry tetrahydrofuran (15 ml) was added drop-wise at −78° C. and the reaction mixture stirred at 21° C. for 2 hours. Acetic acid (4 ml) in dry tetrahydrofuran (4 ml) was added followed by toluenesulphonic acid (0.1 g) and the reaction mixture was heated at 50° C. for 1 hour and then concentrated. The residue was partitioned between saturated bicarbonate solution and ethyl acetate; the aqueous layer separated and extracted thrice more with ethyl acetate. The organic solutions were combined and were dried with brine and over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by flash chromatography using cyclohexane:ethyl acetate (6:1) as eluent to give the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>CO>[C:7]([CH:6]1[NH:5][CH:4]=[N:3][C:2]1=[N:1][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:8]
Reactant: O=Cc1ccccc1
Reactant: N#Cc1[nH]cnc1N
Solvent: CCOCC
Solvent: CO
Product: N#CC1NC=NC1=NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a stirred solution of 4-amino-1H-imidazol-5-carbonitrile (1.1 g, 0.01 mole) in 25 ml of methanol was added 1.1 grams of benzaldehyde. The reaction mixture was then stirred at ambient temperature for 16 hours, heated on a steam bath for 20 minutes, cooled to ambient temperature, then stirred with 25 ml of diethyl ether. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was recrystallized from toluene-butanol to give 5-cyano-4-phenylmethylimino-1H-imidazole (0.92 g; mp, 200°-202°).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:8]1.Br[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:20]([N:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:8]1)[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrC/C=C/c1ccccc1
Reactant: CCOC(=O)/C=C/c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cnn(CC=Cc2ccccc2)c1
Temperature: 40 °C
Yield: 75.8 %

Procedure:
Cesium carbonate (0.490 g, 1.5 mmol) was added to a solution of (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.167 g, 1 mmol) in ACN (8 mL) at room temperature. The suspension was stirred and 1-((E)-3-bromoprop-1-enyl)benzene (0.256 g, 1.30 mmol) was added. The mixture was heated at 40° C. overnight. After cooling down to room temperature, the precipitated solids were filtered off. The filtrate was concentrated and purified by silica gel column chromatography using a 0-60% gradient of EtOAc in hexanes to provide the title compound as a colorless oil (0.214 g, 76%). ES+(M+H)+283
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10])[CH:5]=[C:17]([C:16](=[O:21])[CH3:15])[C:18](=[O:20])[CH3:19]
Reactant: O=Cc1cc(O)c(O)c(C(F)(F)F)c1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1cc(O)c(O)c(C(F)(F)F)c1)C(C)=O

Procedure:
The procedure described in Example 7 was repeated using 2.06 g of 3,4-dihydroxy-5-trifluoromethyl-benzaldehyde and 1.00 g of 2,4-pentanedione. Yield 1.39 g (45%), m.p. 198°-205° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH2:9]=[CH:10][CH:11]=[CH2:12]>>[CH2:12]([C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[CH:1][C:2]=1[CH3:8])[CH2:11][CH:10]=[CH2:9]
Reactant: Cc1cccc(O)c1
Reactant: C=CC=C
Product: C=CCCc1ccc(O)cc1C

Procedure:
As shown in Reaction Scheme 1, meta-cresol (m-CH3C6H4OH) is reacted with butadiene (C4H6) to form 4-(but-3-enyl)-3-methylphenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:42][CH2:41]2)[CH2:36][CH2:35]1.O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:44][CH2:45]2)[CH2:36][CH2:35]1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)c(C)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 65.9 %

Procedure:
5-Fluoro-4-methyl-2-nitrophenyl methyl ether (2.76 g, 14.9 mmol) was dissolved in DMSO (50 mL), and K2CO3 (10.3 g, 74.5 mmol) and phenylmethyl 4-(4-piperidinyl)-1-piperazinecarboxylate bis(trifluoroacetate) salt (Example 112, step B) (8.0 g, 15 mmol) were added. Reaction was stirred overnight. Poured into H2O and extracted (2×) with EtOAc. Combined organic layers were back-extracted (5×) with H2O and then dried over MgSO4, filtered, concentrated on to silica gel and flash chromatographed to give the title compound of step C (4.6 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (s, 1H), 7.03-7.46 (m, 5H), 6.64 (s, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.06-3.59 (m, 6H), 2.67 (t, J=11.5 Hz, 2H), 2.26-2.57 (m, 5H), 2.15 (s, 3H), 1.81 (d, J=11.5 Hz, 2H), 1.36-1.68 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([S:19][CH3:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][C:10]=3[N:11]=[C:12]([S:19][CH3:20])[N:13]=2)=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Solvent: CC#N
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Yield: 59.7 %

Procedure:
The solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine (915 mg, 3 mmol) from Example 24. B. and 4-tert-butylaniline (537 mg, 3.6 mmol) in acetonitrile (5 mL) was irradiated in microwave at 180° C. for 10 min. Solid thus formed was filtered out and washed by hexanes. Product was obtained as a light brown solid (750 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[N:17]1([C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27](O)=[O:28])[CH:21]=[CH:20][CH:19]=[CH:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:27]([C:23]4[S:24][CH:25]=[CH:26][C:22]=4[N:17]4[CH:21]=[CH:20][CH:19]=[CH:18]4)=[O:28])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1sccc1-n1cccc1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4sccc4-n4cccc4)CC3C2)n1
Yield: 71.7 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 3-pyrrol-1-yl-thiophene-2-carboxylic acid (58.4 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (79.0 mg, 73%). MS (ESI) mass calcd. for C21H23N5OS, 393.51; m/z found [M+H]+. 1H NMR (CDCl3): 7.42-7.39 (m, 1H), 7.04-7.01 (m, 1H), 6.85 (t, J=2.1, 2H), 6.29 (s, 1H), 6.14 (t, J=2.1, 2H), 3.88-3.73 (m, 2H), 3.66-3.52 (m, 2H), 3.50-3.41 (m, 1H), 3.32-3.20 (m, 1H), 3.00-2.86 (m, 2H), 2.80-2.66 (m, 1H), 2.60-2.47 (m, 1H), 2.34-2.25 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][N:8]=1)([O-])=O.[BH4-].[Na+]>CO.O.[Pd]>[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[NH2:1])[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1nccn1CCN1CCOCC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1nccn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
The product from Step 1 (0.64 g, 2.81 mmol) is suspended in methanol (20 mL) and water (2 mL). Palladium on carbon (0.065 g, 0.281 mmol) is added and the mixture is degassed with nitrogen for 10 min before sodium borohydride (0.15 g, 3.93 mmol) is added portion-wise. The reaction is cooled with an ice bath and after 30 mins warmed to room temperature and stirred for 16 h at room temperature. The palladium is filtered through celite and washed with methanol (3×30 mL). The filtrate is concentrated in vacuo and the residue partitioned between dichloromethane (100 mL) and water (10 mL). The aqueous layer is extracted with dichloromethane (5×50 mL+1 mL MeOH). The organic layers are combined, dried (MgSO4) and solvent removed in vacuo to give an orange oil (0.42 g, 77%). NMR (400 MHz, CDCl3) =2.47-2.60 (m, 4H), 2.64-2.66 (m, 2H), 3.62-3.72 (m, 4H), 3.77-3.83 (m, 2H), 4.76 (brs, 2H), 6.49 (s, H), 6.61 (s, 1H).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:4]1(=[O:12])[N:5]([CH2:6][CH3:7])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12.[C:19]1([NH:18][SH:8](=[O:10])=[O:9])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)c2ccccc2C1=O
Product: O=[SH](=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
2-Phthalimidoethanesulfonyl chloride (2.0 g) was added in portions to a solution of aniline (2.3 g) in chloroform (15 ml) and the resulting mixture was stirred at room temperature for 16 hours. The organic phase was then washed with water and 1 M HCl. Removal of the solvent gave the crude product as a solid that was recrystallised from EtOH to yield 1.76 g (65%) of the title compound as a solid. 1H-NMR (CDCl3) δ (ppm) 7.87-7.83 (m, 2H), 7.77-7.70 (m, 2H), 7.32-7.10 (m, 5H), 4.09-4.03 (m, 2H), 3.47-3.41 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Na].[H-].[Na+]>CN(C)C=O>[N:23]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCn1ccnc1

Procedure:
A 99.0 g amount of 2-(10-bromodecyl)-1H-isoindole-1,3(2H)-dione (prepared as described above) was dissolved in 300 ml of warm N,N-dimethylformamide with stirring. This solution was added to a stirred solution of 1H-imidazole, sodium salt (prepared by stirring a mixture of 20 g of imidazole and 14.0 g 50% sodium hydride in 500 ml of N,N-dimethylformamide at room temperature for 48 hours). The resulting mixture was heated on a steam bath for 14 hours, then taken to dryness in vacuo. The residue was partitioned between 500 ml of dichloromethane and 250 ml of water. The organic layer was washed with 250 ml of water, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave 85.4 g of 2-[10-(1H-imidazol-1-yl)decyl]-1H-isoindole-1,3(2H)-dione as an oil which solidified on standing at room temperature.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:15][NH2:16].CCN=C=NCCCN(C)C.CN(C=[O:32])C>CN(C1C=CN=CC=1)C>[CH3:11][CH:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:15]([NH2:16])=[O:32]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
BOC-β-alanine (0.50 g, 2.64 mmol) was dissolved in 4 mL DMF. Methylamine hydrochloride (198 mg, 2.93 mmol) and DMAP (427.2 mg, 3.50 mmol) were added, followed by EDCI (1.06 g, 5.53 mmol). After stirring at room temperature for 2 days the solvent was removed in a stream of nitrogen and the residue dried in vacuo. It was dissolved in 5 mL 1 M HCl, and the solution was extracted five times with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to yield 0.43 g (2.13 mmol, 81%) of BOC-β-alanine methylamide (14) as a white solid. mp. 117-118° C., 1H-NMR (300 MHz, CDCl3) δ 5.78 (b, NH), 5.15 (b, NH), 3.38 (q, J=6.1 Hz, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.36 (t, J=6.1 Hz, 2H), 1.40 (s, 9H) 13C-NMR (75.5 MHz, CDCl3) δ 171.74(C), 79.15 (C), 36.41 (CH2), 36.03 (CH2), 28.17 (3 CH3), 26.04 (CH3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH:37][CH3:38]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CNCCOC
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COCCN(C)CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and N-(2-methoxyethyl)methylamine (TCI America) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2447, observed 539.2449.