Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25]>ClCCCl.CCOC(C)=O>[CH3:27][O:26][C:24](=[O:25])[NH:13][C:12]1[CH:14]=[CH:15][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 104.3 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (150 mg, 0.685 mmol) and pyridine (0.277 mL, 3.43 mmol) in 1,2-dichloroethane (3.5 mL) was added methyl chloroformate (0.058 mL, 0.754 mmol) at 0° C. and stirred at 60° C. for 6 hours. The mixture was diluted with AcOEt, washed with 1N HCl, brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated to afford the desired product (198 mg, quant) as a pale yellow oil. 1HNMR (CDCl3) 400 MHz δ: 7.75 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.64 (br s, 1H), 3.78 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:5]=2[N:4]=1.[CH3:14][Si:15]([CH3:20])([CH3:19])[C:16]#[C:17][CH3:18]>>[F:13][C:11]1[CH:10]=[CH:9][C:6]2[N:7]([CH3:8])[C:3]([CH2:2][CH2:18][C:17]#[C:16][Si:15]([CH3:20])([CH3:19])[CH3:14])=[N:4][C:5]=2[CH:12]=1
Reactant: Cn1c(CCl)nc2cc(F)ccc21
Reactant: CC#C[Si](C)(C)C
Product: Cn1c(CCC#C[Si](C)(C)C)nc2cc(F)ccc21
Yield: 99.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (270 mg, 1.36 mmol) and trimethyl(prop-1-ynyl)silane (183 mg, 1.63 mmol). The crude residue was used in the next step without any purification. 5-fluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (373 mg, Yield: 100%) as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>C1COCC1.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11]2)=[N:16][CH:17]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc([N+](=O)[O-])cn2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cn2)C1
Yield: 100.5 %

Procedure:
To a solution of tert-butyl methyl(1-(5-nitropyridin-2-yl)pyrrolidin-3-yl)carbamate (1.02 g, 3.2 mmol) in THF (50 mL) was added Pd/C (10 wt. %, 500 mg). The reaction mixture was stirred under 1 atm of hydrogen for 16 h, filtered through celite and concentrated to afford the desired product (940 mg, 100%) as a red oil. ESI MS m/z 293 [C15H24N4O2+H]+
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:33][CH:34]([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:20][C:2]([CH3:21])([CH3:1])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:37]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])=[O:12])=[O:4]
Reactant: CC(C)CCNCCC(C)C
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N(CCC(C)C)CCC(C)C)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 18.0 μL di-iso-amylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 70-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.67 min. (m/Z=430.4, 346.2, 452.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13](O)=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:13]1[C:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:17][N:16]=[C:15]([CH3:18])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2O)cc1
Product: COc1ccc(S(=O)(=O)c2cnc(C)nc2Cl)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 5-(4-methoxy-benzenesulfonyl)-2-methyl-pyrimidin-4-ol (200 mg, 0.714 mmol) in phosphorus oxychloride (4 mL) was refluxed under N2 for 2 h and then cooled to room temperature. Solvents were removed in vacuo, and the residue was poured into ice water with stirring. The mixture was neutralized with saturated sodium bicarbonate to pH˜7 and extracted with methylene chloride (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:1 ethyl acetate/hexanes) to provide 4-chloro-5-(4-methoxy-benzenesulfonyl)-2-methyl-pyrimidine (177 mg, 83%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 7.93 (d, J=7.2 Hz, 2H), 7.01 (d, J=7.2 Hz, 2H), 3.89 (s, 3H), 2.77 (s, 3H); ESI MS m/z 299 [(M+H)+, calcd for C12H12ClN2O3S, 299.0].
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][CH2:12][CH:11]=[CH:10][O:9][CH2:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.[OH-:17].[Na+].OO>C1COCC1>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:8][O:9][CH2:10][CH:11]([OH:17])[CH2:12][CH2:13]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1
Reactant: [OH-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC=COC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(O)COC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
Borane dimethyl sulfide complex (2.0 mol/L) in THF (0.91 mL, 1.82 mmol) was added to a solution of 1-methyl-4-nitro-5-(2,3,4,5-tetrahydrooxepin-3-yl)pyrazole (204 mg, 0.91 mmol) in anhydrous THF (8 mL) at 0° C. The mixture was stirred at 0° C. for 15 min then warm to RT for 2 h. 1M NaOH (1.5 mL) and hydrogen peroxide (30 mass % in water) (0.8 mL) were added and the mixture was stirred at RT for 2 h. The reaction was quenched with water and extracted with DCM (2×) and EA (1×). Combined organic layers were washed with brine (10 ml) and concentrated to dryness. The residue was purified via silica gel chromatography (0-100% EtOAc/heptane) to afford 6-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol (53 mg, 24%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:36](=[O:49])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55](Cl)=[O:56]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:55](=[O:56])[CH2:54][CH2:53][CH2:52][CH2:51][Br:50])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:49])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[S:38]3(=[O:39])=[O:40])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C(Cl)CCCCBr
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N)cc4)cc3)cc2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(NC(=O)CCCCBr)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (74 mg, 0.1 mmol) was treated as described in general procedure U using 5-bromovaleryl chloride (40 mg, 0.2 mmol) to give the intermediate 5-bromo-pentanoic acid [4′-(4-(2,4-dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-amide, which was treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (46 mg, 0.3 mmol) at 0° C. in 1 mL anhydrous DMF (stirring at room temperature under nitrogen over night), followed by regular ethyl acetate/water workup and silica gel column chromatography to give 1-[4′-(4-(2,4-dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperidin-2-one, which was finally treated as described in general procedure W to give the desired compound 1-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperidin-2-one.
Reaction SMILES: Br[C:2]1[C:3]([S:8][CH2:9][C:10]([O:12]C)=[O:11])=[N:4][CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]#[N:33])=[CH:24][CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1>[C:32]([C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([C:2]2[C:3]([S:8][CH2:9][C:10]([OH:12])=[O:11])=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:23][CH:24]=1)#[N:33]
Reactant: CC1(C)OB(c2ccc(C#N)c3ccccc23)OC1(C)C
Reactant: COC(=O)CSc1ncncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cncnc2SCC(=O)O)c2ccccc12
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of methyl 2-(5-bromopyrimidin-4-ylthio)acetate (220 mg, 0.84 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (237 mg, 0.85 mmol) palladium tetrakis triphenylphoshine (46 mg, 0.04 mmol) and aqueous sodium carbonate solution (2M, 1.5 mL, 3 mmol) in dioxane (3 mL) was heated to 100° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and aqueous sodium hydroxide solution added (1M, 30 mL). The mixture was washed with ethyl acetate (2×20 mL), and the aqueous layer acidified to pH 4 resulting in formation of a precipitate which was isolated by filtration and dried under vacuum to yield 2-(5-(4-cyanonaphthalen-1-yl)pyrimidin-4-ylthio)acetic acid (143 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH:15]=[O:16])[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[C:12]1[CH:11]=[N:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]=1[CH3:14]
Reactant: OCCO
Reactant: COc1ccc(-n2ncc(C=O)c2C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2ncc(C3OCCO3)c2C)cc1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 1-(4-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbaldehyde (0.5 g, 2.3 mmol), ethylene glycol (1.44 g, 23.1 mmol) and p-toluenesulfonic acid (0.2 g, 1.2 mmol) in toluene (10 mL) was refluxed for 18 h (Dean Stock to remove water formed). After it was allowed to cool to room temperature, the reaction mixture was diluted with ethyl acetate, washed with sat. NaHCO3 (aq) and brine, and dried over Na2SO4. After concentrated, the residue was purified by a column chromatography on silica gel to yield the title compound (0.35 g, 58%); MS (APCI) m/z: 261 (M+1, 80).
Reaction SMILES: CC(C)C(C1C=CC=CC=1)C([NH:6][C@@H:7]1[C@H:14]2[C@H:10]([CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13]2)[CH2:9][CH2:8]1)=O.C(N(CC)CC)C.[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>ClCCl>[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([S:48]([NH:6][C@@H:7]2[C@H:14]3[C@H:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=4)[CH2:13]3)[CH2:9][CH2:8]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3aS*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E (200 mg, 0.703 mmol) in dichloromethane (2 mL) was added triethylamine (0.147 mL, 1.055 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.124 mL, 0.774 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organics were reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compounds were eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][O:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][O:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2COCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2COCCO2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
103 mg (0.17 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoyl}amino)benzoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 2. Yield: 60 mg (64% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH2:33]>>[CH2:31]([NH:34][C:35]([NH:30][C:29]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[N:13][C:12]=2[N:28]=1)=[O:36])[CH:32]=[CH2:33]
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 26.2 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.186 g of allyl isocyanate according to the general procedure of Example 37. The product was purified by chromatography and crystallized from ethyl acetate to give 0.31 g of 1-allyl-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=529 (Base), 472, 446; mp 104°-108° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 89.1 %

Procedure:
A solution of ethyl 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperidine-4-carboxylate (1.12 g, 3.53 mmol), an aqueous 2 N sodium hydroxide solution (4 ml), tetrahydrofuran (20 ml) and ethanol (12 ml) was stirred at 80° C. for 1 hour. Thereto 2 N hydrochloric acid (4 ml) was added and the solvent was distilled off under reduced pressure. The residue was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to yield 910 mg (89.2%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C].[Pd].O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A mixture of ethyl (E)-3-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)propenoate (2.70 g), 5% palladium-carbon (3.00 g) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at room temperature for 3 hrs. Palladium-carbon was filtered off and the filtrate was concentrated. The obtained crystals were collected by filtration to give ethyl 3-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)propionate (1.78 g, yield 89%), which was then recrystallized from ethyl acetate-hexane. melting point: 123–124° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.Br[CH:33]([CH2:41][CH2:42]Br)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:37]([O:36][C:34]([CH:33]1[CH2:41][CH2:42][N:1]1[C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CCN1[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 9 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (300 mg, 0.69 mmol) in DMF (3 mL) were added t-butyl 2,4-dibromobutyrate (322 μL, 1.5 mmol) and DIPEA (297 μL), 1.7 mmol). The reaction mixture was stirred at 60° C. for 9 h. The reaction mixture was then diluted with EtOAc and washed with 1M Na2CO3, water (×4) and brine. The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 116 mg of 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidine-2-carboxylic acid tert-butyl ester.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)(=O)=O)=CC=1.[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:28][C@@:26]1([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[C:59]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([OH:71])=[CH:67][CH:66]=2)[CH:58]=1)[OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[O:28][C@@:26]1([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[C:59]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[CH:67][CH:66]=2)[CH:58]=1)[OH:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(OC2CCOC2)cc1

Procedure:
0.10 g tetrahydrofuran-3-yl toluene-4-sulphonate are added to a mixture of 0.24 g 1-(2,3,4,6-tetra-O-benzyl-(β-D-glucopyranos-1-yl)-3-(4-hydroxy-benzyl)-4-methyl-benzene and 0.13 g caesium carbonate in 2.5 ml of dimethylformamide. The mixture is stirred for 4 h at 65° C., before water is added. It is extracted three times with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is removed. The residue is purified through silica gel purified (cyclohexane/ethyl acetate 10:1->4:1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:35]=[CH:34][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][S:28]([CH:31]5[CH2:33][CH2:32]5)(=[O:30])=[O:29])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:1]1[CH:5]=[C:4]([C:6]2[CH:35]=[CH:34][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][S:28]([CH:31]5[CH2:32][CH2:33]5)(=[O:29])=[O:30])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1)(=[O:38])[CH3:37]
Reactant: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1)C1CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)n1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)cn1
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of the compound of Example 203 (50 mg, 0.101 mmol) in DCM (1 ml) was added TEA (0.1 ml, 0.69 mmol, 6.9 eq.) followed by acetyl chloride (12 mg, 0.142 mmol, 1.4 eq.). The mixture was stirred for 2 h and quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to yield the product in 74% yield (40 mg). H-NMR (300 MHz, DMSO-D6) δ=8.93 (bs, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.24 (s, 1H), 7.83 (d, 1H), 7.76-7.70 (m, 2H), 7.58 (bs, 2H), 7.50-7.40 (m, 2H), 7.30-7.20 (m, 1H), 3.15 (s, 3H), 2.90-2.80 (m, 1H), 2.67 (s, 3H), 1.01 (d, 4H); LC-MS (ESI): Calculated mass: 533.55; Observed mass: 534.1 [M+H]+ (rt: 1.55 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
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: COCCOC
Product: O=[N+]([O-])c1cnccc1-c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
In a sulfonation flask 6.9 g (44 mmol) of 4-chloro-3-nitropyridine, 6.5 g (42 mmol) 4-chloro-phenylboronic acid, 6.0 g (44 mmol) potassium carbonate (saturated solution in water) and 1.0 g (0.9 mmol) tetrakis(triphenylphosphine)palladium are dissolved in 100 ml of dimethoxyethane (DME). The mixture is heated under reflux conditions under a constant nitrogen stream for 5 hours. Then the solvent is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and after drying of the organic phase with sodium sulfate, the solvent is removed in a water jet vacuum. The resulting crude product is purified by column chromatography over silica gel (eluant: hexane/ethylacetate 1:1). Yield: 8.9 g 4-(4′-chlorophenyl)-3-nitropyridine in the form of brownish crystals; m.p. 74–76° C.