Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][O:24][CH3:25])=O)=[CH:7][C:6]=1[CH2:27][CH3:28])(=O)C.[NH2:29][C:30]([NH2:32])=[O:31].Cl>O1CCOCC1>[CH2:27]([C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][CH2:23][O:24][CH3:25])[NH:32][C:30](=[O:31])[N:29]=2)[CH:9]=[CH:10][C:5]=1[NH2:4])[CH3:28]
Reactant: NC(N)=O
Reactant: CCc1cc(C(=O)CC(=O)c2ccccc2OCCOC)ccc1NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(-c2cc(-c3ccccc3OCCOC)[nH]c(=O)n2)ccc1N
Temperature: 110 °C

Procedure:
A flask was charged with 1-(4-acetamido-3-ethylphenyl)-3-(2-(2-methoxyethoxy)phenyl)propane-1,3-dione (4.0 g, 10.4 mmol), urea (3.0 g, 50 mmol) and 4 N HCl in dioxane (80 mL). The mixture was heated to 110° C. overnight. The reaction was cooled down, concentrated, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to result in 4-(2-ethylanilin-4-yl)-6-[2-(2-methoxyethoxy)phenyl]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15][C:9]=1[OH:8]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(O)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
To a solution of 2-(benzyloxy)-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}aniline (26 g) in a mixture of tetrahydrofuran (200 mL) and methanol (50 mL) was added palladium on carbon (5 g, 10 wt %, wet), and the mixture was stirred at room temperature for 5 h under hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residual oil was solidified with diethyl ether, and the solid was washed with ethyl acetate-diethyl ether to give the title compound (17.28 g, 88%) as a grayish solid. MS 281 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]=O.N1CCCCC1.C(O)(=O)C>O.C1(C)C=CC=CC=1>[CH3:23][O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[C:15]=1[CH:16]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cccc(OC)c1C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=Cc1c(OC)cccc1OC)C(=O)OCC

Procedure:
A mixture of 1.52 ml of diethyl malonate, 1.66 g of 2,6-dimethoxybenzaldehyde, 0.1 ml of piperidine, 0.11 ml of glacial acetic acid and 100 ml of toluene was boiled at 110° C. on a water separator for 3.5 hours. The solution was extracted with 10% NaHCO3 solution and back-washed with saturated NaCl solution. The organic phase was dried, filtered under suction and evaporated under reduced pressure. There were obtained 2.8 g of diethyl (2,6-dimethoxybenzylidene)malonate, as a dark yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[N+:9]([C:3]1[CH:4]=[C:5]([O:8][C:13]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: Clc1nccc(-c2cccnc2)n1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]

Procedure:
A solution of 4-amino-3-nitro-phenol (1 eq) and 2-chloro-4-(3-pyridyl)pyrimidine (1 eq) in N,N-dimethylformamide was microwaved at 150° C. for 10 mins. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was concentrated and purified on silica gel to yield 2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine. MS: MH+=309.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.CN(C=O)C.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([Cl:42])=[O:30])=[CH:27][CH:26]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)Cl)cc1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of compound 10 (0.215 g; 0.487 mmol) and anhydrous DMF (120 uL) in 8 mL of methylene chloride, oxalyl chloride (0.18 g; 5 mmol) was added dropwise at room temperature and the reaction mixture was stirred for 2 h. Then it was concentrated and the oxalyl chloride carefully removed by distillation to yield compound L (0.217 g; 97%). The compound was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[CH:7]2)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc2c(cnn2C2CCCCO2)c1
Yield: 55.3 %

Procedure:
To a solution of 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (3.69 g, 14.9 mmol) in a mixture of ethyl acetate (50 ml) and ethanol (50 ml) was added 10% Pd—C (300 mg), followed by catalytic reduction at ordinary temperature and atmospheric pressure. After completion or the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended in ethyl acetate, and the solid precipitated was collected by filtration and dried under reduced pressure to obtain 1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (1.79 g, 55%).
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[C:11](OCC)=[O:12])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:6](=[O:24])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].CO>CCO>[C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][OH:12])[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:6](=[O:24])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1C2C1N(Cc1ccc(F)cc1)C(=O)CN2C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(CO)C21
Reaction time: 8 h

Procedure:
To a solution of the exo isomer of ethyl 5-acetyl-2-(4-fluorobenzyl)-3-oxo-2,5-diazabicyclo[4.1.0]heptane-7-carboxylate (3.3 g, 9.87 mmol) in 32 ml EtOH at room temperature was added sodium borohydride (398 mg, 10.5 mmol). After stirring overnight, the reaction mixture was treated with 200 mL MeOH, stirred for 1 h and then concentrated. The residue was dissolved in dichloromethane (100 mL), treated with 1N HCl (10 mL) and water (20 mL). The aqueous phase was back extracted with chloroform (2×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate and methanol as eluents to give title product.
Reaction SMILES: [Si](OC1C2C(=CC(C3C=CC(OC)=CC=3N)=CC=2)CC1)(C(C)(C)C)(C)C.BrC1C=CC(OCCN2CCCCC2)=CC=1.[Si]([O:50][CH:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:61]=3[NH:68][C:69]3[CH:74]=[CH:73][C:72]([O:75][CH2:76][CH2:77][N:78]4[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]4)=[CH:71][CH:70]=3)=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)(C(C)(C)C)(C)C>>[CH3:67][O:66][C:63]1[CH:64]=[CH:65][C:60]([C:56]2[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=2)[CH:51]([OH:50])[CH2:52][CH2:53]3)=[C:61]([NH:68][C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:76][CH2:77][N:78]3[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]3)=[CH:71][CH:70]=2)[CH:62]=1
Reactant: COc1ccc(-c2ccc3c(c2)CCC3O[Si](C)(C)C(C)(C)C)c(Nc2ccc(OCCN3CCCCC3)cc2)c1
Agent: Brc1ccc(OCCN2CCCCC2)cc1
Agent: COc1ccc(-c2ccc3c(c2)CCC3O[Si](C)(C)C(C)(C)C)c(N)c1
Product: COc1ccc(-c2ccc3c(c2)CCC3O)c(Nc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 69 %

Procedure:
Synthesized from 2-[1-(tert-butyldimethylsilyloxy)indan-5-yl]-5-methoxyphenylamine and 1-[2-(4-bromophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, {2-[1-(tert-butyldimethylsilyloxy)indan-5-yl]-5-methoxyphenyl}[4-(2-piperidin-1-ylethoxy)phenyl]amine (1.1 g) was used according to an analogous synthetic method to Example 325 to provide the title compound (608 mg).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:19])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)=[CH:28][C:23]=2[O:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([CH2:3][CH2:2][C:1]([N:5]4[CH2:6][CH2:7][N:8]([C:11]5[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:19])[CH:12]=5)[CH2:9][CH2:10]4)=[O:4])[CH2:31]3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: c1cc2c(cc1CC1CCCNC1)OCO2
Reactant: C=CC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN(C(=O)CCN3CCCC(Cc4ccc5c(c4)OCO5)C3)CC2)cc1F

Procedure:
A solution of 4-(4-acryloyl-piperazin-1-yl)-2-fluoro-benzonitrile (0.125 g, 0.48 mmol), (+)-3-benzo[1,3]dioxol-5-ylmethyl-piperidine (0.106 g, 0.48 mmol) and triethylamine (0.088 ml, 0.629 ml) in THF (1.6 ml) is stirred at rt for 25 h. The mixture is diluted with CH2Cl2 and washed with sat. aq. Na2CO3 solution The organic layer is separated off, dried over Na2SO4 and evaporated. The residue is purified by MPLC (60 g silica gel, eluent CH2Cl2:MeOH 9:1) to give the title compound, (+)-4-{4-[3-(3-benzo[1,3]dioxol-5-ylmethyl-piperidin-1-yl)-propionyl]-piperazin-1-yl}-2-fluoro-benzonitrile, as a colourless foam:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30]O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:43]1[CH2:49][CH2:48][CH2:47][C@@H:44]1[CH2:45][OH:46]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:27][C@H:28]([CH2:30][N:43]4[CH2:49][CH2:48][CH2:47][C@@H:44]4[CH2:45][OH:46])[CH2:29]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Reactant: OC[C@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC[C@@H]2CO)C1

Procedure:
The title compound is prepared in analogy to Example 116 starting from 0.35 g (0.84 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol and 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml dry pyridine, followed by 0.631 ml (6.33 mmol) D-prolinol (Fluka, Buchs, Switzerland). Analytical HPLC: tR=9.08 min (Grad 1); ES-MS: m/eo=498.2; NMR (DMSO-d6; not all signals reported): 8.07/s (1H), 7.25-7.5/several m's (6H), 7.02/“d” (1H); 6.94/s (1H); 6.89/“d” (1H); 5.4-6.0/b (NH2); 5.13/s (2H); 4.78/m (1H); 4.34/b (OH); 2.22/s (3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([O:31][CH2:32][CH2:33][O:34][CH3:35])([C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:46]1([N:52]2[CH:56]=[C:55](B3OC(C)(C)C(C)(C)O3)[CH:54]=[N:53]2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:55]3[CH:54]=[N:53][N:52]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:56]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([O:31][CH2:32][CH2:33][O:34][CH3:35])([C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Temperature: 90 °C
Yield: 73 %

Procedure:
A mixture of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (3.06 g, 3.93 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.38 g, 5.11 mmol), PdCl2(dppf)CH2Cl2 (321 mg, 0.393 mmol), and K3PO4 (2.50 g, 11.8 mmol) in dioxane/H2O (40/4 mL) was degassed and then heated at 90° C. for 16 h. The reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.6 in 50% EtOAc/Hexanes) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a brown oil (2.28 g). HPLC-MS TR=3.25 min (UV 254 nm, 5 min method); mass calculated for formula C40H62N6O7Si2 794.4, observed LCMS m/z 795.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:50])[C:5]([CH3:49])([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2CC2C=CC(OC)=CC=2)=[CH:9][CH:8]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:50])[C:5]([CH3:49])([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (60 mL) is added dropwise to a solution of 3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (3.46 g, 5.0 lmmol) and triethylsilane (1.6 mL, 10.0 mmol, d=0.728). The reaction mixture is stirred at ambient temperature for 2 hours, concentrated, and diluted with ethyl acetate. The solution is washed with a saturated solution of aqueous sodium bicarbonate, water, and brine, then dried over Na2SO4, and concentrated in vacuo to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.23-7.14 (m, 4H), 6.97 (t, 1H, J=7.4 Hz), 6.82 (d, 2H, J=7.4 Hz), 6.78-(d, 2H, J=7.4 Hz), 4.44, 4.38 (ABq, 2H, J=15.6 Hz), 4.20 (q, 2H, J=7.4 Hz), 4.07-3.99 (m, 2H), 3.96-3.89 (m, 1H), 3.47 (t, 1H, J=8.2 Hz), 3.27, 3.09 (ABq, 2H, J=14.1 Hz), 3.04, 3.02 (ABq, 1H, J=6.7 Hz), 2.08-1.99 (m, 1H), 1.98-1.92 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=6.7 Hz). MS [EI+] 571 (M+H)+, [EI−] 569 (M−H)+. Rf=0.07 in 33% acetone in hexanes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][OH:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.[F:29][C:30]([F:41])([F:40])[CH2:31]OS(C(F)(F)F)(=O)=O.[H-].[Na+]>C1COCC1>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[N:25][C:24]([CH2:27][O:28][CH2:31][C:30]([F:41])([F:40])[F:29])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:5]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-yl]methanol (Example 295, 30 mg, 79 μmol) in anhydrous THF (10 mL) was added trifluoromethanesulfonic acid 2,2,2-trifluoro-ethyl ester (56 mg, 239 μmol). The solution was cooled to 0 C and sodium hydride (60% dispersion in mineral oil, 7 mg, 159 μmol) was added under an inert atmosphere and the mixture was stirred at room temperature for 24 h. The reaction mixture was then re-treated with trifluoromethanesulfonic acid 2,2,2-trifluoro-ethyl ester (56 mg, 239 μmol) and sodium hydride (60% dispersion in mineral oil, 7 mg, 159 μmol) and stirred for an additional 48 h at room temperature. The reaction mixture was quenched with water (20 mL) and extracted into EtOAc (3×25 mL). Combined organics were dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (3% MeOH in DCM) and then re-purified by preparative HPLC-MS (Method B) to afford the title compound as an off white solid (5.6 mg, 15%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8](COCC[Si](C)(C)C)[CH:7]=2)=[N:2]1.FC(F)(F)C(O)=O.N>>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[NH:8][CH:7]=2)=[N:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc[nH]n5)c34)n(-c3ccccc3)c(=O)c12
Yield: 57 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (39 mg, 0.07 mmol) was treated with trifluoroacetic acid (1.4 mL, 18.17 mmol) and a solution of ammonia (7N in methanol, 1.4 mL, 9.8 mmol) according to the method described in Example 27 to give 18 mg (60% yield) of the title compound. Purity 100%.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([C:22]([O:24]CC)=[O:23])[N:14]=[C:13]3[CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[NH:41][N:40]=[N:39][N:38]=1.[OH-].[K+].C(O)C.Cl>O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([C:22]([OH:24])=[O:23])[N:14]=[C:13]3[CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[NH:41][N:40]=[N:39][N:38]=1
Reactant: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(C(=O)O)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
A mixture of the product of Example 18 (117 mg), potassium hydroxide (31.6 mg), ethanol (1.14 ml) and water (253 μl) were stirred at room temperature for 18 h prior to acidification to pH 4 (2N HCl). The resultant mixture was extracted into ethyl acetate (3×10 ml) and the combined organic phases dried and concentrated in vacuo to afford the title compound (73 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([Si](C)(C)C)=[CH:7][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:5][N:4]=1.[I:17]I.ClCCl>CO.F[B-](F)(F)F.[Ag+]>[I:17][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=1
Reactant: II
Reactant: COc1ncc(C(F)(F)F)cc1[Si](C)(C)C
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ncc(C(F)(F)F)cc1I
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-Methoxy-3-trimethylsilyl-5-trifluoromethylpyridine (1.30 g, 5.21 mmol) in methanol (15 ml) was treated with silver tetrafluoroborate (1.22 g, 6.27 mmol), cooled to 0° C. and then iodine (1.32 g, 5.20 mmol) in methanol (25 ml) was slowly added. The solution was stirred at 0° C. for 4 hrs then at 22° C. for 16 hrs, before being refluxed for 8 hrs. After cooling, dichloromethane (50 ml) was added and the solution was washed with sodium thiosulphate solution (30 ml), brine (50 ml), then dried (Na2SO4) and concentrated to give a 1:1 mixture of the product and starting material as an oil (1.23 g).
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]2)[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 53.2 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (25 mg, 0.08 mmol) and 2-aminothiazole (9.4 mg, 0.09 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 0.22 mL, 0.15 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then filtered through a pad of celite (methylene chloride as eluent). The filtrate was washed with a 1N aqueous hydrochloric acid solution. The organics were dried over sodium sulfate, filtered and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (16.4 mg, 54%) as light tan oil: EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+H)+ 385.0537. found 385.0542.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:12]3[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=3)[S:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+]>O.C(O)(=O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)[S:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCC(c2cc(Cn3ccnc3)cs2)=NN1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2cc(Cn3ccnc3)cs2)n[nH]1

Procedure:
Analoguous to Example 4, the reaction is carried out with 3 g of 4.5-dihydro-6-[4-(imidazol-1-yl-methyl)-thien-2-yl]-3(2H)-pyridazinone (prepared analoguous to Example 3, m.p. 178° to 179° C.), 2.9 g of the sodium salt of 3-nitrobenzenesulfonic acid and 2 g of sodium hydroxide in 40 ml of water. The reaction mixture is neutralized by the addition of 2.5 ml of acetic acid.